[Meningoencephalomyelitis caused by Borrelia burgdorferi: a case without epidemiologic history or chronic migratory erythema]
[Article in Spanish]
Ponz E, Graus F, Alvarez R, Sarmiento X, Vidal J, Grau JM.
A patient is reported with meningoencephalomyelitis with polyradiculitis caused by Borrelia burgdorferi infection. Neurological features developed without previously known tick bite nor the characteristic skin lesion, chronic migratory erythema (CME). The vector of the disease (the tick Ixodes ricinus) exists in Spain, but only one case of meningopolyradiculitis with CME has been reported in Asturias. Our case stresses that B. burgdorferi infection should be suspected in cases of meningoencephalomyelitis or meningopolyradiculitis even without previous skin or joint lesion.
Autism is growing at epidemic rates. (1) It is reported to be prevelant in 1-150 children, some states 1-80 children. Autism is a complex neurological disorder with seemingly provable and many etiologies such as maternal viruses and bacteria (2), immediate cord clamping and birth drugs (3), metabolic insufficiency during development in utero or infancy (ie, thyroid t3 and t4) (4), purine disorders, adenosine deaminse deficiency (5), mitochondrial disorders (6), iron fragile metabolism (7), metallothionein deficiency (8), oxidative stress, childhood vaccinations which act as triggers to events above through viral persistance in gut and brain (9), and heavy metal poisoning from additives in vaccines (10), and lastly chronic disseminated lyme neuroborreliosis disease. Lyme disease is transmitted through a tick bite. But it can also be transmitted through semen, breast milk and gestational fluids. This means that a fetus can be infected by its mother. B. burgdorferi has been proven by PCR analysis to establish a persistent infection in the mammalian host (Straubinger, R. Persistence of B. burgdorferi in experimentally infected dogs after antibiotic treatment. J.Clin.Microbiol.1997 Jan; 35(l): 111-116).
Lyme disease is the fastest growing vector-borne disease in the nation. In 2001, the Center for Disease Control recorded 18,000 new cases, but some experts estimate that the actual number is closer to 200,000 This is four times the number of HIV cases per year. Autism grows as exponetially as that, and an NIH bulliten explained of late it is seen in 1/166 children. Amongst those statistics, is the further frightening 1-6 children now have a developmental, psychiatric problems in the US.
Lyme disease AND autism results in underconnectivity of brain areas, defects of the fusiform gyrus and loss of purkinje cells in the cerebellum. Recently reports of white matter disease are prevelant in children and adults with autism paralleling patterns in lyme disease. (11) Late in the progression of this disease neurological, cognitive, and psychiatric symptoms predominate, overlapping symptoms of autism, such as food avoidance, facial recognition problems, sleep disorders, ocular symtpoms such as light sensitivity, speech and language loss or word retrieval problems, noise sensitivity, bed wetting, aggression, panic attacks, headaches, movement disorders, sore throats and poor swallowing, hypofusion-poor blood flow particularly to temporal lobes, swollen tongues and lymphs, chronic fatigue symptoms, hyperactivity, gut problems (ie, diahrreah, constiptation, IBD symtpoms, Celiac symptoms), liver dysfunction, thyroid problems (t3 and t4 conversions), iron disorders, heavy metal toxicity, tics, food sensitivities, depression, serotonin uptake problems, autoimmune brain antibodies, problems with sequencing, problems with sensory perceptions, seizures, cardiac conduction abnormalities, illiod hyperplasia, heavy metal toxicity, co infections of HHV6 and Mycoplasma (12), various aches and pains masked as lyme arthritis particularly in the neck area, and zinc copper iron imbalances.
The basic hierarchy is pre-frontal cortex, para limbic association areas, limbic structures, and brain stems - hypothalamus. Lyme encephalopathy can result in dysfunction of the modulation centers, inhibitory pathways, and stimulatory pathways. (13) Autopsies, animal studies, and brain imaging tests have contributed to this understanding. The presenting symptoms of NPLD are sometimes emotional in nature, and include obsessive-compulsive disorder, depression, and aggression, panic disorder, and other phobic disorders. These self same observations are also seen in autism as reports from parents of these symptoms are typical.
All involved with late state Lyme disease agree there is a large amount of inaccurate information on this subject. This disagreement exists at every level - journals, scientific meetings, clinical practice, and media outlets. The same can be said of autism, in which denials of it's etiologies are profusely displayed as only genetic, and never any environmental iaotragenic factors involved. Profusely are denials of the existance that autism is based on the bodies response to a foreign material either of neurotoxicity, bacteria or virus, such as lyme, such as vaccinal viruses, such as autoimmune processes that become overabundant. Reports are clear, that parents of autistic children seem to have higher incidences of autoimmune conditions. This is telling us something. It is my belief, this is a sign that the parents themselves have lyme disease-and are giving this infection to their children. Lyme disease is prevelant in all fifty states of the union, and know no geographical areas. However, it is interesting to note, that in states that have the less lyme, there is more availability of selenium in the soils, which is a immune neuro protectant against viruses and bacteria. Parents of autistic children routinely show low levels of selenium in blood work, as well as metallothionein deficiency, a glutathione dependent oxidant. Parents also have higher sedimentation rates (ESR) and thrombaphilia and fibrin deposits showing inflammation as well as thyroid TRH dysfunction. (14) They also often have skewed hormonal balances. Lyme is capable of changing these aspects on blood work.
Interestingly, susceptibility genes for autism parallel the susceptibility genes for arthritis and other autoimmune disorders, such as HLA-B27, and HLA-DR4. Complement immune deficiencies are common in both diseases, including C4B and C3A. The frequency of autoimmune disorders was significantly higher in families of the PDD probands compared with families of both the autoimmune and healthy control probands. Autoimmunity was highest among the parents of PDD probands compared with parents of the healthy control subjects. Hypothyroidism/Hashimoto’s thyroiditis and rheumatic fever were significantly more common in families with PDD probands than in the healthy control families. Interestingly, reports of Hashimotos and hypothyroidism are prevalent in lyme disease. (15) Interestingly, reports of mycoplasma are consistent with parents having a mycoplasmal infection, and giving that to their children. (16) Mycoplasma medications are alleviated by the self same medications for lyme disease. Many parents report that lyme and mycoplasma are prevelant in their children with autism. Familial association studies have also reported an increased risk of several systemic autoimmune diseases among relatives of patients with a systemic autoimmune disease. This association may reflect a common etiologic pathway with shared genetic or environmental influences among these diseases. Environmentally, there is increases in levels of heavy metals, toxicity, neurotoxicants, mold, and most of all but not least, the prevelance of the lyme bacterium. Prolactin may also have important immune-modulating influences affecting the risk of autoimmune disease . The prolactin gene is located close to the MHC region of chromosome 6, hotspots for lyme AND autism. (17) Another protein eaten by lyme is melatonin, which may account for levels of serotonin, prolactin and the ability to detox heavy metals. In autism, melatonin levels are dysregulated, causing sleep disorders, and antibodies are found against serotonin.
Recently there have been reports of short term antibiotic use to kill clostridium and or AGBN's. Vancomycin was recently used, and reports are that when on the antibiotic for thirty days, symptoms of autism decreased. The Jarish Herxheimer reaction is seen when antibiotics are having a therapeutic effect as well, as evidenced when the child is on the antibiotics. This often scares off the weary parent of an autistic child, stopping the antibiotic for fear it is contributing to their autism symptoms when in reality it was killing lyme with mild to moderate reactions. Unfortunately, in these studies, the children regressed back to autism symptoms as soon as they were removed after thirty days. If the bacteria is not completely eliminated, the symptoms will return. This tells us, I believe, that lyme is involved in their autism. This reasoning has made others think of why these children respond so favorably while on the antibiotic. It could be that it is going after the lyme bacterium (however not it's stages due to it's short length), but also calming down the cytokine and chemokine activity in the immune system, and having some kind of effect on viruses which depend on cytokines and chemokines. Typically those viruses are of the herpes CMV class. Reports of HHV6 and autism are abundant. Many children have high herpes titres, sometimes to that of 4-6 times of normal, often corrolating with autism symptoms or seizures. Although the American Academy of Pediatrics recommends a three week course of antibiotics, Dr. Jones-a pediatric lyme speclialist, has found that the bacteria that causes Lyme has become increasingly hardy and even when the disease is caught early, it often needs to be treated with an eight to twelve week course of antibiotics or beyond.
Lyme has many names. Among its "symptoms" are ALL of the "ideopathic" (unknown-cause) diseases that plague americans, too many to list here - it affects the body by making sugar turn to lactic acid, which in turn can scar the kidneys over time, irritate the bladder, damage the liver, and upset the pancreas. Lactic acid causes muscle soreness and sensitive intestines/cramping problems (nervous stomach). Interestingly, it is reported that many autistic children have skewed lactic and pyruvate ratios. This creates a mitochondrial disorder, oxidative stress in these children. Lyme also eats proteins, many types. It eats myelin protein, which is known to be going missing in MS patients. The localities for MS hot spots exactly match the pattern of lyme disease, and I believe it is the same disease with a different name. Myelin is what nerves are made of - and damage to myelin, without a meat and potatos diet to replace protein constantly, causes brain troubles (alzheimers, parkinsons, alateral myotrophic scleroses, myocarditis), numbness of the bladder and/or muscle spasms in the elderly mistaken as "incontinence", nerve troubles, stuttering, etc. This corrolates nicely with what we are seeing in autism. Typically there are myelination antibodies in children with autism, even Neural Axon Filament Protein antibodies, and various other antibodies against brain tissue. Many children with autism lose their ability to sleep through the night without bedwetting. Stuttering is often seen in children with autism.
It is also reported that when these children harbor heavy metals, that viruses and bacteria seem to live in areas of that damage. Since these children lack the oxidant metallothionein, they cannot detox the EPA over standard of safe of thimerosol that were in childhood vaccine series, or other environmental factors including their mothers in utero exposure of amalgams. Unfortunately, they still are according to HAPI, a NPO who just tested mercury free vaccines (ARI newsletter 2004). As they work in consortium, there is a theory that the heavy metals bind to these bacteria and viruses, and when they are eliminated, heavy metals start to chelate out of the body. This is evidenced by EDTA chelation which has the ability to kill nanobacteria. Observations and biomarkers of damage are seen soon after vaccinations, but what is equally intriguing, is that lyme may be awoken after an immune lowering event such as vaccinations.
Recent reports show that children with autism are harboring lyme disease. The cry for chromosomal faults are numerous, and often paid and backed to be equally the only way you get autism. What researchers know, is that no money is funded or researched or goes into the immune lowering/autoimmunity events that create autism, and is simply put down. The cogent finding of lyme bacterium being a major risk factor for autism needs to be explored. This is superimposed on the already sustained belief, that autism is an autoimmune disorder. Many of the imbalances of autism could be explained as the body's inability to detox and to work on this bacteria. Lyme could also be a trigger or a circumstance that initiate or worsening of the autistic condition. This includes milk allergies, strep infections, mercury, dietary intolerances of wheat and milks, and inability to deal with toxic inhibitors. Interestingly, many of the imbalances and deficiencies can be caused by lyme bacteria.
Many of the meds used for autism seem to also slow down the lyme bacterium, such as digestive enzymes, anti fungals, of course, antibiotics, anti parasticals, addressing food allergies, increasing zinc, antiinflammatories and even secretin (secretin is tied to insulin, which lyme attacks). Lately, the use of Methylcolbalamine B-12 with folinic acid would also reduce lyme symptoms. Since there is already evidence of abnormal gut bacteria and exaggerated production of cytokines which result in irreversable cellular damage, it behooves parents and clinicians and researchers to look into this paralell and seek state of the art laboratory connections to lyme and autism. Three labs are recommended, STONYBROOK, BOWEN and IGENEX. This may result in the first of it's kind treatment for autism via lyme therapy.
References (1) Changes in the Population of Persons with Autism and PDD, Dept Develop Services, California, Health and Human Services March 1 1999
(2) The Journal of Neuroscience, January 1, 2003, 23(1):297-302 Maternal Influenza Infection Causes Marked Behavioral and Pharmacological Changes in the Offspring
(4) Abramson J, Stagnaro-Green A. Thyroid antibodies and fetal loss: an evolving story. Thyroid 2001;11(1):57-63.
(5) Adenosine Deaminase - Neurogenetics. 2001 Mar;3(2):111-3. Related Articles, Links Autism: evidence of association with adenosine deaminase genetic polymorphism. Bottini N, De Luca D, Saccucci P, Fiumara A, Elia M, Porfirio MC, Lucarelli P, Curatolo P. Department of Internal Medicine, Tor Vergata University of Rome, Rome, Italy
(6) J Child Neurol. 2000 Jun;15(6):357-61. Related Articles, Links Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutation. Graf WD, Marin-Garcia J, Gao HG, Pizzo S, Naviaux RK, Markusic D, Barshop BA, Courchesne E, Haas RH. Department of Pediatrics, University of Washington, Seattle, USA. wgraf@...
(7) Arch Dis Child 1997;76:264-267 ( March ) Fragile X, iron, and neurodevelopmental screening in 8 year old children with mild to moderate learning difficulties N Corrigan,a M Stewart,a M Scott,b F Feec a North and West Belfast Community Paediatric Unit, Belfast, Northern Ireland, b Queens University Belfast Department of Epidemiology and Public Health, Belfast, Northern Ireland, c Belfast Education and Library Board, Belfast, Northern Ireland
- And Life Sci. 2004 Oct 8;75(21):2539-49. Related Articles, Links Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin--the antioxidant proteins. Chauhan A, Chauhan V, Brown WT, Cohen I. NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314, USA.
(8) - Metallothionein Deficiency - see www.hriptc.org Walsh, W, Monograph: Metallothionein and Autism". {Pfeiffer Treatment Center, Illinois, Oct 2001, Over 100 articles referenced.
(9) - Wakefield AJ, A Anthoney et al "Enterocolitis in Children with Developmental Disorders" Am.J Gastroenterology 95 No 9 (2000) p 2285-2295
(10) A case control study of mercury burden in Autistic children in autistic spectrum disorders (Journal of American Physicians and Surgeons, Vol 8, No 3, 3 Fall 2003) J Bradstreed, MD, D Geier, J Kartzinel, Md, J Adams PhD, M Geier, MD, PhD.
(11) Cure Autism Now Foundation, White Matter Disease and Autism, see website
(12) HHV-6 and Autism - Clin Immunol Immunopathol. 1998 Oct;89(1):105-8. Related Articles, Links Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Singh VK, Lin SX, Yang VC. College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109-1065, USA.
(13) Activation of the fusiform gyrus when individuals with autism spectrum disorder view faces, N Hadjikahmi, RM Joseph, J Synder, CF Chabris, J Clark, S Steel, L McGrath, M Vangel, I Aharon, E Feczko, GJ Harris, and H Tager-Flusberg, Neuroimage, Vol 22, No 3 July 2004, contact nouchine@...
(14) J Neuroimmunol. 2004 Jul;152(1-2):176-82. Related Articles, Links Autoantibody repertoires to brain tissue in autism nuclear families. Silva SC, Correia C, Fesel C, Barreto M, Coutinho AM, Marques C, Miguel TS, Ataide A, Bento C, Borges L, Oliveira G, Vicente AM. Instituto Gulbenkian de Ciencia, Rua da Quinta Grande 6, 2781-196 Oeiras, Portugal.
(15) Pediatrics. 2003 Nov;112(5):e420. Related Articles, Links Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ. Department of Psychiatry, Indiana University School of Medicine, and James Whitcomb Riley Hospital for Children Indianapolis 46202-4800, USA.
(16) Chronic Mycoplasmal Infections in Autism Patients Garth L. Nicolson,1 PhD, Marwan Y. Nasralla,2 PhD, Paul Berns,1 MD and Jeorg Haier,3 MD, PhD 1 The Institute for Molecular Medicine, Huntington Beach, California, USA,, 2 International Molecular Diagnostics, Inc., Huntington Beach, California, USA, 3 Department of Internal Medicine, and 3Department of Surgery, Wilhelm-University, Munster, Germany. Correspondence: Prof. Garth L. Nicolson, Office of the President, The Institute for Molecular Medicine, 15162 Triton Lane, Huntington Beach, California 92649. Tel: 714-903-2900; Fax: 714-379-2082; Email: gnicolson@...; Website: www.immed.org
(17) Am J Med Genet. 1999 Nov 5;87(1):17-22. Related Articles, Links Subtle overlapping deletions in the terminal region of chromosome 6q24.2-q26: three cases studied using FISH. Sukumar S, Wang S, Hoang K, Vanchiere CM, England K, Fick R, Pagon B, Reddy KS. Cytogenetics Department, Quest Diagnostics Inc., San Juan Capistrano, California Journal of Nuclear Medicine 2004 45: 8-9 http://jnm.snmjournals.org/cgi/content/full/45/10/8A
AUTISM-A TYPE OF LYME DISEASE Medical Hypothesis
Kathy Blanco December 15, 2004
Autism is growing at epidemic rates. (1) It is reported to be prevelant in 1-150 children, some states 1-80 children. Autism is a complex neurological disorder with seemingly provable and many etiologies such as maternal viruses and bacteria (2), immediate cord clamping and birth drugs (3), metabolic insufficiency during development in utero or infancy (ie, thyroid t3 and t4) (4), purine disorders, adenosine deaminse deficiency (5), mitochondrial disorders (6), iron fragile metabolism (7), metallothionein deficiency (8), oxidative stress, childhood vaccinations which act as triggers to events above through viral persistance in gut and brain (9), and heavy metal poisoning from additives in vaccines (10), and lastly chronic disseminated lyme neuroborreliosis disease. Lyme disease is transmitted through a tick bite. But it can also be transmitted through semen, breast milk and gestational fluids. This means that a fetus can be infected by its mother. B. burgdorferi has been proven by PCR analysis to establish a persistent infection in the mammalian host (Straubinger, R. Persistence of B. burgdorferi in experimentally infected dogs after antibiotic treatment. J.Clin.Microbiol.1997 Jan; 35(l): 111-116).
Lyme disease is the fastest growing vector-borne disease in the nation. In 2001, the Center for Disease Control recorded 18,000 new cases, but some experts estimate that the actual number is closer to 200,000 This is four times the number of HIV cases per year. Autism grows as exponetially as that, and an NIH bulliten explained of late it is seen in 1/166 children. Amongst those statistics, is the further frightening 1-6 children now have a developmental, psychiatric problems in the US.
Lyme disease AND autism results in underconnectivity of brain areas, defects of the fusiform gyrus and loss of purkinje cells in the cerebellum. Recently reports of white matter disease are prevelant in children and adults with autism paralleling patterns in lyme disease. (11) Late in the progression of this disease neurological, cognitive, and psychiatric symptoms predominate, overlapping symptoms of autism, such as food avoidance, facial recognition problems, sleep disorders, ocular symtpoms such as light sensitivity, speech and language loss or word retrieval problems, noise sensitivity, bed wetting, aggression, panic attacks, headaches, movement disorders, sore throats and poor swallowing, hypofusion-poor blood flow particularly to temporal lobes, swollen tongues and lymphs, chronic fatigue symptoms, hyperactivity, gut problems (ie, diahrreah, constiptation, IBD symtpoms, Celiac symptoms), liver dysfunction, thyroid problems (t3 and t4 conversions), iron disorders, heavy metal toxicity, tics, food sensitivities, depression, serotonin uptake problems, autoimmune brain antibodies, problems with sequencing, problems with sensory perceptions, seizures, cardiac conduction abnormalities, illiod hyperplasia, heavy metal toxicity, co infections of HHV6 and Mycoplasma (12), various aches and pains masked as lyme arthritis particularly in the neck area, and zinc copper iron imbalances.
The basic hierarchy is pre-frontal cortex, para limbic association areas, limbic structures, and brain stems - hypothalamus. Lyme encephalopathy can result in dysfunction of the modulation centers, inhibitory pathways, and stimulatory pathways. (13) Autopsies, animal studies, and brain imaging tests have contributed to this understanding. The presenting symptoms of NPLD are sometimes emotional in nature, and include obsessive-compulsive disorder, depression, and aggression, panic disorder, and other phobic disorders. These self same observations are also seen in autism as reports from parents of these symptoms are typical.
All involved with late state Lyme disease agree there is a large amount of inaccurate information on this subject. This disagreement exists at every level - journals, scientific meetings, clinical practice, and media outlets. The same can be said of autism, in which denials of it's etiologies are profusely displayed as only genetic, and never any environmental iaotragenic factors involved. Profusely are denials of the existance that autism is based on the bodies response to a foreign material either of neurotoxicity, bacteria or virus, such as lyme, such as vaccinal viruses, such as autoimmune processes that become overabundant. Reports are clear, that parents of autistic children seem to have higher incidences of autoimmune conditions. This is telling us something. It is my belief, this is a sign that the parents themselves have lyme disease-and are giving this infection to their children. Lyme disease is prevelant in all fifty states of the union, and know no geographical areas. However, it is interesting to note, that in states that have the less lyme, there is more availability of selenium in the soils, which is a immune neuro protectant against viruses and bacteria. Parents of autistic children routinely show low levels of selenium in blood work, as well as metallothionein deficiency, a glutathione dependent oxidant. Parents also have higher sedimentation rates (ESR) and thrombaphilia and fibrin deposits showing inflammation as well as thyroid TRH dysfunction. (14) They also often have skewed hormonal balances. Lyme is capable of changing these aspects on blood work.
Interestingly, susceptibility genes for autism parallel the susceptibility genes for arthritis and other autoimmune disorders, such as HLA-B27, and HLA-DR4. Complement immune deficiencies are common in both diseases, including C4B and C3A. The frequency of autoimmune disorders was significantly higher in families of the PDD probands compared with families of both the autoimmune and healthy control probands. Autoimmunity was highest among the parents of PDD probands compared with parents of the healthy control subjects. Hypothyroidism/Hashimoto’s thyroiditis and rheumatic fever were significantly more common in families with PDD probands than in the healthy control families. Interestingly, reports of Hashimotos and hypothyroidism are prevalent in lyme disease. (15) Interestingly, reports of mycoplasma are consistent with parents having a mycoplasmal infection, and giving that to their children. (16) Mycoplasma medications are alleviated by the self same medications for lyme disease. Many parents report that lyme and mycoplasma are prevelant in their children with autism. Familial association studies have also reported an increased risk of several systemic autoimmune diseases among relatives of patients with a systemic autoimmune disease. This association may reflect a common etiologic pathway with shared genetic or environmental influences among these diseases. Environmentally, there is increases in levels of heavy metals, toxicity, neurotoxicants, mold, and most of all but not least, the prevelance of the lyme bacterium. Prolactin may also have important immune-modulating influences affecting the risk of autoimmune disease . The prolactin gene is located close to the MHC region of chromosome 6, hotspots for lyme AND autism. (17) Another protein eaten by lyme is melatonin, which may account for levels of serotonin, prolactin and the ability to detox heavy metals. In autism, melatonin levels are dysregulated, causing sleep disorders, and antibodies are found against serotonin.
Recently there have been reports of short term antibiotic use to kill clostridium and or AGBN's. Vancomycin was recently used, and reports are that when on the antibiotic for thirty days, symptoms of autism decreased. The Jarish Herxheimer reaction is seen when antibiotics are having a therapeutic effect as well, as evidenced when the child is on the antibiotics. This often scares off the weary parent of an autistic child, stopping the antibiotic for fear it is contributing to their autism symptoms when in reality it was killing lyme with mild to moderate reactions. Unfortunately, in these studies, the children regressed back to autism symptoms as soon as they were removed after thirty days. If the bacteria is not completely eliminated, the symptoms will return. This tells us, I believe, that lyme is involved in their autism. This reasoning has made others think of why these children respond so favorably while on the antibiotic. It could be that it is going after the lyme bacterium (however not it's stages due to it's short length), but also calming down the cytokine and chemokine activity in the immune system, and having some kind of effect on viruses which depend on cytokines and chemokines. Typically those viruses are of the herpes CMV class. Reports of HHV6 and autism are abundant. Many children have high herpes titres, sometimes to that of 4-6 times of normal, often corrolating with autism symptoms or seizures. Although the American Academy of Pediatrics recommends a three week course of antibiotics, Dr. Jones-a pediatric lyme speclialist, has found that the bacteria that causes Lyme has become increasingly hardy and even when the disease is caught early, it often needs to be treated with an eight to twelve week course of antibiotics or beyond.
Lyme has many names. Among its "symptoms" are ALL of the "ideopathic" (unknown-cause) diseases that plague americans, too many to list here - it affects the body by making sugar turn to lactic acid, which in turn can scar the kidneys over time, irritate the bladder, damage the liver, and upset the pancreas. Lactic acid causes muscle soreness and sensitive intestines/cramping problems (nervous stomach). Interestingly, it is reported that many autistic children have skewed lactic and pyruvate ratios. This creates a mitochondrial disorder, oxidative stress in these children. Lyme also eats proteins, many types. It eats myelin protein, which is known to be going missing in MS patients. The localities for MS hot spots exactly match the pattern of lyme disease, and I believe it is the same disease with a different name. Myelin is what nerves are made of - and damage to myelin, without a meat and potatos diet to replace protein constantly, causes brain troubles (alzheimers, parkinsons, alateral myotrophic scleroses, myocarditis), numbness of the bladder and/or muscle spasms in the elderly mistaken as "incontinence", nerve troubles, stuttering, etc. This corrolates nicely with what we are seeing in autism. Typically there are myelination antibodies in children with autism, even Neural Axon Filament Protein antibodies, and various other antibodies against brain tissue. Many children with autism lose their ability to sleep through the night without bedwetting. Stuttering is often seen in children with autism.
It is also reported that when these children harbor heavy metals, that viruses and bacteria seem to live in areas of that damage. Since these children lack the oxidant metallothionein, they cannot detox the EPA over standard of safe of thimerosol that were in childhood vaccine series, or other environmental factors including their mothers in utero exposure of amalgams. Unfortunately, they still are according to HAPI, a NPO who just tested mercury free vaccines (ARI newsletter 2004). As they work in consortium, there is a theory that the heavy metals bind to these bacteria and viruses, and when they are eliminated, heavy metals start to chelate out of the body. This is evidenced by EDTA chelation which has the ability to kill nanobacteria. Observations and biomarkers of damage are seen soon after vaccinations, but what is equally intriguing, is that lyme may be awoken after an immune lowering event such as vaccinations.
Recent reports show that children with autism are harboring lyme disease. The cry for chromosomal faults are numerous, and often paid and backed to be equally the only way you get autism. What researchers know, is that no money is funded or researched or goes into the immune lowering/autoimmunity events that create autism, and is simply put down. The cogent finding of lyme bacterium being a major risk factor for autism needs to be explored. This is superimposed on the already sustained belief, that autism is an autoimmune disorder. Many of the imbalances of autism could be explained as the body's inability to detox and to work on this bacteria. Lyme could also be a trigger or a circumstance that initiate or worsening of the autistic condition. This includes milk allergies, strep infections, mercury, dietary intolerances of wheat and milks, and inability to deal with toxic inhibitors. Interestingly, many of the imbalances and deficiencies can be caused by lyme bacteria.
Many of the meds used for autism seem to also slow down the lyme bacterium, such as digestive enzymes, anti fungals, of course, antibiotics, anti parasticals, addressing food allergies, increasing zinc, antiinflammatories and even secretin (secretin is tied to insulin, which lyme attacks). Lately, the use of Methylcolbalamine B-12 with folinic acid would also reduce lyme symptoms. Since there is already evidence of abnormal gut bacteria and exaggerated production of cytokines which result in irreversable cellular damage, it behooves parents and clinicians and researchers to look into this paralell and seek state of the art laboratory connections to lyme and autism. Three labs are recommended, STONYBROOK, BOWEN and IGENEX. This may result in the first of it's kind treatment for autism via lyme therapy.
References (1) Changes in the Population of Persons with Autism and PDD, Dept Develop Services, California, Health and Human Services March 1 1999
(2) The Journal of Neuroscience, January 1, 2003, 23(1):297-302 Maternal Influenza Infection Causes Marked Behavioral and Pharmacological Changes in the Offspring
(4) Abramson J, Stagnaro-Green A. Thyroid antibodies and fetal loss: an evolving story. Thyroid 2001;11(1):57-63.
(5) Adenosine Deaminase - Neurogenetics. 2001 Mar;3(2):111-3. Related Articles, Links Autism: evidence of association with adenosine deaminase genetic polymorphism. Bottini N, De Luca D, Saccucci P, Fiumara A, Elia M, Porfirio MC, Lucarelli P, Curatolo P. Department of Internal Medicine, Tor Vergata University of Rome, Rome, Italy
(6) J Child Neurol. 2000 Jun;15(6):357-61. Related Articles, Links Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutation. Graf WD, Marin-Garcia J, Gao HG, Pizzo S, Naviaux RK, Markusic D, Barshop BA, Courchesne E, Haas RH. Department of Pediatrics, University of Washington, Seattle, USA. wgraf@...
(7) Arch Dis Child 1997;76:264-267 ( March ) Fragile X, iron, and neurodevelopmental screening in 8 year old children with mild to moderate learning difficulties N Corrigan,a M Stewart,a M Scott,b F Feec a North and West Belfast Community Paediatric Unit, Belfast, Northern Ireland, b Queens University Belfast Department of Epidemiology and Public Health, Belfast, Northern Ireland, c Belfast Education and Library Board, Belfast, Northern Ireland
- And Life Sci. 2004 Oct 8;75(21):2539-49. Related Articles, Links Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin--the antioxidant proteins. Chauhan A, Chauhan V, Brown WT, Cohen I. NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314, USA.
(8) - Metallothionein Deficiency - see www.hriptc.org Walsh, W, Monograph: Metallothionein and Autism". {Pfeiffer Treatment Center, Illinois, Oct 2001, Over 100 articles referenced.
(9) - Wakefield AJ, A Anthoney et al "Enterocolitis in Children with Developmental Disorders" Am.J Gastroenterology 95 No 9 (2000) p 2285-2295
(10) A case control study of mercury burden in Autistic children in autistic spectrum disorders (Journal of American Physicians and Surgeons, Vol 8, No 3, 3 Fall 2003) J Bradstreed, MD, D Geier, J Kartzinel, Md, J Adams PhD, M Geier, MD, PhD.
(11) Cure Autism Now Foundation, White Matter Disease and Autism, see website
(12) HHV-6 and Autism - Clin Immunol Immunopathol. 1998 Oct;89(1):105-8. Related Articles, Links Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Singh VK, Lin SX, Yang VC. College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109-1065, USA.
(13) Activation of the fusiform gyrus when individuals with autism spectrum disorder view faces, N Hadjikahmi, RM Joseph, J Synder, CF Chabris, J Clark, S Steel, L McGrath, M Vangel, I Aharon, E Feczko, GJ Harris, and H Tager-Flusberg, Neuroimage, Vol 22, No 3 July 2004, contact nouchine@...
(14) J Neuroimmunol. 2004 Jul;152(1-2):176-82. Related Articles, Links Autoantibody repertoires to brain tissue in autism nuclear families. Silva SC, Correia C, Fesel C, Barreto M, Coutinho AM, Marques C, Miguel TS, Ataide A, Bento C, Borges L, Oliveira G, Vicente AM. Instituto Gulbenkian de Ciencia, Rua da Quinta Grande 6, 2781-196 Oeiras, Portugal.
(15) Pediatrics. 2003 Nov;112(5):e420. Related Articles, Links Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ. Department of Psychiatry, Indiana University School of Medicine, and James Whitcomb Riley Hospital for Children Indianapolis 46202-4800, USA.
(16) Chronic Mycoplasmal Infections in Autism Patients Garth L. Nicolson,1 PhD, Marwan Y. Nasralla,2 PhD, Paul Berns,1 MD and Jeorg Haier,3 MD, PhD 1 The Institute for Molecular Medicine, Huntington Beach, California, USA,, 2 International Molecular Diagnostics, Inc., Huntington Beach, California, USA, 3 Department of Internal Medicine, and 3Department of Surgery, Wilhelm-University, Munster, Germany. Correspondence: Prof. Garth L. Nicolson, Office of the President, The Institute for Molecular Medicine, 15162 Triton Lane, Huntington Beach, California 92649. Tel: 714-903-2900; Fax: 714-379-2082; Email: gnicolson@...; Website: www.immed.org
(17) Am J Med Genet. 1999 Nov 5;87(1):17-22. Related Articles, Links Subtle overlapping deletions in the terminal region of chromosome 6q24.2-q26: three cases studied using FISH. Sukumar S, Wang S, Hoang K, Vanchiere CM, England K, Fick R, Pagon B, Reddy KS. Cytogenetics Department, Quest Diagnostics Inc., San Juan Capistrano, California
Autism is growing at epidemic rates. (1) It is reported to be prevelant in 1-150 children, some states 1-80 children. Autism is a complex neurological disorder with seemingly provable and many etiologies such as maternal viruses and bacteria (2), immediate cord clamping and birth drugs (3), metabolic insufficiency during development in utero or infancy (ie, thyroid t3 and t4) (4), purine disorders, adenosine deaminse deficiency (5), mitochondrial disorders (6), iron fragile metabolism (7), metallothionein deficiency (8), oxidative stress, childhood vaccinations which act as triggers to events above through viral persistance in gut and brain (9), and heavy metal poisoning from additives in vaccines (10), and lastly chronic disseminated lyme neuroborreliosis disease. Lyme disease is transmitted through a tick bite. But it can also be transmitted through semen, breast milk and gestational fluids. This means that a fetus can be infected by its mother. B. burgdorferi has been proven by PCR analysis to establish a persistent infection in the mammalian host (Straubinger, R. Persistence of B. burgdorferi in experimentally infected dogs after antibiotic treatment. J.Clin.Microbiol.1997 Jan; 35(l): 111-116).
Lyme disease is the fastest growing vector-borne disease in the nation. In 2001, the Center for Disease Control recorded 18,000 new cases, but some experts estimate that the actual number is closer to 200,000 This is four times the number of HIV cases per year. Autism grows as exponetially as that, and an NIH bulliten explained of late it is seen in 1/166 children. Amongst those statistics, is the further frightening 1-6 children now have a developmental, psychiatric problems in the US.
Lyme disease AND autism results in underconnectivity of brain areas, defects of the fusiform gyrus and loss of purkinje cells in the cerebellum. Recently reports of white matter disease are prevelant in children and adults with autism paralleling patterns in lyme disease. (11) Late in the progression of this disease neurological, cognitive, and psychiatric symptoms predominate, overlapping symptoms of autism, such as food avoidance, facial recognition problems, sleep disorders, ocular symtpoms such as light sensitivity, speech and language loss or word retrieval problems, noise sensitivity, bed wetting, aggression, panic attacks, headaches, movement disorders, sore throats and poor swallowing, hypofusion-poor blood flow particularly to temporal lobes, swollen tongues and lymphs, chronic fatigue symptoms, hyperactivity, gut problems (ie, diahrreah, constiptation, IBD symtpoms, Celiac symptoms), liver dysfunction, thyroid problems (t3 and t4 conversions), iron disorders, heavy metal toxicity, tics, food sensitivities, depression, serotonin uptake problems, autoimmune brain antibodies, problems with sequencing, problems with sensory perceptions, seizures, cardiac conduction abnormalities, illiod hyperplasia, heavy metal toxicity, co infections of HHV6 and Mycoplasma (12), various aches and pains masked as lyme arthritis particularly in the neck area, and zinc copper iron imbalances.
The basic hierarchy is pre-frontal cortex, para limbic association areas, limbic structures, and brain stems - hypothalamus. Lyme encephalopathy can result in dysfunction of the modulation centers, inhibitory pathways, and stimulatory pathways. (13) Autopsies, animal studies, and brain imaging tests have contributed to this understanding. The presenting symptoms of NPLD are sometimes emotional in nature, and include obsessive-compulsive disorder, depression, and aggression, panic disorder, and other phobic disorders. These self same observations are also seen in autism as reports from parents of these symptoms are typical.
All involved with late state Lyme disease agree there is a large amount of inaccurate information on this subject. This disagreement exists at every level - journals, scientific meetings, clinical practice, and media outlets. The same can be said of autism, in which denials of it's etiologies are profusely displayed as only genetic, and never any environmental iaotragenic factors involved. Profusely are denials of the existance that autism is based on the bodies response to a foreign material either of neurotoxicity, bacteria or virus, such as lyme, such as vaccinal viruses, such as autoimmune processes that become overabundant. Reports are clear, that parents of autistic children seem to have higher incidences of autoimmune conditions. This is telling us something. It is my belief, this is a sign that the parents themselves have lyme disease-and are giving this infection to their children. Lyme disease is prevelant in all fifty states of the union, and know no geographical areas. However, it is interesting to note, that in states that have the less lyme, there is more availability of selenium in the soils, which is a immune neuro protectant against viruses and bacteria. Parents of autistic children routinely show low levels of selenium in blood work, as well as metallothionein deficiency, a glutathione dependent oxidant. Parents also have higher sedimentation rates (ESR) and thrombaphilia and fibrin deposits showing inflammation as well as thyroid TRH dysfunction. (14) They also often have skewed hormonal balances. Lyme is capable of changing these aspects on blood work.
Interestingly, susceptibility genes for autism parallel the susceptibility genes for arthritis and other autoimmune disorders, such as HLA-B27, and HLA-DR4. Complement immune deficiencies are common in both diseases, including C4B and C3A. The frequency of autoimmune disorders was significantly higher in families of the PDD probands compared with families of both the autoimmune and healthy control probands. Autoimmunity was highest among the parents of PDD probands compared with parents of the healthy control subjects. Hypothyroidism/Hashimoto’s thyroiditis and rheumatic fever were significantly more common in families with PDD probands than in the healthy control families. Interestingly, reports of Hashimotos and hypothyroidism are prevalent in lyme disease. (15) Interestingly, reports of mycoplasma are consistent with parents having a mycoplasmal infection, and giving that to their children. (16) Mycoplasma medications are alleviated by the self same medications for lyme disease. Many parents report that lyme and mycoplasma are prevelant in their children with autism. Familial association studies have also reported an increased risk of several systemic autoimmune diseases among relatives of patients with a systemic autoimmune disease. This association may reflect a common etiologic pathway with shared genetic or environmental influences among these diseases. Environmentally, there is increases in levels of heavy metals, toxicity, neurotoxicants, mold, and most of all but not least, the prevelance of the lyme bacterium. Prolactin may also have important immune-modulating influences affecting the risk of autoimmune disease . The prolactin gene is located close to the MHC region of chromosome 6, hotspots for lyme AND autism. (17) Another protein eaten by lyme is melatonin, which may account for levels of serotonin, prolactin and the ability to detox heavy metals. In autism, melatonin levels are dysregulated, causing sleep disorders, and antibodies are found against serotonin.
Recently there have been reports of short term antibiotic use to kill clostridium and or AGBN's. Vancomycin was recently used, and reports are that when on the antibiotic for thirty days, symptoms of autism decreased. The Jarish Herxheimer reaction is seen when antibiotics are having a therapeutic effect as well, as evidenced when the child is on the antibiotics. This often scares off the weary parent of an autistic child, stopping the antibiotic for fear it is contributing to their autism symptoms when in reality it was killing lyme with mild to moderate reactions. Unfortunately, in these studies, the children regressed back to autism symptoms as soon as they were removed after thirty days. If the bacteria is not completely eliminated, the symptoms will return. This tells us, I believe, that lyme is involved in their autism. This reasoning has made others think of why these children respond so favorably while on the antibiotic. It could be that it is going after the lyme bacterium (however not it's stages due to it's short length), but also calming down the cytokine and chemokine activity in the immune system, and having some kind of effect on viruses which depend on cytokines and chemokines. Typically those viruses are of the herpes CMV class. Reports of HHV6 and autism are abundant. Many children have high herpes titres, sometimes to that of 4-6 times of normal, often corrolating with autism symptoms or seizures. Although the American Academy of Pediatrics recommends a three week course of antibiotics, Dr. Jones-a pediatric lyme speclialist, has found that the bacteria that causes Lyme has become increasingly hardy and even when the disease is caught early, it often needs to be treated with an eight to twelve week course of antibiotics or beyond.
Lyme has many names. Among its "symptoms" are ALL of the "ideopathic" (unknown-cause) diseases that plague americans, too many to list here - it affects the body by making sugar turn to lactic acid, which in turn can scar the kidneys over time, irritate the bladder, damage the liver, and upset the pancreas. Lactic acid causes muscle soreness and sensitive intestines/cramping problems (nervous stomach). Interestingly, it is reported that many autistic children have skewed lactic and pyruvate ratios. This creates a mitochondrial disorder, oxidative stress in these children. Lyme also eats proteins, many types. It eats myelin protein, which is known to be going missing in MS patients. The localities for MS hot spots exactly match the pattern of lyme disease, and I believe it is the same disease with a different name. Myelin is what nerves are made of - and damage to myelin, without a meat and potatos diet to replace protein constantly, causes brain troubles (alzheimers, parkinsons, alateral myotrophic scleroses, myocarditis), numbness of the bladder and/or muscle spasms in the elderly mistaken as "incontinence", nerve troubles, stuttering, etc. This corrolates nicely with what we are seeing in autism. Typically there are myelination antibodies in children with autism, even Neural Axon Filament Protein antibodies, and various other antibodies against brain tissue. Many children with autism lose their ability to sleep through the night without bedwetting. Stuttering is often seen in children with autism.
It is also reported that when these children harbor heavy metals, that viruses and bacteria seem to live in areas of that damage. Since these children lack the oxidant metallothionein, they cannot detox the EPA over standard of safe of thimerosol that were in childhood vaccine series, or other environmental factors including their mothers in utero exposure of amalgams. Unfortunately, they still are according to HAPI, a NPO who just tested mercury free vaccines (ARI newsletter 2004). As they work in consortium, there is a theory that the heavy metals bind to these bacteria and viruses, and when they are eliminated, heavy metals start to chelate out of the body. This is evidenced by EDTA chelation which has the ability to kill nanobacteria. Observations and biomarkers of damage are seen soon after vaccinations, but what is equally intriguing, is that lyme may be awoken after an immune lowering event such as vaccinations.
Recent reports show that children with autism are harboring lyme disease. The cry for chromosomal faults are numerous, and often paid and backed to be equally the only way you get autism. What researchers know, is that no money is funded or researched or goes into the immune lowering/autoimmunity events that create autism, and is simply put down. The cogent finding of lyme bacterium being a major risk factor for autism needs to be explored. This is superimposed on the already sustained belief, that autism is an autoimmune disorder. Many of the imbalances of autism could be explained as the body's inability to detox and to work on this bacteria. Lyme could also be a trigger or a circumstance that initiate or worsening of the autistic condition. This includes milk allergies, strep infections, mercury, dietary intolerances of wheat and milks, and inability to deal with toxic inhibitors. Interestingly, many of the imbalances and deficiencies can be caused by lyme bacteria.
Many of the meds used for autism seem to also slow down the lyme bacterium, such as digestive enzymes, anti fungals, of course, antibiotics, anti parasticals, addressing food allergies, increasing zinc, antiinflammatories and even secretin (secretin is tied to insulin, which lyme attacks). Lately, the use of Methylcolbalamine B-12 with folinic acid would also reduce lyme symptoms. Since there is already evidence of abnormal gut bacteria and exaggerated production of cytokines which result in irreversable cellular damage, it behooves parents and clinicians and researchers to look into this paralell and seek state of the art laboratory connections to lyme and autism. Three labs are recommended, STONYBROOK, BOWEN and IGENEX. This may result in the first of it's kind treatment for autism via lyme therapy.
References (1) Changes in the Population of Persons with Autism and PDD, Dept Develop Services, California, Health and Human Services March 1 1999
(2) The Journal of Neuroscience, January 1, 2003, 23(1):297-302 Maternal Influenza Infection Causes Marked Behavioral and Pharmacological Changes in the Offspring
(4) Abramson J, Stagnaro-Green A. Thyroid antibodies and fetal loss: an evolving story. Thyroid 2001;11(1):57-63.
(5) Adenosine Deaminase - Neurogenetics. 2001 Mar;3(2):111-3. Related Articles, Links Autism: evidence of association with adenosine deaminase genetic polymorphism. Bottini N, De Luca D, Saccucci P, Fiumara A, Elia M, Porfirio MC, Lucarelli P, Curatolo P. Department of Internal Medicine, Tor Vergata University of Rome, Rome, Italy
(6) J Child Neurol. 2000 Jun;15(6):357-61. Related Articles, Links Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutation. Graf WD, Marin-Garcia J, Gao HG, Pizzo S, Naviaux RK, Markusic D, Barshop BA, Courchesne E, Haas RH. Department of Pediatrics, University of Washington, Seattle, USA. wgraf@...
(7) Arch Dis Child 1997;76:264-267 ( March ) Fragile X, iron, and neurodevelopmental screening in 8 year old children with mild to moderate learning difficulties N Corrigan,a M Stewart,a M Scott,b F Feec a North and West Belfast Community Paediatric Unit, Belfast, Northern Ireland, b Queens University Belfast Department of Epidemiology and Public Health, Belfast, Northern Ireland, c Belfast Education and Library Board, Belfast, Northern Ireland
- And Life Sci. 2004 Oct 8;75(21):2539-49. Related Articles, Links Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin--the antioxidant proteins. Chauhan A, Chauhan V, Brown WT, Cohen I. NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314, USA.
(8) - Metallothionein Deficiency - see www.hriptc.org Walsh, W, Monograph: Metallothionein and Autism". {Pfeiffer Treatment Center, Illinois, Oct 2001, Over 100 articles referenced.
(9) - Wakefield AJ, A Anthoney et al "Enterocolitis in Children with Developmental Disorders" Am.J Gastroenterology 95 No 9 (2000) p 2285-2295
(10) A case control study of mercury burden in Autistic children in autistic spectrum disorders (Journal of American Physicians and Surgeons, Vol 8, No 3, 3 Fall 2003) J Bradstreed, MD, D Geier, J Kartzinel, Md, J Adams PhD, M Geier, MD, PhD.
(11) Cure Autism Now Foundation, White Matter Disease and Autism, see website
(12) HHV-6 and Autism - Clin Immunol Immunopathol. 1998 Oct;89(1):105-8. Related Articles, Links Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Singh VK, Lin SX, Yang VC. College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109-1065, USA.
(13) Activation of the fusiform gyrus when individuals with autism spectrum disorder view faces, N Hadjikahmi, RM Joseph, J Synder, CF Chabris, J Clark, S Steel, L McGrath, M Vangel, I Aharon, E Feczko, GJ Harris, and H Tager-Flusberg, Neuroimage, Vol 22, No 3 July 2004, contact nouchine@...
(14) J Neuroimmunol. 2004 Jul;152(1-2):176-82. Related Articles, Links Autoantibody repertoires to brain tissue in autism nuclear families. Silva SC, Correia C, Fesel C, Barreto M, Coutinho AM, Marques C, Miguel TS, Ataide A, Bento C, Borges L, Oliveira G, Vicente AM. Instituto Gulbenkian de Ciencia, Rua da Quinta Grande 6, 2781-196 Oeiras, Portugal.
(15) Pediatrics. 2003 Nov;112(5):e420. Related Articles, Links Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ. Department of Psychiatry, Indiana University School of Medicine, and James Whitcomb Riley Hospital for Children Indianapolis 46202-4800, USA.
(16) Chronic Mycoplasmal Infections in Autism Patients Garth L. Nicolson,1 PhD, Marwan Y. Nasralla,2 PhD, Paul Berns,1 MD and Jeorg Haier,3 MD, PhD 1 The Institute for Molecular Medicine, Huntington Beach, California, USA,, 2 International Molecular Diagnostics, Inc., Huntington Beach, California, USA, 3 Department of Internal Medicine, and 3Department of Surgery, Wilhelm-University, Munster, Germany. Correspondence: Prof. Garth L. Nicolson, Office of the President, The Institute for Molecular Medicine, 15162 Triton Lane, Huntington Beach, California 92649. Tel: 714-903-2900; Fax: 714-379-2082; Email: gnicolson@...; Website: www.immed.org
(17) Am J Med Genet. 1999 Nov 5;87(1):17-22. Related Articles, Links Subtle overlapping deletions in the terminal region of chromosome 6q24.2-q26: three cases studied using FISH. Sukumar S, Wang S, Hoang K, Vanchiere CM, England K, Fick R, Pagon B, Reddy KS. Cytogenetics Department, Quest Diagnostics Inc., San Juan Capistrano, California
También se menciona el western blot para Lyme entre las pruebas de laboratorio que deben hacerse los pacientes de SFC en función de su historial médico:
ADDITIONAL TESTING: In addition to the routine laboratory tests, additional tests
should be chosen on an individual basis depending on the patient’s case history,
También se menciona el western blot para Lyme entre las pruebas de laboratorio que deben hacerse los pacientes de SFC en función de su historial médico:
ADDITIONAL TESTING: In addition to the routine laboratory tests, additional tests
should be chosen on an individual basis depending on the patient’s case history,
Melissa Kaplan's Chronic Neuroimmune Diseases Information on CFS, FM, MCS, Lyme Disease, Thyroid, and more... Last updated February 27, 2004
Balance the Th1/Th2 Immune System
From a talk by Paul Cheney, MD
Transcription by Dallas-Ft Worth CFS Support Group
Written by our group facilitator, this issue's articles are based on tapes of her October 2000 visit. Dr. Cheney gave permission to share this information, but has not reviewed or edited it. Articles on other topics will be in the April 2001 newsletter and will soon be available on our website in the section on Dr. Cheney. These articles likely apply also to FMs patients experience cognitive difficulties in addition to pain and fatigue, since Dr. Cheney believes they may also have CFIDS. Dr. Cheney plans to speak in the Dallas - Ft. Worth area on October 20, 2001. Contact the DFW support group for information, particularly about the videos that will be available of the seminar.
CFIDS patients are Th2 activated. This means they over-respond to toxins, allergens, normal bacteria and parasites, and under-respond to viruses, yeast, cancer and intracellular bacteria. Dr. Cheney suggests six products that can help rebalance the immune system.
Dr. Cheney explained that the immune system has two different modes of attack, based on the type of invader. One is Th1 (T Helper 1). It goes after organisms that get inside our cells ‚ intracellular pathogens. It is also known as cell-mediated immunity. The other is Th2 (T Helper 2). It attacks extracellular pathogens ‚ organisms that are found outside the cells in blood and other body fluids. Some call this humoral or antibody-mediated immunity. A healthy immune system is dynamic, able to switch back and forth as needed, quickly eradicating one threat and then resting before responding to the next.
(Dr. Cheney began this conversation by drawing a large inverted "V". At the top point he wrote "Th0", which he called "Th naught". The left arrow pointed down to "Th1" and the right arrow to "Th2". The arrow on the right was much darker and thicker, indicating that CFIDS patients are Th2 activated.)
Th0 are the naive, or unformed, cells of the immune system. They are resting, just waiting for an invader. When infection occurs, they convert to either Th1 or Th2, depending on the type of threat. When the resting cell is exposed to a virus, cancer, yeast, or intracellular bacteria (like mycoplasma or chlamydia pneumonia), the Th1 response is initiated. (Dr. Cheney wrote these organisms beside the left arrow.) The weapons of the Th1 system include cytotoxic T cells and Natural Killer (NK) cells. (Cheney drew these below "Th1".)
On the other side are normal bacteria, parasites, toxins, and allergens. (Likewise written beside the right arrow.) These trigger a predominately Th2 response. Its weapons include eosinophiles (Eos), polymononuclear cells (PMN), and antibody secreting cells (Ab). (Likewise written below "Th2".)
How does the naive cell know which pathway to take? It depends on the cytokine information received. The presence of any organism from the left side triggers production of a cytokine called Interleukin 12. IL-12 causes the Th0 cell to move down the Th1 path. On the other hand, organisms on the right side trigger the production of Interleukin 10 (IL-10), which causes the Th0 cell to move down the Th2 path. (Cheney added small vertical dotted lines on each side, pointing upward to "IL-12" on the left and "IL-10" on the right. He then drew horizontal dotted arrows from "IL-12" and "IL-10", each pointing inward toward the "Th0", indicating that these cytokines determine whether it will become Th1 or Th2.)
Cheney said this is the point where it gets very interesting. Viruses, especially herpes viruses like EBV, CMV and HHV6, make proteins that mimic IL-10. The virus deceives the immune system into thinking that the threat is coming from the opposite side! So the immune system shifts from the Th1 mode that attacks viruses to the Th2 mode that does not. The virus increases its chances of survival by diverting the immune system. It is now thought that many, if not most, pathogens have this ability. (To represent this effect, Cheney drew a horizontal arrow about half way down the inverted "V", originating from the left side and pointing toward, but not quite touching, the right side. The line was labeled "IL-10 like peptides". Below it he drew a similar arrow from the right side that almost reached the left side. It was labeled "IL-12 like peptides".)
Researchers have demonstrated that most CFIDS patients end up stuck in Th2 mode. This has several consequences. When the Th2 system activates, it blocks the Th1 system. This suppresses the Th1 weapons, particularly NK function. Accordingly, there is also an increase in the Th2 weapons - the white cells and antibodies. Most notable is increased antibody production. Dr. Cheney said that if you measure antibodies to anything a CFIDS patient has ever been exposed to, they will very likely be elevated. (At this point he drew small arrows beside the "weapons": They pointed down on the left side to indicated suppression / lower levels; and they pointed up on the right side to indicate activation / higher levels.)
Cheney notes that other problems ensue. Patients get into trouble on both sides: they overreact to things on the right side and under-react to those on the left. When they are Th2 activated, they no longer have the defense mechanisms to keep dormant all the things they caught in the past. They cannot suppress or control them anymore, and the EBV, chlamydia pneumonia, CMV, etc. reactivate. The yeast also begins to appear.
The only defense against being eaten alive at this point is RNase L. (For more information about RNase-L, see The Three Phases of CFIDS and other articles in the Cheney section of our website.) RNase-L cannot kill any of these things. It only stops them from reproducing. According to Cheney, "It's a line in the sand saying 'No more replication', and it waits for Th1 to come and kill them. But Th1 never comes. RNase L sits there and grinds away, possibly going up and down as the pathogens activate and reactivate. But they never get wiped out. RNase L holds the line, waiting for the cavalry that never arrives."
While it is valiantly trying to hold the line, it is also chewing up human messenger RNA, inhibiting all the enzymes in the body, disrupting protein synthesis, and generally making patients miserable. As RNase-L grinds away, it eventually shifts into "after-burner" desperation mode - the more powerful and deadly low molecular weight form discovered in CFIDS patients by Suhaldonik.
Cheney commented "RNase-L is a very good anti-cancer defense. So as long as you're involved in this scenario, you don't get cancer. But a lack of growth hormone will wipe out RNase-L, and we now know there is profound loss of growth hormone in CFIDS. Growth hormone is responsible for protein synthesis, and RNase L is a protein. So if you lose growth hormone, you lose protein synthesis, including RNase L. That may explain why, as the disease wears on and you get more injury, you stop seeing high levels of RNase L. You can't make it anymore."
He believes this is a very scary situation. Patients are Th2 activated and Th1 suppressed. The things on the left come out and there is nothing to stop them. There is no Th1, and eventually no Rnase L. He also believes patients need to balance the immune system - to push it a little more towards Th1. That way they will lose some of the overreaction on the right and gain some control on the left.
Cheney recommends the following to help shift the immune system from one mode to another. They are called "right to left shifters". Three of them are published, or near publication.
1) Kutapressin (published, prescription) Kutapressin is an immune modulator and a broad spectrum anti-viral. Dr. Cheney has found that it is most effective when the dose is varied or "pulsed". The dose should vary from 1 to 4 cc daily; see the section on Isoprinosine for this theory. Dr. Cheney strongly suspects Ampligen is a right-to-left shifter also. He has said in the past that Kutapressin is rather like a weak form of Ampligen.
2) Isoprinosine (published, prescription) Published for use in CFIDS, this anti-viral enhances NK function. Dr. Cheney believes it would also be good against intracellular bacteria since it is a Th2 - Th1 shifter. It appears to raise IL-12 and lower IL-10, which turns off Th2 and turns on Th1.
It is also called Imunovir and is very nontoxic, very safe. It has been approved in Europe and Canada for just about any viral infection for 18 years. It is not approved in the US (for political reasons not safety concerns) but is easy to get from Ireland with a prescription. Week one, take 6 tablets a day, Monday through Friday, and none on the weekend. Week two, take 2 tablets a day, Monday through Friday, and none on the weekend. Repeat this cycle. But do not treat every month. Do two months on and then one month off of this "pulsing" dose. This medicine works best when you do not treat regularly. If you treat continuously at the same dose, it stops working. It is an immune modulator, and Dr. Cheney suspects all immuno-modulators are like this. If taken continuously they stop working. The dose must vary so the immune system never knows what to expect.
3) Pine Cone Extract. Cheney said, "They make a tea from this in Southern Japan and they have significantly reduced cancer rates. It's thought to work at the gene level in lymphocytes, where it turns on IL-12. It also shuts down IL-10 at the gene level, and that causes a shift towards Th1. Pine Cone extract is expensive, but at just 10 drops a day (in the morning), of all the possibilities, it's probably the cheapest per day." It is called PineExtra, and 1 oz is about $60, but it lasts a long time.
4) Earth Dragon Peptides (supplement, www.nutricology.com, www.needs.com) Earth Dragon is round worm peptides. It causes a shift to the left, and is believed to be very similar to IL-12. There has been a huge surge in the use of ED peptides to treat Inflammatory Bowel Disease, specifically Crohn's Disease. One professor at UNC treats all his Crohn's Disease patients with Earth Dragon. It is very non-toxic and safe. This is a good choice for those who want to balance their immune system and also have bowel problems. Earth Dragon is about $36 for 150 caps. The dose is two a day.
5) Heparin (prescription). Heparin is a Th2 - Th1 shifter. One advantage for many patients is that it is also an anticoagulant. Dr. Cheney only recommends this if a patient has a coagulopathy. About half of his patients do, according to the ISAC test.
6) Formula 560 Transfer Factor (to be published, supplement, www.immunitytoday.com) Formula 560 is an immune modulator. Dr. Cheney likes this product. It reportedly works against HHV6 and Lyme Disease, as well as other problems. It costs about $585 for the first three months, then the dose drops one-third. It averages out to about $130 a month for the first six months, and $65 thereafter. (The cost of this product has reported dropped since this was first published.)
Which should you use? Cheney recommends that you pick one and see what it does to your NK function. It is a question of whether it will work and how much it costs. NK levels will rise if there is a shift from Th2 towards Th1. Before beginning one of these products it is best to get a baseline on NK function. Then test again after having been on the product for one to three months. Dr. Cheney uses the lab of Mary Ann Fletcher, an NK specialist and colleague of renowned researcher Nancy Klimas, at the University of Miami. Her lab is no more expensive than commercial labs, and is top quality. Cheney emphasizes that you must have a quality lab do this test: do not use just any lab. For test information, phone 305-243-6288 or fax 305-243-4674. The test is called "Natural Killer Cell Function Assay" and costs $350.
Note: This is not medical advice. See your healthcare provider for medical advice.
Medications Information Melissa Kaplan
I searched the 'net and found the following resources for the drugs/herbs/supplements recommended by Cheney for the Th1/Th2 protocol.
Earth Dragon Peptides (Lumbricus Tonic): roundworm peptide useful in some immune-related bowel diseases such as Crohn's.
Nutricology, Inc. 30806 Santana Street Hayward, CA 94544 Info 800.545.9960; Order 800.782.4274; Fax 800.688.7426
Needs.com
Heparin: an injectible anticoagulant/blood thinner.
See Hypercoagulation: the CFS Plot Thickens
Isoprinosine (Imunovir; Inosine Pranobex): by prescription outside of the U.S. (Similar product available as Inosine) Those in the U.S. may order it from:
Newport Pharmaceuticals (markets both Imunovir and Isoprinosine) Dublin, Ireland Email Ph. 353-1-890-3011; Fax 353-1-890-3016
Pharmacia Sucre, S.A. San Jose, Costa Rica Email Ph. 506-00-233-6380,506-223-1715; Fax 506-00-233-9869 (There is no area/city code for Costa Rica so you may not need to dial the 00)
See below for more information on isoprinosine.
Kutapressin: an injectible drug not currently labled for use in the US.
Can be ordered by pharmacies with a prescription. [MK notes: when I tried this in 1992, it was $80/vial]
Pine Cone Extract: immune system stimulant with anti-tumor and antiviral properties.
Lifestyle Management Inc. 11306 Carrollwood Drive Tampa, FL 33618 1-800-238-9861
Transfer Factor Formula 560: immune modulator effective in Lyme Disease and HHV6.
Immunity Today (at 3 caps a day, this lower price works out to $450 for the first three months) 513A N Mur-Len Olathe, KS 66062 USA Ph. 1-888-217-2200; Fax 1-913-780-2317
For other sources of Transfer Factor, see Hypercoagulation: The CFS/FM/MPS Plot Thickens.
Tests
Natural Killer Cell Assay
Mary Ann Fletcher University of Miami Dept of Medicine -R42; RSMB Room 8168 1600 NW 10th Ave Miami FL 33136 Ph. 305-243-6288; Fax 305-243-4674
The Natural Killer Cell Function Assay Test ($350) requires one small EDTA purple tube and one medium heparin green top tube, drawn in the afternoon and shipped immediately overnight air freight, ambient temperature, with AM delivery. It must get there within 24 hours. They do not supply a kit. They do accept Medicare if you send them the prescribing doctor's UPIN number.
AAL Reference Lab, Inc. (dba Antibody Assay Lab) 1715 E. Wilshire Avenue, Suite 715 Santa Ana, CA 92705 800-522-2611; 1-714-972-9979 Fax 714-543-2034
Other Diagnostic Labs
Isoprinosine Information
From Thriveonline Isoprinosine is a nucleoside (one of the basic compounds comprising cells in the body). It is marketed as a drug in many nations (but not yet in the United States). It is used as an immune stimulator for cancer, herpes, and AIDS.
Other names for Isoprinosine include: Isoprinosine Pranobex.
Ask your doctor, nurse, or pharmacist if you need more information about this medicine or if any information in this leaflet concerns you.
Before Using: Tell your doctor if you: are taking medicine or are allergic to any medicine (prescription or over-the-counter (OTC) or dietary supplement) are pregnant or plan to become pregnant while using this medicine are breastfeeding have any other health problems, such as high blood pressure or heart or blood vessel disease
Dosage: There are many doses for this medicine. Isoprinosine should only be used under direct supervision of your health care professional, please consult them for proper dosing.
To store this medicine: Keep all medicine locked up and away from children. Store medicine away from heat and direct light. Do not store your medicine in the bathroom, near the kitchen sink, or in other damp places. Heat or moisture may cause the medicine to break down and not work the way it should work. Throw away medicine that is out of date or that you do not need. Never share your medicine with others.
Warnings: Before taking Isoprinosine, tell your doctor if you are pregnant or breastfeeding. Those with gout or a predisposition to develop gout should not use Isoprinosine.
Side Effects: Stop taking your medicine right away and talk to your doctor if you have any of the following side effects. Your medicine may be causing these symptoms which may mean you are allergic to it. Breathing problems or tightness in your throat or chest Chest pain Skin hives, rash, or itchy or swollen skin
Other Possible Side Effects: This medicine may also cause other side effects. Tell your doctor if you have side effects that you think are caused by this medicine.
From VitaminShoppe.com:
What does it do? Inosine is a nucleoside, one of the basic compounds comprising cells. It is a precursor to adenosine, an important energy molecule, and plays many supportive roles in the body, including releasing insulin, facilitating the use of carbohydrate by the heart, and, potentially, participating in oxygen metabolism and protein synthesis. Based upon anecdotal reports by Russian and Eastern European athletes, inosine has been investigated for ergogenic (exercise boosting) effects. Results of controlled studies have been disappointing, however, suggesting that inosine does not improve athletic performance and may even impair it.1 2
Where is it found? Inosine is found in Brewer’s yeast and organ meats. It is also available as a supplement.
Who is likely to be deficient? Inosine is not an essential nutrient, so deficiencies do not occur.
How much is usually taken? Although a common amount of inosine taken by athletes is 5,000–6,000 mg per day, little scientific evidence supports the use of this supplement at any level.
Are there any side effects or interactions? No side effects have been reported with the use of inosine for two to five days in the limited research available. However, unused inosine is converted by the body to uric acid, which may be hazardous to people at risk for gout.
References:
1. Starling RD, Trappe TA, Short KR, et al. Effect of inosine supplementation on aerobic and anaerobic cycling performance. Med Sci Sports Ex 1996;28(9):1193–98. 2. Williams MH, Kreider RB, Hunter DW, et al. Effect of inosine supplementation on 3-mile treadmill run performance and VO2 peak. Med Sci Sports Exerc 1990 Aug;22(4):517–22.
From The Body
Isoprinosine/Imunovir (Inosine) Dosage The information here reiterates some of the dosages referenced in the research on isoprinosine:
There is no way to know what the proper dose is. However the clinical studies thus far have examined between 1 - 4 grams per day. The Danish study used 1 gram three times a day. The tablets we distribute are 500 MG each. To take the doses used in the studies, you would take between 2 and 8 tablets every day. To our knowledge, only one study has evaluated how isoprinosine is absorbed and excreted in humans. This study demonstrated that isoprinosine doesn't stay in the body very long. To keep consistent levels of isoprinosine in the body would require fairly frequent oral doses, three or more times a day. Taking isoprinosine as an injection or an enema may deliver initially higher doses into the blood, but the body eliminates this isoprinosine just as quickly. We don't know whether the body requires consistent levels of an immune modulator in order to respond to it, but if it does, oral dosing is the easiest way to acheive this.
Again, Cheney's recommended dosing and frequency for Th1/Th2 dysregulation:
Week one, take 6 tablets a day, Monday through Friday, and none on the weekend. Week two, take 2 tablets a day, Monday through Friday, and none on the weekend. Repeat this cycle. But do not treat every month. Do two months on and then one month off of this "pulsing" dose. This medicine works best when you do not treat regularly. If you treat continuously at the same dose, it stops working. It is an immune modulator, and Dr. Cheney suspects all immuno-modulators are like this. If taken continuously they stop working. The dose must vary so the immune system never knows what to expect.
Byron Hyde MD's preliminary report on isoprinosine research can be found at his Nightingale Foundation site.
AACFS Seventh International Conference Madison, Wisconsin October 8-10, 2004
Reprinted with permission of Richard A. Van Konynenburg
Introduction
WHAT IS GLUTATHIONE? [Refs. 1--5]
" A tripeptide composed of the amino acids glutamic acid, cysteine, and glycine. Its molecular weight is 307.33 Da.
" Found in all cells in the body, in the bile, in the epithelial lining fluid of the lungs, and, at much smaller concentrations, in the blood.
" The predominant nonprotein thiol (molecule containing an S-H or sulfhydryl group) in cells.
" Its active form is the chemically reduced form, called "GSH."
" GSH is compartmentalized, with concentrations ranging from 0.5 to 10 millimolar in various organs and cell types.
" GSH serves as a substrate for enzymes, including the glutathione peroxidases and the glutathione-S-transferases.
" When oxidized, two glutathione molecules join together via a disulfide bond to form "oxidized glutathione," or "glutathione disulfide," referred to as "GSSG."
" Inside cells, the concentration of GSSG is normally maintained at less than 1% of total glutathione by the enzyme glutathione reductase, which is powered by NADPH, produced by the pentose phosphate shunt, part of normal carbohydrate metabolism.
WHAT ARE SOME OF THE FUNCTIONS OF GLUTATHIONE (GSH)? [Refs. 1--5]
" Maintains proper oxidation-reduction (redox) potential inside cells. Redox affects the oxidation state of sulfur in enzymes, and thus affects the rates of biochemical reactions in cells.
" Scavenges peroxides and oxidizing free radicals directly and also serves as the basis for the antioxidant network.
" Performs Phase II detoxication of heavy metals (such as mercury), organophosphate pesticides, chlorinated hydrocarbon solvents, estradiol, prostaglandins, leukotrienes, acetaminophen, and other foreign and endogenous toxins.
" Stores and transports cysteine throughout the body.
" Transports amino acids, especially cystine into kidney cells.
" Regulates the cell cycle, DNA and protein synthesis and proteolysis, and gene expression.
" Regulates signal transduction.
" Participates in bile production.
" Protects thyroid cells from self-generated hydrogen peroxide.
In carrying out several of the above functions, GSH plays very important roles in (1) maintaining mitochondrial function and integrity, (2) regulating cell proliferation, and (3) supporting the immune system.
HOW IS GLUTATHIONE (GSH) SYNTHESIZED IN THE BODY? [Refs. 1--5]
" GSH is synthesized inside cells by a two-step process. The first step involves the ATP-powered enzyme glutamate cysteine ligase (formerly called gamma-glutamylcysteine synthetase). This step is normally the rate-limiting reaction, and is controlled by the cellular redox state and feedback inhibition, among other factors. The second step makes use of the ATP-powered enzyme glutathione synthetase.
" The necessary substrates are cysteine (which is often the rate-limiting substrate when GSH is depleted), glutamic acid (or glutamine) and glycine. Cysteine and glutamic acid are joined together in the first step, and glycine is added in the second step.
" The liver is the main producer and exporter of GSH.
" A few epithelial cell types can import GSH molecules intact.
" Most cell types use the gamma glutamyl (or GSH scavenging) cycle. This cycle makes use of the plasma-membrane-bound exoenzymes gamma-glutamyl transpeptidase and dipeptidase. This cycle disassembles GSH outside the cell and imports the parts for reassembly inside. It also serves as a transport mechanism to bring other amino acids into the cell, cystine (di-cysteine) being favored.
IS GLUTATHIONE DEPLETED IN CHRONIC FATIGUE SYNDROME?
There is considerable evidence that it is, at least in a substantial fraction of CFS patients. Here are the results of all the published studies that bear on this question:
" GSH depletion in CFS was first suggested by Droge and Holm [6]. " Cheney [7,8] reported that his CFS clinical patients were almost universally low in GSH. " Richards et al. [9] found that patients could be divided statistically into two distinct groups, one having significantly elevated erythrocyte GSH relative to a healthy control group, and the other having significantly lower values. " Fulle et al. [10] found elevated total (reduced plus oxidized) glutathione in muscle biopsy specimens from PWCs relative to healthy controls, but they did not report values for reduced glutathione alone. " Manuel y Keenoy et al. [11] found that a subgroup of fatigued patients with low magnesium, which did not improve with supplementation, had significantly lower GSH. " Manuel y Keenoy et al. [12] did not find a significant difference between CFS patients and fatigued controls in terms of whole-blood GSH, but they did not compare with a healthy control group. " Kennedy et al. [13] found significantly lower red blood cell GSH in PWCs compared to healthy controls (p=0.05). " Kurup and Kurup [14] found significantly lower red blood cell GSH in myalgic encephalomyelitis patients compared to healthy controls (p<0.01).
The above is just a small Abstract of the 33 pages long Paper.
You can download the Full Paper as PDF Document: click here
Index Treatment Pages Index CFS Pages
Disclaimer:
Information on this site is provided for informational purposes only and is not meant to substitute the advice provided by your own physician or other medical professionals. Consult your own physician regarding the applicability of any information listed on this website with respect to your symptoms or medical condition
REPORT FROM THE SEVENTH ANNUAL AACFS INTERNATIONAL CONFERENCE
October 8-10, 2004, Madison, Wisconsin
by Paula Carnes
Reprinted with Permission of Paula Carnes
Dharam Ablashi, DVM, MS, Dip.Bact., and current president of the American Association for Chronic Fatigue Syndrome stood before us with a small, pleased smile on his face. "This conference is what we wanted to have when we first started the AACFS." The 2004 conference held in Madison, Wisconsin October 8 -10 included research and clinical presentations. Ablashi stated, "It [research] should be good enough to take it to the bedside."
Anthony Komaroff, MD, Harvard School of Medicine, began the conference with an overview of current CFS/FM research. This summary alone was worth the trip to Madison. Reduction of function in CFS patients is substantial as demonstrated by a study using SF 36 scores. The CDC has determined that the total cost to the US each year from productivity losses due to cfs is $9.1 billion. Cases of CFS followed three years show a relapsing remitting course with slight improvement in symptoms but not in employment over time. There is only a 10% rate of total remission. Studies of the brain in CFS indicate evidence of CNS involvement and hypothalamic-pituitary axis abnormalities. Cognition studies reveal slowed processing of information. Sleep disorders involve non-restorative sleep, sleep apnea, and restlessness. Treatment is of only modest benefit. Studies of immune activation indicate that "activated lymphocytes can pass through the blood-brain barrier in small numbers…and thereby activate lymphocytic and dendritic cells that reside in the brain, particularly microglia and perivascular cells, and this state of low-level activation can last decades. Activated microglia, like macrophages, secrete pro-inflammatory cytokines. (e.g., TNF alpha, IL-1 beta) and NO (nitric oxide)." There is increased neutrophil apoptosis in CFS. The following infections have been found in CFS patients: enterovirus (coxackie B-like virus), post-Q fever (coxiella burnetii, a rickettsia), post-parvovirus syndrome with elevated IFN gamma, TNF alpha, mycoplasmas (68% of 261 patients in one study). Gene expression studies were done by the CDC. A rheumatology study indicated low vitamin D levels in FMS patients. Omega 3 fatty acid treatment may reduce viral activity and inflammation.
William C. Reeves, MD from the CDC began his presentation of their new epidemiology studies by stating clearly that the "fatigue" in chronic FATIGUE syndrome is not just "tired." It is a fatigue not relieved by rest and includes hurting all over. He then moved on to some startling new information. The CDC study found 235 cases of CFS per 100,000 in their Wichita study. Women are more likely than men to have it, but CFS is more common than breast cancer among women. These details are familiar, but here is a list of surprises. Rural rates of CFS are twice those of urban areas Minorities have the highest risk Lower socioeconomic groups have a much greater risk Eighty percent have a GRADUAL onset No regional differences in the disease are manifest Median duration of the illness is 2-7 years Only 16% of the cases uncovered in the survey are diagnosed Unemployed or cases on disablity total 25% Level of disability equals that of patients with major health problems such as COPD The cost in lost productivity ($9 billion) is equal to WalMart’s annual profit margin, or the cost of the hurricane in Miami in 2004. The cost to a family with CFS for one year is $20,000. This includes the cost of treatment. In the UK it is costing the government $4 billion to treat CFS patients.
The CDC is working to develop a network system to create more clinical studies of CFS. The next epidemiological study will be in the Atlanta, Georgia area, and will include both urban and rural counties. The location in the CDC area will enable them to do the complex studies efficiently.
"Let me come clean here. I hate tender points," spoke Dr. Daniel J. Clauw, MD in his overview of fibromyalgia. His point was that in FMS pain is everywhere, and there are many other symptoms in addition to pain. The level of pain seems to be related to the level of stress, but stress is not the cause. Patients’ brains have become more sensitive to signals of all sorts, sensory, affective, and cognitive. Using functional MRIs, pain levels have been studied indicating that areas of the FMS patient’s brain activate at levels far lower than normal healthy individuals. This means that FMS patients are indeed feeling more pain than normal individuals.
These constant levels of pain and stress tend to reveal three groups of patients. One group has low pain and is emotionally stable. One group has high pain and is out of emotional control. The third group is experiencing a high level of pain but is able to remain stable.
Cerebrospinal fluid of FMS patients has high levels of corticotropin releasing hormone (CRH) even after controlling for melancholic depression. Increasing serotonin and norepinephrine levels reduces pain signaling, thus using antidepressants that raise both levels may be useful. Examples of this type of combination drug would be milnacipram and imipramine.
The following microbiology/immunology papers indicated possible infection and immune disregulation in CFS:
Robert Suhadolnik, Ph.D. reviewed the evidence and effect of upregulated 2-5A synthetase RNase L antiviral defense pathway. There is a 500 fold excess of bioactive 2-5A. This was determined in a study of 53 CFS patients and 37 controls. The higher the RNase L activity, the lower the patient’s ability to function. These patients also have a low molecular weight 37 kDa RNase L which is not found in healthy controls, patients with only depression, or fibromyalgia patients. What are the effects of elevated RNase L activity and low molecular weight RNase L? The patient has lowered signal transduction, lowered cell proliferation, lowered ATP production, lowered cellular metabolism, lowered protein synthesis, impaired natural killer cell function, abnormal exercise response, loss of potassium from muscle, abnormal sodium retention, hyperventilation, central fatigue, sleep disturbances, and muscle cramps and weakness. This probably sounds familiar to many patients.
Charles L. Raison, MD from the CDC presented information on the fatiguing effects of interferon alpha on hepatitis C patients. IFN alpha is released by the body early in a viral infection. It causes fatigue and activation of inflammatory TNF alpha, IL 1 and IL 6. When 154 hepatitis C patients were given IFN alpha (ribavirin) for 24 weeks they developed a CFS-like syndrome. On ribavirin 45% of them looked exactly like CFS patients. It was difficult to predict which patients would develop these symptoms, but it became apparent that the ones with the highest fatigue score were the ones unable to clear the virus. Either these patients were not able to clear the virus or they had an increased pro-inflammatory response to IFN gamma. These data suggest a role for viruses and/or antiviral immune responses in fatiguing illnesses including CFS.
James F. Jones, MD presented a study of prolonged fatigue following acute infection with mononulceosis, Ross River Virus, and Q fever in Dubbo, Australia. A post infection syndrome occurred in 10% of these patients and was predicted by the severity of the acute infection.
Konstance Knox, PhD, presented evidence that CFS patients have reduced signal transducers and activators of transcription, specifically STAT1. This would seem to follow Suhadolnik’s study showing lowered signal transduction due to the cleaved low molecular weight RNase L. The conclusion drawn by Knox and Carrigan was "a subpopulation of CFS patients may exist who suffer from an abnormally low STAT1 response to interferons. This immunodeficiencty may underlie the increased susceptibility to infections seen in many CFS patients." [However, if one looks at the RNase L research it is just as likely that the STAT1 deficiency is caused by infections, especially when one considers that some CFS patients never seem to get other infections such as colds or flu.] (Ed. - Information uncovered by the NCF in a patent application suggests STAT I degradation occurs prior to RNase L fragmentation.)
Kevin J. Maher, PhD, from the University of Miami, presented evidence that "key proteins associated with the cytolytic process are present at lower cellular concentrations in NK cells from individuals with CFS."
Delia Racciatti, MD, PhD summarized a study in Italy of 130 cfs patients. In 66 of the total patients 37.9% had chlamydia trachomatis, 50% had ureaplasma urealyticum, and 12.1% mycoplasma species. The same urogenital infections were detected in 6 sexual partners of the patients. There was often a lack of serological evidence due to a low immune system response. When patients were treated with antibiotics 22 of the 66 patients who were infected had a recovery from "fatigue." "The authors recommended that the diagnostic protocol for rheumatologic diseases and CFS should include investigations for infectious agents of sexually transmitted diseases."
Marc Fremont, PhD, from RED Laboratories, Belgium, reported that patients show a genetic susceptibility to immune dysfunction. He commented that Dr.Vojdani is finding the same RNase L dysfunction as Suhadolnik. Some patients have a reduced capacity to mount a normal immune and inflammatory response, while other patients have an increased PKR expression and activation leading to induction of nitric oxide (NO) which furthers the inflammatory response. Symptoms of this would include neuronal reactivity, muscle function, and abnormal vasodilatory response. The thyroid is producing thyroid hormones, but these hormones are not able to interact with cells. PKR is activated by certain infections and chemicals. They are finding mycoplasma infection is high in patients with RNase L dysfunction at 69.4%.
Jo Nijs, PhD, presented a study from Belgium in which 16 CFS patients preformed a bicycle exercise stress test. The level of elastase was the only factor related to the reduction in oxygen uptake, the protein kinase R activity was the principle factor related to the reduction in workload, and the elastase level was the principle factor related to the reduction in % of target heart rate achieved. This is evidence for an association between intracellular immune deregulation and impairments on cardiorespiratory fitness in CFS patients. This study indicates subtle underlying lung damage. Further study is needed. A question was asked following this presentation: How does one reduce elastase? The reply was, "Antibiotics.
Epidemiology is the sphere of the Centers for Disease Control. Dieter Wagner, PhD presented data on the relationship between the Multidimensional Fatigue Inventory (MFI) and the Short-Form 36 (SF36) scales in CFS patients. Both the MFI and the SF36 correlate with fatigue levels in CFS patients.
Ashley Morris, a professor in computer science, has devised a computer list of 26 survey questions to accurately diagnose CFS.
Hemex research on hypercoagulability due to genetic factors was presented by Harold Harrison, MD, PhD. The study compared the ISAC panel of tests for low-level activation of coagulation with the Hereditary Thrombotic Risk Panel data. These data support the general hypothesis of concerted genetic contribution(s) of coagulation protein abnormalities to CFS/FMS and are consistent with family histories.
The next study presented by Rosemary Underhill, MB, presented a pilot study of the role of heredity and environment in CFS. A study involving 219 CFS patients revealed that 20.5% of the patients had family members with CFS. About twice as many were blood relatives. Secondary cases of CFS occurring in the genetically unrelated household members of CFS patients indicates that an infectious agent which can cause CFS may persist in at least some CFS patients and can be shed into the environment. The increased prevalence of CFS in non-household genetic relatives indicates that genetic factors may also be involved in a subgroup of patients.
The neurophysiology of CFS is characterized by chronic orthostatic intolerance. Julian M. Steward, MD, PhD, presented evidence of three variants of POTS in CFS patients. In all three there was enhanced thoracic hypovolemia related to inadequate cardiac venous return during orthostasis. One group had a higher than normal resting heart rate, one had lower blood volume, and one had a high blood flow. This typically follows a viral infection.
A study from Japan presented by Hirohiko Kuratsune, MD, D. Med. Sci. revealed that CFS patients had cerebral hypoperfusion in a variety of brain regions. These results suggested that CNS dysfunction might be related to the neuropsychiatric symtoms found in CFS. This cannot be explained by a psychiatric diagnosis."
The cerebral blood flow (CBF) of healthy sedentary controls was compared to CBF of CFS patients in a study done in Japan and presented by Kazuhiro Yoshiuchi, MD, PhD. Blood flow was shown to be reduced in the temporal regions and the right inferior frontal cortex. Psychiatric status and illness severity did not play a role in this reduced blood flow.
Five physiology studies were presented. The first, presented by Susan Levine, MD, was an analysis of metabolic features of CFS. There was a detection of elevated lactate production in 20% of the patients studied. It is thought that some of the symptoms observed among these patients are caused by an accumulation of the potent oxidant, peroxynitrite which produces both nitric oxide and superoxide.
Ulf Hannestad, MSc, described a small study that demonstrated that CFS patients secreted a significantly increased amount of beta-alanine in the urine. Other reports suggest that there is an active transport of beta-alanine and GABA from CNS over the blood-brain barrier. This means that it could be possible that an excretion of abnormal amounts of beta-alanine or GABA in the urine reflects abnormally high concentrations of GABA in CNS. Many symptoms of CFS are seen in patients being treated with antiepileptic drugs. These symptoms increase GABA activity in CNS giving side effects like fatigue, headache, impaired concentration, and muscle weakness.
In an ongoing study presented by Barry Hurwitz, PhD, it was determined that CFS patients have low red blood cell volume. This was more common in women (77%) than men (33%). These patients will be treated with Epoetin Alpha.
An in vitro study from Belgium, presented by Marc Fremont, PhD, showed that cells with the low molecular weight forms of RNase L demonstrate a much higher sensitivity to mercury exposure. This causes an initial membrane depolarization followed by cell death. Alteration of MRP-1 activity by interactions with the ankyrin fragment of RNase L could be a mechanism explaining the high sensitivity of patients to different chemicals, including heavy metals. MRP-1 is also involved in the maintenance of the Th1/Th2 balance.
Martin L. Pall, PhD presented a hypothesis for the disease state found in CFS, MCS and FM. All are reported to produce increases in nitric oxide. The consequent elevation of nitric oxide and it oxidant product, peroxynitrite, is proposed to initiate a biochemical/physiological vicious cycle mechanism that is responsible for the chronic nature of these illnesses. The basic mechanism is local, because mechanisms act at the level of the individual cell and because nitric oxide, superoxide and peroxynitrite have limited diffusion in tissues. This provides an explanation for the symptom variation from one case to another. The variation is largely due to variation in tissue distribution from one case to another.
Angela Lyden, MS, began the Clinical Program presentations with a study on 27 FMS patients. Their response to pain, thumbnail pressure and thermal pain was compared to controls. The FMS patients experienced 11 times more pain than controls. The two groups also were evaluated for perceived exertion on exercise bikes. The FMS patients had an increased sense of work level compared to controls. Patient response to pain and exertion correlated well.
A Spanish study on CFS and aerobic exercise, presented by Anna Garcia-Quintana, MD, demonstrated that CFS patients compared to sedentary, healthy controls are 24% lower functioning than the sedentary group. The physically active group of controls reached maximal heart rate values similar to those of the sedentary individuals, while the CFS patients reached much lower values. The average maximal oxygen uptake of the CFS patients on a cycle-ergometer was only 15.2, whereas the sedentary but healthy controls were 25.9, and the physically active controls were 66.6.
A second study from the same clinic in Barcelona, presented by Jose Alegre-Martin, PhD, evaluated 350 subjects for CFS definitional symptoms. Some of these results were startling and fit in with the CDC information from Kansas. Patients were predominantly women 85% and the mean age was 40 Predominant symptoms were weakness, muscle pain, malaise >24 hrs, unrefreshing sleep, joint pain, new, headache, impaired memory concentration Onset was gradual in 50% of patients Only 10% of patients improved, worsening was seen in 53% Only 33% of patients were able to work
Do support groups help CFS patients? This was a study presented by Fred Friedberg, PhD. The conclusion was that support groups helped patients to legitimatize their illness, but were not used to locate physicians.
Jo Nijs, PhD, presented information on how to evaluate a CFS patient for disability. His conclusion was that the associations between either exercise capacity parameters, or self-reported disability (i.e. the CFS-APQ total scores or the SF-36 subscale scores), and the current employment status are too weak to predict occupational disability.
Ampligen is the only drug currently being developed especially for CFS. David R. Strayer, MD presented a study of 40 weeks of Ampligen treatment in 234 severely ill CFS patients. Results showed a medically and statistically significant increase in the primary endpoint, exercise treadmill duration, (two-fold improvement) compared to placebo. There were no adverse events related to Ampligen. Hemispherx Biopharma will be applying for FDA drug approval in the near future. No date was given.
Leonard Jason, PhD discussed the case definitions of CFS and ME. His comments can be viewed at http://condor.depaul.edu/~ljason/cfs. In conclusion Jason said that we need an empirically derived case definition. It must be objective and based on standardized interviews.
Further information on defining CFS fatigue was presented by James Jones, MD, CDC. Jones covered the causes of fatigue in fatiguing illness. He questioned whether "memory of fatigue/illness alters behavior?" He compared this to PTSD in which flashbacks or memories of an old trauma create the same symptoms of anxiety and fear in a person. He wondered if the immune system might be doing this in CFS. He also questioned CFS patient surveys asking, "What is the patient remembering?" [This was an overview of articles and not a new study. I found it difficult to grasp the significance of this other than to comment that it is difficult for patients to objectively define their fatigue to themselves. Was the point that we may have permanent damage to our memory of fatigue, so that just thinking about how fatigued we were makes us feel tired right now? I may have missed the point.]
Kenny DeMeirleir, MD, PhD, presented "Diagnosis and Management of CFS As an Immuno Vigilance Disorder." CFS is a host response to initiating multiple factors. Evidence based medicine does not apply to the heterogeneous nature of CFS. Infection and innate immune defects activate the OAS and PKR pathways. DeMeirleir mentioned finding endogenous retroviruses as DeFrietas and Urnovitz have found in the past. He compared PKR in MS (down) and CFS (up). DeMeirleir mentioned that the digestive tract is altered by the disease. Bacterial gut infections need to be treated with antibiotics and probiotics.
He also mentioned that resistance to the thyroid horomone causes hypothyroidism not detectable in the usual tests, severe fatigue and weight gain. He suggested that heavy metals such as mercury may need to be chelated. His list of therapies include the following: decrease microorganisms, restore intestinal flora, balance hormones, decrease PKR activity, treat metal allergy.
Autonomic dysfunction was reviewed by Dr. Charles Lapp, MD. He stated that a TILT test should be done with no medication, including no vitamins for 24 hours. The person should not be anemic, have diabetes, dehydration as these would cause fainting apart from autonomic dysfunction and invalidate the results. The room should be warm, dark and quiet with no talking. Lapp prefers a passive test without the use of drugs. Heart and blood pressure should be continuously monitored. Most patients will faint within 30 minutes if they have autonomic dysfunction. Treatments consist of extra salt and water, fludrocortisone, Midodrine, or Atenolol. SSRIs may be helpful as may IV erythropoetin.
Dr. David Bell, MD, presented a case study of a 24 year old with acute onset of polyuria and polydipsia, "a compulsive water drinking diagnosis." This patient’s plasma blood volume was normal but the red blood cell mass was 60-70% below normal. Patients having their blood volume measured may appear to be normal if they have been drinking a lot of water. Also IV saline may have a placebo effect in which the blood volume is increased but the red blood cell mass is still abnormally low.
This information led to Dr. Barry Hurwitz’ presentation on an ongoing study of patients taking Erythropoetin to stimulate development of red blood cells. These patients were also given iron and salt tablets as this is needed in order for the Erythropoetin to work. It is of note that a greater sed rate and lower red blood cell volume is an indication of chronic inflammatory conditions. This study has one more year to go.
In the Doctor to Doctor session Nancy Klimas, MD presented the CDC hope to develop a network for CFS research among clinical doctors. For example doctors such as Teitelbaum and Lapp claim an 80% success rate. Several say that 80% of their patients improve, but we must do testing and evaluation to determine which treatments are working. Some expressed concern that a network might further limit individual researchers from getting government funding.
This was followed by a question and answer time with a panel. Here are several comments of note:
Adult ADD and FMS seem to have similarities. CNS stimulants such as Provigil may give some improvement. (Lapp is seeing 60% improvement. DeMeirleir stated that CFS moms have more children with ADD and autism. He suggested that this may be caused by strep infections and can be treated with penicillin. He said that amphetamines seem to work because penicillin interacts with the same brain receptors when used to treat strep. Natelson spoke up to say that the Provigil trial was negative. Bateman said that in her practice some responded to Provigil, but she prefers Aderol. If the patient had an onset of a flu-like illness it does not work.
Klimas mentioned the need for hrt in menopausal women, and another doctor discussed using GHB to treat sleep disorder.
Natelson discussed giving a complete neuro exam, in particular a tandem Rombert balance with eyes closed. He commented that peripheral neuropathy can be diagnosed by touching the patient’s toe with piece of cotton. The patient will be unable to feel it.
Teitelbaum mentioned that low testosterone can lead to low red blood cell mass.
Lapp said that exercise tolerance testing measuring VO2 max is the best way to measure physical ability to do work, and is also a good follow-up to measure improvement. The Ampligen studies indicated that the VO2 max will drop before FX36.
Erhlich commented that she is seeing an interaction of strep and Lyme toxins in her Madison, WS patients.
Opiods seem to give some patients a wonderful response. This may be explained because the inflammatory cytokines cross the blood/brain barrier. When the opiods block the opiod channel the cytokines cannot get in. Brigita Evengard, MD from Sweden spoke up that Swedish patients are not keen on the meds. They prefer therapy instead. She also commented that borreliosis is endemic in Sweden, and it is seronegative. Pat Fennell stated that this is also a huge problem in upstate New York. This led to some discussion of possible CFS subtypes.
Klimas pointed out that we may have no clue how to group subtypes since the immune system tends to shift over time in the course of the disease. Also it is not even clear what rapid onset and slow onset really mean. Natelson seemed to think that illness severity is the key to grouping. Rich VanKonynenberg stated that we do not have a well-posed problem yet. We must look at all the input before we attempt to subgroup patients.
The discussion of subgrouping in terms of Lyme was continued in the next presentation.
"Are CFS and Chronic Lyme One and the Same?" asked Dr. Stanley N. Schwartz, MD, director of The Warren Clinic in Tulsa, Oklahoma and current vice-president of the AACFS. Schwartz hastened to state that Oklahoma did not have many cases of Lyme, but he had been asked to overview the existing literature to see how likely there was to be an overlap of Lyme and cfs. In reviewing the literature Schwartz set four limiting guidelines. Only randomized controlled trials Only observational studies Only expert published opinion Only available in Medline
He added the caveat, "The plural of anecdote is not data." – Kotsonis
"Experience without measurement is not data." – Schwartz
[This did not bode well for my later comment that three of us in my family were now positive for borrelia in a state, South Carolina, where supposedly Lyme is not prevalent. I was to be both anecdotal and from a state not considered a Lyme state. One of the CDC doctors told the conference that Lyme in the southeast is a different strain of borrelia and is a mild disease lasting only three weeks. I did make the point that my particular southeastern version of borrelia was a severe illness that had already lasted at least years.]
Schwartz drew a distinction between late Lyme and chronic Lyme. This distinction was that late Lyme had objective signs and serologic confirmation. Chronic Lyme only had serologic confirmation in some cases and no reliable objective signs. His comments on which serology was reliable are as follows:
Reliable: ELISA, western blot, skin culture, synovial fluid PCR
Unreliable: urinary antigen assay, borreliacidal antibody, VisE, PCR, immune complex disruption, t-cell proliferative response to borrelia antigens. If the patient had a classic Lyme rash that would be helpful, but one would still be diagnosed with CFS if there was no positive serology.
Schwartz presented four studies. The first, Klempner (N Engl J Med, 2001, Jul 12;345(2):85-92) http://content.nejm.org/cgi/content/abstract/345/2/85 may indicate that 3 month treatment with antibiotics will not cure Lyme disease, but it does not indicate whether there is such a thing as late Lyme or chronic Lyme. Without a clear transition his presentation moved from considering if there were such a thing as ongoing chronic borrelia infection to whether long term antibiotics would treat whatever these patients actually had. The conclusion of the presentation was "Basically an unresolved issue" It was not clear which issue or both were unresolved. A study from Germany by D. Hassler showed that patients did recover with longterm antibiotics, but one of Schwartz’s conclusions was that European borreliosis may be different from US borreliosis.
The final day of presentations involved three speakers on the use of therapy to help patients deal with their illness. The most encouraging presentation was by Elke Van Hoof, PhD, Clinical Psychologist working with Dr. DeMeirLeir in Belgium. She takes patients through four steps: 1. Defining the crisis of their illness 2. Stabilization 3. Meaning and restructuring 4 Integration and rehabilitation including graded exercise. She explains what is going on with their illness and always includes the patient’s partner or a friend. She makes sure in follow-up that the patient is following the treatment. The partner is critical to implementing and following treatment. She uses EMDR to treat the patient’s sense of victimization. Her final statement was a joy. Because she works with Dr. DeMeirleir and his patients are recovering she stated, "I don’t have to worry about patients who do not improve."
There were a large number of poster presentations. I will briefly mention only those which suggest treatment options for CFS.
Roundworm structures of c. pulmoni have been found in CFS patients. These roundworms are endemic to Southeast Asia and in the post Vietnam era with increased world travel these roundworms may have spread to other parts of the world. Patients who wish to get tested for this can contact Lawrence Klapow, PhD, Bioscience, 2841 Creekside Rd. Santa Rosa, CA 95405, 707-546-4101 klapow123@...
Dr. Berg of Hemex presented further research on blood coagulation problems in CFS. This coagulation problem can be caused by various infections and/or genetic predisposition. Treatment involves low dose heparin. For further information contact http://ww.hemex.com
Richard Van Konynenburg, PhD presented a study which indicates glutathione levels are depleted in CFS. It is possible to increase glutathione levels using IV glutathione, sublingual glutathione, and by taking undenatured whey protein.
Dr. Ritchie Shoemaker, MD runs the Chronic Fatigue Center in Maryland. He is testing and treating patients for chronic neurotoxins. Information on his treatment can be found at http://www.chronicneurotoxins.com
T. Wijlhuizen has done studies on B 12 deficiency in CFS. He has developed a sublingual B 12 which delivers the same amount of B 12 as injections. He can be contacted at http://www.vaakmoe.nl
Trevor Marshall, PhD, developed a treatment protocol for sarcoidosis patients. His research indicates that sarcoidosis and CFS are caused by intracellular pathogens such as borrelia and mycoplasmas among others. These pathogens increase the secosteroid hormone 1,25 D levels in the body in order to avoid detection by the immune system. By using an angiotensin-II blockade and temporarily avoiding vitamin D sources one can lower the D hormone level. Then a low dose, pulsed, appropriate antibiotic is added to aid the immune system in killing the pathogens. For more information visit http://www.marshallprotocol.comTrevor.m@...
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[Lyme borreliosis: how is it manifested in Spain?]
[Article in Spanish]
Guerrero A, Quereda C, Marti-Belda P, Escudero R.
Seccion de Enfermedades Infecciosas, Hospital Ramon y Cajal, Universidad de Alcala de Henares, Madrid.
BACKGROUND: Lyme borreliosis is not usually diagnosed in Spanish patients since before 1987. The aim of this study was to know the clinical spectrum of infection by Borrelia burgdorferi in Spain by a prospective epidemiologic study. METHODS: The period of collection of cases was from 1987 to 1989 and the follow-up period was of 2 years following diagnosis. Detection of serum antibodies was performed by indirect immunofluorescence and ELISA to patients with clinical suspicion of Lyme borreliosis established in 17 Spanish hospitals. The clinical and serologic data and the possibility of other disease which could justify the symptoms were evaluated with the doctor responsible for the patient. RESULTS: Fifty-four patients with clinical manifestations and serologic data indicative of the disease and in whom other diagnosis were excluded were detected. Other diseases which could be the cause of the symptomatology were diagnosed in 26 patients with positive serology. Sixty-three percent of the patients had neurologic symptoms, 46% articular symptoms, 44% cutaneous symptoms and 9% cardiac symptoms. CONCLUSIONS: Lyme borreliosis is not exceptional in Spain. Its clinical spectrum may be situated half way between American and European epidemiologic descriptions. Serology must be interpreted by the clinical manifestations.
The Lyme Disease Network Medical / Scientific Abstract
Title: First isolation of Borrelia burgdorferi from an iris biopsy. Authors: Preac-Mursic V, Pfister HW, Spiegel H, Burk R, Wilske B, Reinhardt S, Bohmer R Source: J Clin Neuroophthalmol 1993 Sep;13(3):155-61; discussion 162 Organization: Max v. Pettenkofer Institut fur Hygiene u. Medizinische Mikrobiologie, LM-Universitat Munchen, Germany.
Abstract: The persistence of Borrelia burgdorferi in six patients is described. Borrelia burgdorferi has been cultivated from iris biopsy, skin biopsy, and cerebrospinal fluid also after antibiotic therapy for Lyme borreliosis. Lyme Serology: IgG antibodies to B. burgdorferi were positive, IgM negative in four patients; in two patients both IgM and IgG were negative. Antibiotic therapy may abrogate the antibody response to the infection as shown by our results. Patients may have subclinical or clinical disease without diagnostic antibody titers. Persistence of B. burgdorferi cannot be excluded when the serum is negative for antibodies against it.
Rapid subtyping of Borrelia burgdorferi sensu lato species in specimens from patients with different manifestations of Lyme borreliosos
Kooperation:
Leo Schouls (National Institute of Public Health and the Environment, Bilhoven)
Elisabeth Aberer (Dermatologie, Universitätsklinik Graz)
Since the cousative agent of Lyme disease was discovered in 1982 and subsequently described as a unique species, molecular studies have led to the description of different genomic groups constituting a complex named Borrelia burgdorferi sensu lato. Of the 10 different genospecies of B. burgdorferi which have been characterized to date, only B. burgdorferi sensu stricto, B. garinii , and B. afzelii have been identified as being pathogenic in humans. Based on serological data and PCR-based typing analyses, there is growing evidence that these species possess different organotropisms and may preferentially cause distinct clinical manifestations of Lyme borreliosis. Therefore, the identification of the causative species in patients with Lyme borreliosis appears to be of epidemiological, pathogenetic, and diagnostic importance.
Recently, Rijpkema et al. described the genotyping of B. burgdorferi strains in Dutch Ixodes ricinus ticks by amplifying the intergenic spacer region between 23S rRNA (rrlA and rrlB) and 5S rRNA (rrfA and rrfB) genes and subsequent characterization of amplicons by hybridization to multiple species-specific oligonucleotide probes immobilized on a membrane. This reverse line blotting (RLB) allows the simultaneous identification of gene polymorphisms at a PCR-amplified DNA locus within a single procedure.
Our study aimed at employing this hybridization assay for the rapid and easy genotyping of B. burgdoferi species in European patients with Lyme disease. Six reference strains of different B. burgdorferi sensu lato species and B. hermsii as specificity control were examined. A total of 27 patients with different clinical manifestations of Lyme borreliosis were investigated. In all of these patients B. burgdorferi DNA could be detected by PCR. RLB was done according to the protocol described by Rijpkema et al. For the characterization of PCR products, one probe which reacted with all genomic groups and three sequence-specific oligonucleotides for the distinct detection of B. burgdorferi sensu stricto, B. garinii , and B. afzelii were used (figure 1).
The results showed that the reference strains could always be attributed to the anticipated genomic groups by hybridization of rrfA-rrlB spacer PCR products of the ribosomal genes to the respective species-specific oligonucleotides. In 9 of the 12 PCR-positive clinical samples (8 urine samples and 1 synovial fluid sample) from patients suffering from Lyme arthritis, B. burgdorferi sensu stricto could be identified, while in 2 urine samples B. garinii and in 1 urine sample B. afzelii was detected. In contrast, in the 10 PCR-positive samples from patients suffering from neuroborreliosis (9 urine specimens and 1 CSF sample), only B. garinii (10 of 10) could be identified. The 5 PCR-positive skin biopsies from patients with acrodermatitis were shown to contain DNA from B. afzelii exclusively. Double or pluri-infections were not observed. The present study demonstrates that rrfA-rrlB spacer PCR combined with RLB is a reliable and rapid laboratory method for the distinct detection of B. burgdorferi sensu lato species both in bacterial cultures and clinical specimens. This method is a powerful tool for epidemiological studies and to further investigate the association between infections with B. burgdorferi sensu lato species and clinical manifestations of Lyme disease.
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IgG Subclasses in Lyme Borreliosis: A Study of Specific IgG Subclass Distribution in an Interferon-gamma-Predominated Disease
Authors: WIDHE M. 4; EKERFELT C. 4; FORSBERG P. 1; BERGSTROM S. 5; ERNERUDH J. 4
Source: Scandinavian Journal of Immunology, June 1998, vol. 47, no. 6, pp. 575-581(7)
Publisher: Blackwell Publishing < previous article | next article > View Table of Contents
Abstract:
Lyme borreliosis has shown a T helper type 1 (Th1)-like immune response with high production of interferon-gamma. Since the cytokine environment seems to be important in the regulation of immunoglobulin production and in the switch between different isotypes and subclasses, and since the subclasses of IgG have different functions, we wanted to examine the IgG subclass distribution in Lyme borreliosis. We have developed an ELISA measuring flagellin-specific antibodies of the different IgG subclasses in serum and cerebrospinal fluid (CSF). Thirty-five seropositive patients with varying manifestations of Lyme borreliosis were included in the study. According to the results, the predominating subclasses in both serum and CSF were IgG1 and IgG3. In samples taken early in disease this pattern was more pronounced in patients with a subacute disease, defined as recovery within 3 months, compared to patients that later on developed chronic borreliosis. The levels of IgG2 were generally low and IgG4 was below detection level. Thus, in the IFN-gamma-predominated immune response seen in Lyme borreliosis, mainly IgG1 and IgG3 were found, i.e. the subclasses that are complement activating as well as opsonizing in humans. Increased levels of these two subclasses early in disease might contribute to recovery and counteract the development of chronicity. The absence of IgG4 is in accordance with the presumed Th1-like situation of Lyme borreliosis.
Language: English
Document Type: Research article
Affiliations: 1: Department of Health & Environment, Division of Infectious Diseases, Faculty of Health Sciences, University Hospital, Linkoping, Sweden 4: Department of Neuroscience and Locomotion, Clinical Research Centre, Faculty of Health Sciences, University Hospital, Linkoping, Sweden 5: Department of Microbiology, University of Umea, Umea, Sweden *
CRITERIOS PARA EL DIAGNÓSTICO Hay grandes coincidencias entre las características del llamado Síndrome de la Fatiga Crónica (SFC) (publicados en inglés con las siglas CFS) y la fatiga crónica laboral. Tal vez se deba a que son la misma patología con sus múltiples variantes del polimorfismo que caracteriza a ambas. La coin- cidencia sintomática hará que se esté describiendo la misma patología, y tal vez la divergencia esté en discriminar el ori-
en laboral como causa. El diagnóstico no es sencillo, y en principio debe excluir cualquier otra enfermedad concreta que requiera su correspondiente tratamiento específico. Una enfermedad psicológica determinada, y diagnosticada como tal puede excluir que se trate de SFC. Del mismo modo debe descartarse la existencia de cualquier enfermedad orgánica que curse con fatiga entre sus síntomas siendo éstos los más significativos. La revisión del estado de salud debe incluir un hemogra- ma completo, con bioquímica, velocidad de sedimentación globular, y análisis de la hormona estimulante del tiroides. En determinados casos se añade una radiografía de tórax, y/u otras pruebas como la determinación de anticuerpos antinu- cleares, factor reumatoide, anticuerpos frente a la enferme- dad de Lyme, anticuerpos frente a la hepatitis A y B y anti- cuerpos anti VIH. Se plantea la posibilidad de ser diagnosticada como SFC cuando hay una fatiga de larga evolución (crónica), inexpli- cable a pesar del reposo, que persiste o que recidiva, que no mejora con el reposo, que no se debe a un esfuerzo con- creto y que reduce las capacidades de la persona tanto en el ámbito laboral como formativo, o personal y social
Nicolson G: Diagnóstico y tratamiento de las infecciones de células invasoras al micoplasma
Butt H: El desarrollo de los tests de laboratorio para el dolor y la fatiga crónica
Jadin C: Perspectivas clínica y biológica sobre el SFC y enfermedad de Rickettsial
Nix W.A: Transmisión neuromuscular defectuosa en PcSFC.
Resumen:
Los personas con enfermedades tales como SFC/EM, SFM, la Enfermedad del Golfo o la Artritis Reumatoidea, a menudo tienen signos y síntomas comunes. Se ha encontrado que la principal fuente de morbididad es causada por variadas infecciones virales y bacterianas crónicas. Se han encontrado variadas infecciones micoplasmales y se procedió a realizar estudios comparados de SFC y SFM. Se concluyó que habría subgrupos de pacientes del SFC/EM, SFM, enfermedad del Golfo y AR que tienen infecciones micoplasmales y otras infecciones virales y bacterianas crónicas transmisibles, cuyo tratamiento con apropiados antibióticos pueden conducir a una lenta recuperación.
El micoplasma es un agente patógeno que infecta plantas, animales y seres humanos; no es una bacteria ni un virus; no tiene paredes celulares y es caracterizado como un agente infeccioso parecido al virus.
Hay cientos de diferentes tipos de micoplasma y numerosos de ellos aislados sin pertenecer aún a alguna subclase dada. Los micoplasmas tienen una especial interacción con el sistema linforreticular pudiendo comprometer a los linfocitos T, provocando una proliferación a niveles detectables de agentes patógenos que permanecían en estado latente. Los micoplasmas podrían ser parcialmente responsables de algunos de los signos y síntomas que forman parte del cuadro del SFC/EM. Parecen también estar implicados en la activación de las células T observada en estos pacientes.
La enfermedad del Golfo es, en gran grado, debida a las múltiples exposiciones a los diferentes agentes químicos, radiológicos y biológicos que causan enfermedades multifactoriales, las cuales pueden ser transmitidas a los miembros de la familia inmediata e implicar infecciones crónicas. Aunque todavía no hay una definición para la Enfermedad del Golfo, sus signos y síntomas se aproximan en forma a aquellos del SFC y SFM. Los civiles con SFC, SFM o AR muestran a menudo la presencia de infecciones bacterianas (Micoplasma, Rickettsia, Brucella, Borrelia y otros), y estos pacientes pueden ser tratados, en forma similar a los que padecen la enfermedad del Golfo, con antibióticos, antioxidantes y suplementos nutricionales.
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SESION V: El Rnase L en el SFC
Moderadores: B. Lebleu (Francia)
R. Suhadolnik (USA)
Expositores:
Lebleu B. El interferon y la vía activada del 2-5A/Rnase L
Lebleu B 37 Kda 2-5 A, una molécula encadenada como un posible marcado bioquímico para el SFC.
Suhadolnik R.J. Diagnóstico del SFC: determinado por la presencia de una subclase de la enzima Rnase L.
De Meirleir K. Detección de anormalidades en el SFC a través de la vía Rnase L.
Resumen:
El interferon (IFN) fue inicialmente caracterizado como un mecanismo de defensa de amplio alcance contra patógenos y virus particulares. Estudios posteriores han dado evidencias de su compromiso en la regulación inmunológica y en el desarrollo celular. El IFN además de su acción antiviral y antibiótica, induce proteínas y actúa en la proliferación y diferenciación de las células controlando el metabolismo celular. Los interferones son resultado de una familia de multigenes cuyos productos interactúan con receptores específicos de la superficie celular. Los receptores enlazan disparadores intracelulares señalando vías que conducen a la transcripción de la activación de los genes inducidos por el interferon. Los componentes de la vía 2-5 A/Rnase L y su compromiso en el control de la multiplicación de los virus han sido particularmente estudiados.
Una nueva molécula de bajo peso (LMW) 37kDA 2-5 A independiente del Rnase L ha sido recientemente identificada en las extracciones de sangre de los PcSFC/EM a través del PBMC, peripheral blood mononuclear cells. Se procedió a investigar el alcance de la LMW Rnase L como potencial marcador biológico para el SFC/EM.
Ulteriores estudios han revelado anormalidades en la sintetasa (enzima que cataliza la síntesis de una substancia) de la vía antiviral 2-5 A/Rnase L en las células mononucleares periféricas (PBMC) de los pacientes del SFC/EM. Se buscó detectar posibles diferencias en las proteínas encadenadas 2-5 A de las extracciones PBMC de PcSFC/EM, individuos saludables y pacientes de otras enfermedades (depresión y fibromialgia). Se encontró un incremento en el nivel de 2-5 A y un aumento de la actividad Rnase L en PcSFC. Una molécula de bajo peso 37 Kda 2-5A polipéptida fue encontrada en 50 de 57 PcSFC. Por el contrario, cuando podía ser detectada, las cantidades de la proteína 37 Kda fueron muy bajas en los grupos de control.
La presencia de estas proteínas enlazadas 37kDA 2-5 A en extracciones PBMC en PcSFC podrían contribuir en forma objetiva en la distinción de las
PcSFC/EM de las personas saludables, y tendría la posibilidad de llegar a ser un marcador diagnóstico del SFC.
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SESION VI: Diagnóstico
Moderadores: N. McGregor (Australia)
B. Natelson (USA)
Expositores:
Bottero P. Rickettsias y Chlamidozoos en la psicopatología del SFC.
Gaab J. Reactividad del axis hipotalámico- pituitario-adrenal y alteraciones en la sensibilidad glucocorticoide bajo situaciones de estrés psicológico y psicosocial.
Hyde B. La investigación tecnológica del SFC/EM.
Roberts T. El desarrollo de los tests básicos de laboratorio para el SFC: Investigación del daño de la oxidación de los eritrocitos en el SFC.
Moorkens G. Caracterización de la función pituitaria en los PcSFC.
Resumen:
Desde 1981 se realizaron estudios de diagnóstico y tratamiento en 3000 PcSFC y quedó demostrado, por un lado, el rol que bacterias intracelulares, como la Rickettsia y el Chlamidozoo, cumplen en el desarrollo de ciertas condiciones patológicas como el SFC/EM, y por otro lado el consiguiente tratamiento eficiente con antibióticos (macrólidos y/o cíclinos) combinados con medicación vasodilatadora.
La Rickettsia es un género de microorganismos situados entre las bacterias y los virus, con características de ambos. Se conocen diversas especies de Rickettsias patológicas en el hombre, que comparten las siguientes características: son pleomórficas, de forma cocobacilar y fácilmente visibles al microscopio ordinario; se multiplican solamente en animales susceptibles; se encuentran en la naturaleza en diversos artrópodos y producen en el hombre enfermedades febriles agudas acompañadas casi siempre de erupción cutánea. Por su parte el Chlamidozoo es un microorganismo diminuto, generalmente filtrable, que consta de una célula o cuerpo rodeado de una sustancia que lo envuelve a modo de cápsula.
Dado que el axis hipotalámico-pituitario-adrenal (HPA) es responsable de la respuesta adaptativa al estrés, y la mayoría de los pacientes experimentan un empeoramiento de los síntomas después de estar expuestos a situaciones de estrés físico y psicológico, se testeó y se comprobó una fuerte correlación de la reactividad del axis HPA con dos procedimientos que imitan situaciones de estrés de la vida real en PcSFC. Para ello se utilizó el "Trier Social Stress Test" (TSST) que evalúa en forma fidedigna los niveles de producción de cortisona en protocolos estandarizados de tests ergométricos. Para evaluar las consecuencias de la reactivación del HPA, se investigó el rol de la sensibilidad glucocorticoide de las células mononucleares con respecto a la producción de citoquinas pro-inflamatorias bajo situaciones de estrés psicológico y psicosocial.
Se demostró que los PcSFC tienen niveles aumentados de metaemoglobina y de malondialdehyde como marcadores del estrés de oxidación, y un incremento de la media del volumen de eritrocitos comparados con los grupos de control. Los eritrocitos están compuestos principalmente de globulina y hemoglobina, y tienen por misión transportar el oxígeno a la intimidad de los tejidos. La oxidación se produce cuando se combina un elemento o un cuerpo con el oxígeno.
También se mostró que estos pacientes tienen significativas diferencias en los perfiles de parámetros sanguíneos. El estrés de oxidación contribuiría a la patología del SFC. Una evaluación del daño de oxidación, podría conducir a útiles opciones de tratamiento.
La fatiga experimentada en los PcSFC/EM y los grupos de control parece ser similar, pero en la fase de recuperación los PcSFC/EM muestran un restablecimiento más lento que los grupos de control. Así como también, los PcSFC/EM se quejan de una sensación intensa de fatiga durante los estudios, cosa que no se observó en los sujetos sanos. También se evaluó la percepción de la fuerza realizada, que mostró ser diferente para los dos grupos; los PcSFC/EM sienten más dificultad para generar la fuerza, necesitando realizar un esfuerzo para ello, a diferencia de las personas del grupo de control.
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Se estudió el estado oxidativo y el daño muscular en pacientes con SFC/EM. Se concluyó que habría una alteración en las actividades de las enzimas antioxidativas musculoesqueléticas, así como también una alteración en composición de los ácidos grasos y fluidez de las membranas de los músculos en pacientes con SFC/EM. El daño oxidativo muscular podría representar la consecuencia de un deterioro del sistema oxidante/antioxidante, y probablemente esté correlacionado con el aumento de fatigabilidad muscular descripta en el SFC/EM
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Isoprimosine es un medicamento comercializado en Canadá como inmunomodulador y antiviral. Se utiliza desde hace 30 años y no ha presentado ningún efecto adverso. Actúa aliviando los síntomas mas discapacitantes de esta enfermedad. En Canadá fue principalmente utilizado en el tratamiento de niños.
El Ampligen es un inmunomodulador y antiviral, que actúa como un modificador de la respuesta biológica. Los estudios presentados acerca del uso del Ampligen en pacientes con SFC/EM demostraron una alta efectividad, mejorando el rendimiento físico e intelectual, no presentando efectos adversos su administración.
Diagnosis of Lyme Borreliosis by a Whole-Blood Gamma Interferon Assay for Cell-Mediated Immune Responses
LETTER Top Letter References
Serological testing for Lyme borreliosis using conventional enzyme-linked immunosorbent and immunoblot assays is hampered by poor correlation between test results and disease status. The high seroprevalence (around 10 to 20%) of Borrelia burgdorferi-specific antibodies in the general population in areas of high endemicity can confound interpretation of positive serology. Additionally, early Lyme disease patients often do not have a detectable antibody response. The recent introduction of a Lyme vaccine is likely to further complicate serological diagnosis. New approaches towards more reliable detection of Lyme borreliosis are urgently needed, as misdiagnosis remains a cause of controversy with both patients and clinicians.
View larger version (11K): [in this window] [in a new window] FIG. 1. IFN- production in whole blood from Lyme patients and control subjects stimulated with a B. burgdorferi cell sonicate. The cutoff (mean of control samples + 3 standard deviations) is indicated by a dashed line.
In individuals exposed to B. burgdorferi, an early and sustained specific T-cell response develops that often precedes a measurable antibody response (1). T-cell responses in human Lyme disease are characterized by a pronounced bias towards a Th1-type cytokine profile, especially gamma interferon (IFN-) (3, 4). We investigated whether Borrelia-specific T-cell stimulation in whole blood, and subsequent measurement of specific IFN- responses by enzyme immunoassay (EIA), can be used to discriminate between Lyme disease patients and healthy subjects. In this study, 24 volunteers from Connecticut (11 male and 13 female, 7 to 69 years of age [mean, 48.2]) with clinically diagnosed Lyme disease, all of whom had received antibiotic treatment, and 24 healthy volunteers (12 male and 12 female, 23 to 53 years of age [mean, 35.7]) from Australia, where Lyme disease is not endemic, were recruited into the study. Whole-blood aliquots (1 ml) from patients and control subjects were stimulated for 16 h with either 2.5 µg of B. burgdorferi B31 whole-cell sonicate per ml, saline buffer, or mitogen. Plasma samples were then harvested, and IFN- responses were measured by a rapid two-step simultaneous EIA (2). The mean IFN- response for the control subjects plus 3 standard deviations (0.14) was used as the cutoff for the assay. With this criterion, 16 (67%) of 24 Lyme patients treated for Lyme disease had a positive test result, while 23 (96%) of 24 control subjects were negative (P < 0.001 [Mann-Whitney U test]) (Fig. 1). No spontaneous IFN- production was observed in whole blood from any patient or control subject (mean optical densities [OD] for saline buffer alone were 0.039 and 0.038, respectively), while a response to mitogen was detectable at similar levels in both gorups (mean OD, 1.06 in patients and 1.1 in controls.)
The aim of this pilot study was to prove the concept of the whole-blood IFN- assay for diagnosis of B. burgdorferi infection. For an accurate estimation of sensitivity and specificity a larger study is needed, analyzing both infected and uninfected individuals from an area of endemicity, using B. burgdorferi culture as a "gold standard." However, the data from this pilot study supports the concept of using the whole-blood IFN- assay for diagnosis of B. burgdorferi infection. Future studies will analyze Borrelia-specific IFN- responses in patients with early Lyme disease presenting without erythema migrans and in suspected cases of late Lyme disease where antibody titers are below measurable levels. We propose that this rapid means of measuring the cellular immune response to B. burgdorferi can improve the diagnosis of Lyme disease, either alone or as an adjunct to current serological assays.
REFERENCES Top Letter References
1. Dattwyler, R. J., D. J. Volkman, B. J. Luft, J. J. Halperin, J. Thomas, and G. M. Golightly. 1988. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. N. Engl. J. Med. 319:1441-1446[Abstract]. 2. Desem, N., and S. L. Jones. 1998. Development of a human gamma interferon enzyme immunoassay and comparison with tuberculin skin testing for detection of Mycobacterium tuberculosis infection. Clin. Diagn. Lab. Immunol. 5:531-536[Abstract/Free Full Text]. 3. Forsberg, P., J. Ernerudh, C. Ekerfelt, M. Roberg, M. Vrethem, and S. Bergstrom. 1995. The outer surface proteins of Lyme disease Borrelia spirochetes stimulate T cells to secrete interferon-gamma (IFN-); diagnostic and pathogenic implications. Clin. Exp. Immunol. 101:453-460[Medline]. 4. Pohl-Koppe, A., K. E. Balashov, A. C. Steere, E. L. Logigian, and D. A. Hafler. 1998. Identification of a T cell subset capable of both IFN- and IL-10 secretion in patients with chronic Borrelia burgdorferi infection. J. Immunol. 160:1804-1810[Abstract/Free Full Text]. Vijay K. Sikand Tufts University School of Medicine East Lyme, Connecticut 06333
James S. Rothel Roland M. Martin CSL Biosciences Parkville, Victoria 3052 Australia
Reproduced with permission from Elsevier (The Lancet Infectious
Diseases, 2004, Vol 4, pp 603-604)
http://www.lancet.com/
Lyme borreliosis: perspective of a scientist-patient
Ron Hamlen
In their review of Lyme borreliosis, Ulrich Hengge and colleagues[1]
declare, "Extensive and often inaccurate publicity about the risk and
outcomes of Lyme borreliosis has produced considerable anxiety about
the
disease. One result of this reaction is the inappropriate use of
serological testing for Lyme borreliosis to identify the cause of
widely
prevalent, non-specific symptoms, such as pain and fatigue. This
practice, in turn, has led to a virtual epidemic of over-diagnosis
and
over-treatment of patients with Lyme borreliosis". This is one side
of
the intense debate over Lyme borreliosis. There is a division among
physicians; because of their fiercely held positions, communication
among adversaries has not been productive, and issues of diagnosis
and
treatment remain unresolved. [2 and 3] This deplorable situation has
damaged the quality of patient care and makes Lyme borreliosis a
public-health threat. As a Lyme borreliosis patient who has worked in
biological science in academia and industry for over 30 years, I am
compelled to address the conflict between physicians, insurance
companies, and government agencies, as well as the confusion over
patient management.
According to the US Centers for Disease Control and Prevention (CDC),
Lyme borreliosis is the fastest growing zoonotic disease; from 2001-
2002
there was a 40% increase in cases surveyed, to 23763 cases.[4] The
CDC
acknowledges under-reporting. Reliable estimates are at least ten
times
those reported, or about 250000 new cases per year [4]-more than five
times the annual number of new AIDS cases in the USA. [5] According
to
these statistics, there are more than 2 million people with chronic
Lyme
borreliosis in the USA.
Lyme borreliosis is a multisystem, protean infection from multiple
strains[6] and morphological forms [7] of Borrelia burgdorferi. Even
when treated with antibiotics, this spirochete can cause persistent
infection and lead to debilitating chronic illness in some people.[2
and
8] Symptoms during infection vary among patients and can include
erythema migrans, flu-like illness (fever and chills),
rheumatological
(musculoskeletal pain), neurological (headache, fatigue, vertigo,
confusion, and impairments of cognition, sleep, hearing, memory, and
vision), and cardiac manifestations, and psychiatric illness. [2 and
9]
Given the incidence of Lyme borreliosis in the USA, it is perplexing
that people living in endemic areas are ill for months or years
before
they are diagnosed and treated. In the literature, this problem is
attributed to non-specific and fluctuating symptoms, re-infection,
relapse, latent and asymptomatic infection, and the inadequacy of
serological tests.[1, 2, 3, 9 and 10] However, the best explanation
is
the confusion generated by the medical and sociopolitical controversy
over the incidence and seriousness of Lyme borreliosis and the
existence
of persistent infection. [1, 2, 3, 9 and 11]
Physician diagnosis of early B burgdorferi infections is made from
assessment of clinical symptoms. After testing for co-occurring
infections-such as babesia, ehrlichia, bartonella, and anaplasma[2
and
3]-aggressive antimicrobial treatments are prescribed at therapeutic
dosages and duration. [2] Because society is mobile, physicians in
areas
that are non-endemic for Lyme borreliosis can encounter patients with
early to chronic Lyme borreliosis. Misdiagnosis or ineffective
treatment
of early Lyme borreliosis can result in neurological illness and
lead to
expensive, long-term, intravenous antibiotic therapy-a cost that is
difficult for patients and insurance companies to support.
Although there is not a commonly agreed to effective treatment for
Lyme
borreliosis,[2] the widely held medical and political view
(illustrated
in the Hengge review) is that it is a minor illness, easily treated,
and
reliably cured with 14-21 days of oral antibiotic therapy, [1 and 11]
even though there is no objective test to confirm cure. [2] This
conservative position argues that most Lyme borreliosis cases meet
the
CDC restrictive surveillance criteria: [12] erythema migrans,
positive
ELISA, and IgM/IgG western blot results. [1 and 11] However, when
erythema migrans is absent, [3 and 13] serology is negative, [1, 2
and
14] or acute, non-specific symptoms are inconsistent with the
physician's understanding of Lyme borreliosis, the diagnosis may be
overlooked in up to 90% of cases. [2] When diagnosis is delayed and
serology remains negative, physicians tend to dismiss B burgdorferi
infection. The probability of a false-negative result[2 and 14] is
rarely considered even though the CDC warn that surveillance criteria
alone should not determine diagnosis and treatment. [4] Furthermore,
physicians rarely seek the assistance of laboratories and
practitioners
who specialise in tick-borne infections and use western blots with
multiple B burgdorferi strains (assessing dissimilarity in reactivity
patterns that are dependent on the strain used as the antigen
source),[14] PCR [2 and 9] and CD57 [15] assays, or functional brain
imaging (such as single photon emission computed tomography). [16]
In the absence of objective evidence it is not unusual for physicians
who are confronted with fluctuating and non-specific symptoms to tell
their patients: "You don't have Lyme disease, but I don't know what's
wrong with you". If a short-course of empirical antimicrobial
therapy is
prescribed, it is reasonable to ask how many patients remained ill,
did
not return to that physician, but did seek help from a practitioner
experienced with tick-borne infections. The literature discusses the
harmful effects and expense of over-prescribing antibiotics; however,
the discussion rarely encompasses the long-term individual and
societal
consequences of untreated Lyme borreliosis.
Hengge and colleagues state: "Since Lyme borreliosis is a popular
explanation for many poorly understood symptoms, such as arthralgias
or
chronic fatigue syndrome, proper instruction to physicians is key to
prevent misdiagnosis or overdiagnosis". Conversely, the fact that
symptoms of persistent B burgdorferi infection overlap those of
chronic
fatigue syndrome, fibromyalgia, multiple sclerosis, and motor neuron
disease contributes to the misdiagnosis and inadequate treatment of
this
spirochetal illness.[2, 17, 18 and 19]
As numerous specialists are consulted, the patient may feel unheard
and
trivialised, and become overwrought in dealing with multiple
diagnoses,
each aligned with a physician's specialty yet not contributing to
improved health. The suggestion that unresolved emotional issues are
causing the patient's symptoms can be overwhelming for the patient
and
lead to questions of factitious or psychoneurotic illness. Cognitive
impairment[2, 9 and 20] and chronic pain from neuropathy can activate
depressive illness. [2 and 9] Neuropsychiatric manifestations of Lyme
borreliosis in school-age children are often misdiagnosed as
learning,
behavioural, or attention deficit disorders. [9 and 20]
Lyme disease is a complex and extremely serious illness that affects
patients and the entire medical community. I hope my comments will
broaden the perspective on Lyme borreliosis presented in Hengge and
colleagues' review.
References
1. UR Hengge, A Tannapfel, SK Tyring, R Erbel, G Arendt and T.
Ruzicka,
Lyme borreliosis. Lancet Infect Dis 3 (2003), pp. 489-500.
SummaryPlus |
Full Text + Links | PDF (3939 K)
2. ILADS Working Group. Evidence-based guidelines for the management
of
Lyme disease. Expert Rev Anti-infect Ther 2004; 2 (suppl 1): 1-13.
3. RB Stricker and A. Lautin, The Lyme wars: time to listen. Expert
Opin
Investig Drugs 12 (2003), pp. 1609-1614. Abstract-MEDLINE | Full
Textvia CrossRef
4. CDC, Lyme disease-United States, 2001-02. MMWR Morb Mortal Wkly
Rep
53 (2004), pp. 365-369.
5. CDC, Notice to readers: final 2002 reports of notifiable diseases.
MMWR Morb Mortal Wkly Rep 52 (2003), pp. 741-750.
6. DA Mathiesen, JH Oliver, Jr, CP Kolbert et al., Genetic
heterogeneity
of Borrelia burgdorferi in the United States. J Infect Dis 175
(1997),
pp. 98-107. Abstract-MEDLINE
7. I Gruntar, T Malovrh, R Murgia and M. Cinco, Conversion of
Borrelia
garinii cystic forms to motile spirochetes in vivo. APMIS 109 (2001),
pp. 383-388. Abstract-Elsevier BIOBASE | Abstract-EMBASE |
Abstract-MEDLINE | Full Textvia CrossRef
8. V Preac-Mursic, K Weber, HW Pfister et al., Survival of Borrelia
burgdorferi in antibiotically treated patients with Lyme borreliosis.
Infection 17 (1989), pp. 355-359. Abstract-EMBASE | Abstract-MEDLINE
9. BA Fallon, JM Kochevar, A Gaito and JA. Nields, The
underdiagnosis of
neuropsychiatric Lyme Disease in children and adults. Psychiatr Clin
North Am 21 (1998), pp. 693-703. Abstract-PsycINFO | Abstract-EMBASE
10. AC Steere, VK Sikand, RT Schoen and J. Nowakowski, Asymptomatic
infection with Borrelia burgdorferi. Clin Infect Dis 37 (2003), pp.
528-532. Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Abstract-
EMBASE
| Full Textvia CrossRef
11. GP Wormser, RB Nadelman, RJ Dattwyler et al., Practical
guidelines
for the treatment of Lyme disease. Clin Infect Dis 31 suppl 1 (2000),
pp. 1-14. Abstract-MEDLINE | Full Textvia CrossRef
12. CDC, CDC recommendations for test performance and interpretation
from the second national conference on serologic diagnosis of Lyme
disease. MMWR Morb Mortal Wkly Rep 44 (1995), pp. 590-591.
13. AC Steere, A Dhar, J Hernandez et al., Systemic symptoms without
erythema migrans as the presenting picture of early Lyme disease. Am
J
Med 114 (2003), pp. 58-62. SummaryPlus | Full Text + Links | PDF (76
K)
14. R. Kaiser, False-negative serology in patients with
neuroborreliosis
and the value of employing of different borrelial strains in
serological
assays. J Med Microbiol 49 (2000), pp. 911-915. Abstract-EMBASE |
Abstract-Elsevier BIOBASE | Abstract-MEDLINE
15. RB Stricker, JJ Burrascano and EE. Winger, Longterm decrease in
the
CD57 lymphocyte subset in a patient with chronic Lyme disease. Ann
Agric
Environ Med 9 (2002), pp. 111-113. Abstract-EMBASE | Abstract-MEDLINE
16. BA Fallon, J Keilp, I Prohovnik, R Van Heertum and JJ. Mann,
Regional cerebral blood flow and cognitive deficits in chronic Lyme
disease. J Neuropsychiatry Clin Neurosci 15 (2003), pp. 326-332.
Abstract-EMBASE | Abstract-MEDLINE | Abstract-PsycINFO | Full Textvia
CrossRef
17. D Buchwald and D. Garrity, Comparison of patients with chronic
fatigue syndrome, fibromyalgia, and multiple chemical sensitivities.
Arch Intern Med 154 (1994), pp. 2049-2053. Abstract-EMBASE |
Abstract-MEDLINE
18. E. Schmutzhard, Multiple sclerosis and Lyme borreliosis. Wein
Klin
Wochenschr 114 (2002), pp. 539-543. Abstract-EMBASE | Abstract-
MEDLINE
19. Dangond F. Amyotrophic lateral sclerosis.
http://www.emedicine.com/neuro/topic14.htm (accessed Sept 2, 2004)
20. F Tager, B Fallon, J Keilp, M Rissenberg, C Jones and M.
Liebowitz,
A controlled study of cognitive deficits in children with chronic
Lyme
disease. J Neuropsychiatry Clin Neurosci 13 (2001), pp. 500-507.
Abstract-MEDLINE | Abstract-EMBASE | Abstract-PsycINFO | Full Textvia
CrossRef
See LDA comment on this article.
MY HUNGER STRIKE WILL GO ON - MUM
BY DAVID OWEN
11:09 - 23 February 2005
A mother of four today entered the 10th day of a hunger strike in a
desperate bid for specialist hospital treatment.
Christine Jennings, 43, of Strathmore Road, Hinckley, is now too ill
to take some of her medication after refusing food since last
Monday.
Today she said she had been overwhelmed by messages of support from
as far afield as the United States.
Miss Jennings believes she has Lyme disease, which has made her
blind, bound to a wheelchair and reliant on daily steroids and
strong painkillers.
She believes she contracted the disease when bitten by a tick in
Bradgate Park 10 years ago and is angry that her condition has not
been acknowledged.
Miss Jennings, who is taking fluids, has taken the desperate step of
refusing food to highlight her 10-year battle for treatment.
She has been referred to University Hospital Middlesbrough, which
specialises in diagnosing diseases which are difficult to detect.
However, she said she would not stop her hunger strike until she had
received confirmation of an appointment.
Speaking from her bed, where she is being cared for by eldest
daughter Rebecca, 22, she said that, although comfortable, 10 days
without food was beginning to take its toll and meant she could not
take much of the medication she needed.
She said she had been overwhelmed by messages of support, however,
and said the phone had not stopped ringing since the Mercury
published her story last week.
A website to promote her cause has also been inundated with e-mails
from well-wishers, including Lyme disease sufferers from as far
afield as the United States.
She said: "I've had more than 80 e-mails a day, mostly from people
who suffer from the disease or their relatives. We set up a web page
and had 27 messages within the first half-hour."
Her advocate, borough councillor David Thorpe, said: "On Sunday, I
received 104 e-mails. The response has been incredible.
He is now compiling a dossier of sufferers' testimonies which he
will forward to the department of health.
Mr Thorpe said: "The problem is there is no clear Government
guidance. While their figures suggest there are only about 300 cases
of Lyme disease in England and Wales, the message I am getting is
the reality is much, much more.
"We are campaigning for GPs to have information and support
available to refer any suspected case, so sufferers can get the most
appropriate treatment.
"It is unacceptable that after 10 years, someone has to end up blind
and in a wheelchair. Despite three opinions from doctors
specialising in Lyme disease, Christine is still refused the
appropriate treatment.
"For her, a hunger strike is nothing compared to what she's had to
suffer already."
A spokesman for Hinckley and Bosworth Primary Care Trust said a
letter had been sent to Miss Jennings telling her she has been
referred to specialist James Cooke at University Hospital
Middlesbrough.
Miss Jennings's website is at:
www.lymediseaseaction.org.uk
Así estamos, Javier. Y poco se lleva mi armamento textil al tuyo.
Y resulta anecdótico, pues siempre fui de salir a la calle en mangas de camisa, ya fuera verano o el más crudo invierno. Igual daba que estuviéramos bajo cero o a 40 a la sombra. Era lo que más cómodo me resultaba. Así estaba más a gusto y no pasaba frio alguno.
Cuando tocaba partido de fútbol sala, en pleno invierno, el chándal se quedaba en el cajón del armario. La ropa me sobraba.
A mi madre, todo esto le llevaba por la calle de la amargura. Primero por temer por mi salud, de hierro, por cierto, y segundo por gastar dinero en ropa que luego nunca usaría.
Y no es que me sobraran precisamente grasas, más bien tirando a lo contrario, pues nunca metabolicé los lípidos, pero disponía de una energía interior fuera de lo común.
Decirte que también pasé por una tienda especializada en ropa para escalar ochomiles y no, precisamente, para usar el piolet.
Siempre en invierno con camiseta negra, de esas que comentas, bien ceñida al cuerpo. En los pies, igual da lo que pongas. En ocasiones tres pares de los especiales, de escalar ochomiles, pero todo es inútil cuando están frios.
En casa, los pies, en el interior de una especie de calcetines con forro interior de plumas. A parte, los dos o tres pares de rigor. Por la noche con la manta eléctrica. A veces ni siquiera así. Es un frio que te cala los huesos, que lo llevas bien dentro. Ante eso no es suficiente ayuda toda la ropa que te eches encima.
Subject: [lyme_y_otras_zoonosis_cronicas_espanol] Frio como de ochomil
Hombre de dios (Fernando)
Veo que tambien estas helado.
Ultimamente llevo el equivalente en ropa al que se lleva a un ochomil.
Abajo, basico y mas importante, de forma permanente, camiseta de manga larga ceñida con cuello alto ajustado con cremallera.
Tengo dos, de quita y pon, iguales. Las compre en decatlon, son las que llevan los escaladores y los montañeros, esquiadores, etc.
Son de poliester transpirable 100 % y no me las quito ni para ir a la cama.
Luego viene el forro polar ultrajustado o la chaqueta de cremallera siempre de cuello alto, ni camisas ni jerseys "de vestir".
Luego viene la chupa tambien de alta montaña con cuello altisimo, relleno, cutretex (goretex pero en barato).
Como ves toneladas de poliester transpirable de cuello alto. Armazon contra el frio y para proteger el poco calor, hasta dudo que ninguno, que genera el cuerpo.
No he encontrado ropa "de vestir" que ni siquiera se le acerque, por muchas capas que te pongas.
Tres o cuatro capas y todas de decatlon y similares, ropa de deporte discreta, para no hacer ni deporte ni absolutamente nada.
Botas, calcetines tambien de lana-poliester, de poliester doble, termico es la unica palabra que acepto en mi armario, lo que no quita que siempre este helado.
Para dormir, tambien por supuesto forro polar y calcetines, ademas de plumas, manta y la manta electrica de vez en cuando para el dolor y el entumecimiento.
Cualquiera me podria confundir con un habitante de Alaska, Reijavik, Vladivostok o la Patagonia, pero es que estoy ya no helado sino paralizado y malo del frio.
El mejor descubrimiento y la mejor inversion este año (un poco caras) han sido las camisetas negras manga larga cuello ajustado con cremallera de decatlon.
No me las he quitado ni un solo dia en los ultimos tres meses.
No me atrevo.
Ademas todo este cochino poliester tiene la INMENSA ventaja de que no hay que plancharlo y se seca con solo mirarlo.
¿Quien me iba a decir a mi que iba a acabar disfrazado de ochomil cuando no puedo andar ni a la vuelta de la esquina?
Venga cuidaros del frio y recordad lo de las camisetas de petroleo, un gran invento.
Javier
--- En lyme_y_otras_zoonosis_cronicas_espanol@yahoogroups.com, Fernando Almazán Gil <fernandoalmazn@y...> escribió: > Querida Asun, es que no me encuentro, por eso no aparezco mucho. He estado pasando unos días en casa de mi hermana, en Murcia, con mis dos sobrinos, Jorge y Edu. Aquí hace mucho frio y llevo unos días realmente enfermo. Una vez en Murcia, con el clima más benigno la cosa no ha mejorado mucho, todo lo contrario. El cambio de ubicación siempre lo noto mucho, siempre me lleva tres o cuatro días adecuarme al nuevo entorno climático. Todo eso me afecta mucho. Como el primer día que ponen la calefacción. Desde que me levanto, han de transcurrir tres o cuatro horas hasta que puedo abrir bien los ojos; días hay que los paso enteros totalmente cerrado, muy mal. Siento estar tan quejicoso .... > > Estuve para que me sacaran sangre para la IgM del WesternBlot de borrelia, y tuve sus más y mis menos con la doctora del centro. Había dormido dos escasas horas y prácticamente no podía articular palabra. Ya lo hube previsto, así que llevé cuatro folios con mensajes del foro de Lyme, de Miguel Ángel, debidamente seleccionados, en donde se explicaban las razones para realizarse sobretodo esa IgM y como debía de realizarse. Quedé con la doctora en que me llamaría una vez se leyera todas las notas, pero he estado fuera y no sé si ha llamado. Me han dado un mes para volver a recoger los análisis, el doble de tiempo que la primera vez para lo mismo. > > Mañana a las diez y media tengo visita a la MAZ para el estudio del sueño. Me han dicho que me lleve un pijama. Por si acaso me voy a llevar una manta y cuatro o cinco parejas de calcetines de acampada. También me tendría que llevar somníferos (no tomo, ni eso ni nada, y además no me harían efecto), pues mucho me temo que me van a dar las tantas y no voy a poder dormirme. > > También me parece muy mal que ahora te dediques a robar perros. Eso está feo, Asun. Tu sabrás que es lo que haces .... > > Besos, > Fernando > > > > > > > ----- Original Message ----- > From: roquebusqueros > To: lyme_y_otras_zoonosis_cronicas_espanol@yahoogroups.com > Sent: Wednesday, February 16, 2005 6:01 PM > Subject: [lyme_y_otras_zoonosis_cronicas_espanol] Mi pequeña Anap y mi pequeño Fer > > > > A ver, pequeños míos, si llego a saber que la historia negra de mi > familia os causa tal horror que no volvéis a escribir, no la cuento. > Comprendo que historias como esta y la de la noche del kimono verde os > hagan huir, pero ya, ¿no? Es hora de que volváis. Seré buena. No sé si > recordáis una película de Henry Fonda, muy antigua, ya ves, de Henry > Fonda joven, puff, años, de dos familias de granjeros enfrentadas. La > América profunda, Puerto Hurraco. De veras que no somos los O´Timmy ni > los Izquierdo. Un poco extravagantes, un mucho locos, pero no malos > del todo. > > He pasado una semana de vértigo. Recordáis la película de David Lynch > "Blue velvet", pues he estado en el mundo de la oreja, caí > directamente en él. Y todo porque encontré perdido un schnauzer > miniatura sin chip, sin collar y muy muy sucio. Lo llevé al > veterinario, lo desparasité, le compré una correíta y un arnés > preciosos, le puse la pipeta para protegerlo de pulgas y garrapatas y > luego me fui a poner carteles. Esto ya lo he hecho otras veces. > No os contaré detalles, pero cuando apareció aquel hombre de melena > larga a la altura de los hombros y negra, ancho bigote y medallón en > el pecho colgando de un grueso cordón de oro creí morir. Decía que > había puesto dos personas para vigilarme. ¡Pero si yo había puesto > carteles! ¿no sabían leer? ¡si lo sabían todos los veterinarios de > jerez! Si yo ya tengo una golden, no quiero más. Ha sido terrible. Al > final me dieron hasta las gracias, pero es duro intentar hablar con > neandertales, muy, muy duro. > Pero ya veo que no os importa lo que me pase. > > Hasta pronto, > Asun > > > > > > Para cancelar su suscripción a este grupo, envíe un mensaje de correo-e a: > lyme_y_otras_zoonosis_cronicas_espanol- unsubscribe@yahoogroups.com > > > > > Patrocinio de Yahoo! Grupos > > > > ------------------------------------------------------------------- ----------- > Enlaces a Yahoo! Grupos > > a.. Para visitar tu grupo en la web, accede a : > http://es.groups.yahoo.com/group/lyme_y_otras_zoonosis_cronicas_espan ol/ > > b.. Para cancelar tu suscripción a este grupo, envía un mensaje a: > lyme_y_otras_zoonosis_cronicas_espanol- unsubscribe@yahoogroups.com > > c.. El uso que hagas de Yahoo! Grupos está sujeto a las Condiciones del servicio de Yahoo!.
Para cancelar su suscripción a este grupo, envíe un mensaje de correo-e a: lyme_y_otras_zoonosis_cronicas_espanol-unsubscribe@yahoogroups.com
Subject: [InfectionAndInflammation] More About SAM-E (Relevance to Our Illnesses, Mucho Abstracts)
I have now conducted a variety of Pub Med searches to flesh out the relvance of SAM-e [S-adenosylmethionine, also referred to as AdoMet] to our illnesses.
Please note that I am not encouraging anyone to start taking SAM-e, just drawing attention to the possibility that it may be helpful.
1) The most studied effects of SAM-e relate to neuropsychiatric disorders, liver disease and arthritis. In each area, one finds substantial evidence for clinical benefits. More importantly for our purposes, in each area one finds effects of SAM-e which appear relevant for some or all of our illnesses.
2) SAM-e is used to treat depression, but does not mimic the action of other anti-depressant drugs. It appears to be helpful specifically for depression that is secondary to neurological disease.
3) SAM-e can have dramatic benefits for liver health. Within the liver, SAM-e is specifically helpful at restoring functions relevant to our disease, like glutathione synthesis.
4) SAM-e has an established efficacy against osteoarthritis, the most common form of arthritis, rated equal to that of Non Steroidal Anti-Inflammatory Drugs (NSAIDs).
5) SAM-e has important effects on the reaction of the body to endotoxin, which may make it of particular value to inflammatory diseases chronically provoked by bacterial LPS.
5'-methylthioadenosine (MTA) is a nucleoside generated from S- adenosylmethionine (AdoMet) during polyamine synthesis. Recent evidence indicates that AdoMet modulates in vivo the production of inflammatory mediators. We have evaluated the anti-inflammatory properties of MTA in bacterial lipopolysaccharide (LPS) challenged mice, murine macrophage RAW 264.7 cells, and isolated rat hepatocytes treated with pro-inflammatory cytokines.
MTA administration completely prevented LPS-induced lethality. The life-sparing effect of MTA was accompanied by the suppression of circulating tumor necrosis factor-alpha (TNF-alpha), inducible NO synthase (iNOS) expression, and by the stimulation of IL-10 synthesis. These responses to MTA were also observed in LPS-treated RAW 264.7 cells. MTA prevented the transcriptional activation of iNOS by pro-inflammatory cytokines in isolated hepatocytes, and the induction of cyclooxygenase 2 (COX2) in RAW 264.7 cells.
MTA inhibited the activation of p38 mitogen-activated protein kinase (MAPK), c-jun phosphorylation, inhibitor kappa B alpha (IkappaBalpha) degradation, and nuclear factor kappaB (NFkappaB) activation, all of which are signaling pathways related to the generation of inflammatory mediators. These effects were independent of the metabolic conversion of MTA into AdoMet and the potential interaction of MTA with the cAMP signaling pathway, central to the anti-inflammatory actions of its structural analog adenosine. In conclusion, these observations demonstrate novel immunomodulatory properties for MTA that may be of value in the management of inflammatory diseases.
Hepatic deficiency of S-adenosylmethionine (AdoMet) is a critical acquired metabolic abnormality in alcoholic liver disease (ALD) and in many experimental models of hepatotoxicity. Subnormal AdoMet, elevated serum tumor necrosis factor (TNF), and endotoxemia (LPS) are hallmarks of ALD and experimental liver injury.
AdoMet deficiency is attributed to its subnormal synthesis, but mechanisms for increased TNF are not known. AdoMet deficiency may affect the critical balance of proinflammatory (e.g., TNF) and antiinflammatory [e.g., interleukin (IL)-10] cytokines. Rats maintained on a choline-deficient diet with limited amounts of methionine (MCD diet) developed AdoMet deficiency. When challenged with LPS, rats fed MCD diet had significantly increased serum TNF levels and worse liver injury compared with findings for controls. Exogenous AdoMet attenuated liver injury and serum TNF levels.
Results of in vitro studies with the use of RAW 264.7 cells demonstrated that exogenous AdoMet supplementation lowered LPS- induced TNF formation in a dose-dependent manner, and AdoMet deficiency enhanced TNF secretion and TNF gene expression. AdoMet also dose-dependently decreased LPS-stimulated TNF production from monocytes obtained from patients with alcoholic hepatitis.
Finally, AdoMet supplementation stimulated production of the antiinflammatory cytokine IL-10. Interleukin-10 plays a critical role in the modulation of TNF production, and IL-10 may inhibit hepatic fibrosis. This article will review (1) the role of AdoMet in ALD/liver injury, (2) the role of TNF/proinflammatory cytokines in ALD, (3) potential roles of AdoMet in TNF/proinflammatory cytokine regulation in ALD, and (4) conclusions and future directions.
IL-10 is produced by a large variety of cells including monocytes, macrophages, B and T lymphocytes, as well as natural killer cells and is an important suppressor for both immunoproliferative and inflammatory responses. IL-10 exerts antifibrotic effects in the liver, and decreased monocyte synthesis of IL-10 is well documented in alcoholic cirrhosis.
Intracellular deficiency of S-adenosylmethionine (AdoMet) is a hallmark of toxin-induced liver injury. Although the administration of exogenous AdoMet attenuates this injury, the mechanisms of its actions are not fully established. This study was performed to investigate the effect of exogenous AdoMet on IL-10 production in LPS-stimulated RAW 264.7 cells, a murine macrophage cell line. Our results demonstrated that exogenous AdoMet administration enhanced both protein production and gene expression of IL-10 in RAW 264.7 cells. Ethionine, an inhibitor for methionine adenosyltransferases, inhibited LPS-stimulated IL-10 both at the protein and mRNA levels.
Exogenous AdoMet increased the intracellular cAMP concentration as early as 3 h and continued for 24 h after AdoMet treatment; however, the inhibitors for both adenylyl cyclase and PKA did not significantly affect IL-10 production. On the basis of these results, we conclude that AdoMet administration may exert its anti- inflammatory and hepatoprotective effects, at least in part, by enhancing LPS-stimulated IL-10 production.
BACKGROUND: Liver toxicity can be observed during treatment with most chemotherapic agents, and represents one of the principal causes of dose reduction or chemotherapy delays. S- Adenosylmethionine (AdoMet) plays a critical role in the synthesis of polyamines and provides cysteine for the production of glutathione (GSH), the major endogenous hepatoprotective agent. Our study was aimed at assessing the protective effect of AdoMet supplementation in cancer chemotherapy-induced liver toxicity.
PATIENTS AND METHODS: Fifty cancer patients who developed, for the first time, anticancer chemotherapy-induced liver toxicity were studied. Enrolled patients received oral AdoMet supplementation.
RESULTS: AST, ALT and LDH levels recorded at the moment of the recognition of liver toxicity were significantly reduced after one week of AdoMet therapy (respectively p: 0.009, 0.0005 and 0.012). AST, ALT and LDH decrease was confirmed after two weeks of treatment. Furthermore, the effect on these enzyme levels persisted in the following chemotherapy courses, permitting our patients to perform the scheduled chemotherapy courses with a minimal number of dose reductions or administration delays. The efficacy of AdoMet supplementation was not influenced by the presence of liver metastases, and no appreciable side-effects were recognized.
CONCLUSION: The results of our study clearly demonstrate a protective effect of AdoMet in cancer chemotherapy-induced liver toxicity. Further large phase III studies are required to assess the real clinical benefit associated with AdoMet supplementation.
The reactive oxygen species-sensitive transcription nuclear factor- kappaB (NF-kappaB) plays a pivotal role in the development of acetaminophen (APAP) hepatotoxicity. We investigated the efficacy of a diverse series of antioxidants in preventing APAP-induced hepatotoxicity.
BALB/c mice were divided into four groups and provided with antioxidants incorporated into chow as follows: (1) control diet; or diet supplemented with (2) S-adenosylmethionine (SAMe); (3) green tea polyphenols (GrTP); or (4) (RS)-n-propylthiazolidine-4®- carboxylic acid (PTCA). After 5 days on these diets, the animals were further subdivided into (A) given an IP injection with APAP (750 mg/kg), or (B) kept as untreated controls.
The animals were sacrificed at 0, 4 h, and 24 h following APAP administration. PAP/vehicle induced marked decreases in hepatic reduced glutathione (GSH) levels and endogenous SAMe concentrations (46%) when compared to controls. APAP also caused severe centrilobular necrosis and marked increase in serum enzyme ALT activity (38-fold). Oral administration of antioxidants significantly attenuated the APAP-induced liver damage and depletion of hepatic GSH. There were profound increases in serum TNF-alpha levels at 4 h following APAP administration in nonsupplemented compared to antioxidant-treated animals, but no significant differences noted after 24 h.
Serum amyloid A increased in APAP-challenged mice irrespective of antioxidant treatment. Finally, hepatic SAMe concentrations were drastically decreased 24 h following APAP administration, and these decreases were attenuated by pretreatment with antioxidants. In conclusion, these orally administered antioxidants with dissimilar properties provided protection against liver damage, supporting the potential use of antioxidant therapy in patients with APAP toxicity. This is the first report that GrTP and oral administration of PTCA and SAMe can provide protection against APAP injury in this model.
This review focuses on the biochemical and clinical aspects of methylation in neuropsychiatric disorders and the clinical potential of their treatment with ademetionine (S-adenosylmethionine; SAMe). SAMe is required in numerous transmethylation reactions involving nucleic acids, proteins, phospholipids, amines and other neurotransmitters.
The synthesis of SAMe is intimately linked with folate and vitamin B12 (cyanocobalamin) metabolism, and deficiencies of both these vitamins have been found to reduce CNS SAMe concentrations. Both folate and vitamin B12 deficiency may cause similar neurological and psychiatric disturbances including depression, dementia, myelopathy and peripheral neuropathy. SAMe has a variety of pharmacological effects in the CNS, especially on monoamine neurotransmitter metabolism and receptor systems.
SAMe has antidepressant properties, and preliminary studies indicate that it may improve cognitive function in patients with dementia. Treatment with methyl donors (betaine, methionine and SAMe) is associated with remyelination in patients with inborn errors of folate and C-1 (one-carbon) metabolism. These studies support a current theory that impaired methylation may occur by different mechanisms in several neurological and psychiatric disorders.
We investigate the ability of S-adenosylmethionine (SAMe) to antagonize the cyclosporine A (CyA)-induced inhibition of biliary glutathione efflux induced by long-term administration of CyA (10 mg/kg per day-CyA10 or 20 mg/kg per day-CyA20 for 4 weeks) in rats. CyA treatment reduced the liver content of total glutathione and caused a significant increase in the oxidized-to-reduced glutathione ratio and the thiobarbituric acid-reactive substances (TBARS) concentration.
When the rats were concurrently treated with SAMe (10 mg/kg twice daily) and CyA, all these parameters did not significantly differ from control values. Treatment with CyA induced a significant increase in liver GGT activity that was attenuated by coadministration of SAMe. Biliary efflux of total glutathione was significantly reduced in animals treated with CyA. These changes were abolished by SAMe administration. Following inhibition of the intrabiliary catabolism of the tripeptide by acivicin, glutathione efflux rates increased to a lesser extent in animals cotreated with SAMe when compared to those receiving only CyA.
The significant decrease in biliary efflux of oxidized glutathione induced by CyA was totally (S + CyA10) or partially (S + CyA20) prevented by coadministration of SAMe. Our observations confirm that SAMe cotreatment in rats antagonizes CyA-induced inhibition in the biliary efflux of glutathione and suggest that protection against intrabiliary glutathione degradation plays a major role in this protective effect.
Interleukin-6 (IL-6) is a multifunctional cytokine having primarily anti-apoptotic and anti-inflammatory effects. Recent reports have documented that IL-6 plays a key role in liver regeneration.
Intracellular deficiency of S-adenosylmethionine (SAMe) is a hallmark of toxin-induced liver injury. Although the administration of exogenous SAMe attenuates liver injury, its mechanisms of action are not fully understood.
Here we investigated the effects of exogenous SAMe on IL-6 production in monocytes and Kupffer cells. RAW 264.7 cells, a murine monocyte cell line, and isolated rat Kupffer cells were stimulated with lipopolysaccharide (LPS) in the absence or presence of exogenous SAMe. IL-6 production was assayed by ELISA and intracellular SAMe concentrations were measured by HPLC.
We have found that exogenous SAMe administration enhanced both IL-6 protein production and gene expression in LPS-stimulated monocytes and Kupffer cells. Cycloleucine (CL), an inhibitor for extrahepatic methionine adenosyltransferases (MAT), inhibited LPS-stimulated IL-6 production. The enhancement of LPS-stimulated IL-6 production by SAMe was inhibited by ZM241385, a specific antagonist of adenosine (A2) receptor. Our results demonstrate that SAMe administration may exert its anti-inflammatory and hepatoprotective effects, at least in part, by enhancing LPS-stimulated IL-6 production.
ATP:1-methionine S-adenosyltransferase (EC 2.5.1.6, MAT) activity was analyzed in erythrocytes from nine patients with a clinical diagnosis of probable Alzheimer's disease (Pro.AD), four with possible Alzheimer's disease (Pos.AD), three with mild cognitive dysfunction (MCD) and two with dementia of vascular origin (VD), and 10 age-matched control subjects. Significantly lower kinetic parameters (Vmax and Km towards methionine) for MAT were observed in all the dementia cases.
In the subgroup of Pro.AD patients who also had low plasma levels of vitamin B12 (B12), the reduction in MAT Km was significantly correlated with an increase in the serum levels of homocysteine, while no such correlation was observed in all the other dementia groups.
Treatment for 6 months of this subgroup of Pro.AD patients with B12 (1 mg x 7 days + 1 mg/week, i.m.), S-adenosylmethionine (SAM, 200 mg twice daily, p.o.) and folate (2.5 mg every 2 days, p.o.) caused a significant decrease in homocysteine in parallel with a significant increase in Km for MAT. These findings support the hypothesis that aberrations in the B12 dependent transmethylation reactions might be involved in the pathogenesis of dementia, and suggest that the evaluation of erythrocyte MAT activity may be a useful marker for the detection of such an aberration.
Presenilin 1 (PS1) is a key factor for beta-amyloid (Ab) formation in Alzheimer disease (AD). Homocysteine accumulation, frequently observed in AD patients, may be a sign of a metabolic alteration in the S-adenosylmethionine (SAM) cycle, which generates the overexpression of genes controlled by methylation of their promoters, when the cytosine in CpG moieties becomes unmethylated. The methylation of a gene involved in the processing of amyloid precursor protein may prevent Ab formation by silencing the gene. Here we report that SAM administration, in human neuroblastoma SK-N- SH cell cultures, downregulates PS1 gene expression and Ab production
S-Adenosylmethionine is an essential ubiquitous metabolite central to many biochemical pathways, including transmethylation and polyamine biosynthesis. Reduced CSF S-adenosylmethionine levels in Alzheimer's disease have been reported; however, no information is available regarding the status of S-adenosylmethionine or S- adenosylmethionine-dependent methylation in the brain of patients with this disorder.
S-Adenosylmethionine concentrations were measured in postmortem brain of 11 patients with Alzheimer's disease. We found decreased levels of S-adenosylmethionine (-67 to -85%) and its demethylated product S-adenosylhomocysteine (-56 to -79%) in all brain areas examined (cerebral cortical subdivisions, hippocampus, and putamen) as compared with matched controls (n = 14). S-Adenosylmethionine and S-adenosylhomocysteine levels were normal in occipital cortex of patients with idiopathic Parkinson's disease (n = 10), suggesting that the decreased S-adenosylmethionine levels in Alzheimer's disease are not simply a consequence of a chronic, neurodegenerative condition.
Reduced S-adenosylmethionine levels could be due to excessive utilization in polyamine biosynthesis. The severe reduction in levels of this essential biochemical substrate would be expected to compromise seriously metabolism and brain function in patients with Alzheimer's disease and may provide the basis for the observations of improved cognition in some Alzheimer's patients following S- adenosylmethionine therapy.
S-adenosyl-L-methionine (SAMe) is a natural substance which constitutes the most important methyl donor in transmethylation reactions in the central nervous system. Several clinical trials have shown that SAMe possesses an antidepressant activity. This multicentre study was carried out to confirm both efficacy and safety of SAMe in the treatment of major depression.
SAMe was given intramuscularly (i.m.) at a dose of 400 mg/d, double- blind, vs. 150 mg/d oral Imipramine (IMI) in patients with a diagnosis of major depressive episode, with a baseline score on the 21-item Hamilton Depression Rating Scale (HAMD) of >or=18. A total of 146 patients received SAMe whereas 147 received IMI for a period of 4 wk. The two main efficacy measures were endpoint HAMD score and percentage of responders to Clinical Global Impression (CGI) at week 4. Secondary efficacy measures were the final Montgomery-Asberg Depression Rating Scale (MADRS) scores and the response rate intended as a fall in HAMD scores of at least 50% with respect to baseline. The analysis of safety and tolerability was conducted in all treated patients.
SAMe and IMI did not differ significantly on any efficacy measure, either main or secondary. Adverse events were significantly less in patients treated with SAMe compared to those treated with IMI. These data show 400 mg/d i.m. SAMe to be comparable to 150 mg/d oral IMI in terms of antidepressive efficacy, but significantly better tolerated. These findings suggest interesting perspectives for the use of SAMe in depression
Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis.
OBJECTIVE: We assessed the efficacy of S-adenosylmethionine (SAMe), a dietary supplement now available in the Unites States, compared with that of placebo or nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis (OA). STUDY DESIGN: This was a meta-analysis of randomized controlled trials. DATA SOURCES: We identified randomized controlled trials of SAMe versus placebo or NSAIDS for the treatment of OA through computerized database searches and reference lists. OUTCOMES MEASURED: The outcomes considered were pain, functional limitation, and adverse effects.
RESULTS: Eleven studies that met the inclusion criteria were weighted on the basis of precision and were combined for each outcome variable. When compared with placebo, SAMe is more effective in reducing functional limitation in patients with OA (effect size [ES] =.31; 95% confidence interval [CI],.099-.520), but not in reducing pain (ES =.22; 95% CI, -.247 to.693). This result, however, is based on only 2 studies. SAMe seems to be comparable with NSAIDs (pain: ES =.12; 95% CI, -.029 to.273; functional limitation: ES =.025; 95% CI, -.127 to.176). However, those treated with SAMe were less likely to report adverse effects than those receiving NSAIDs.
CONCLUSIONS: SAMe appears to be as effective as NSAIDs in reducing pain and improving functional limitation in patients with OA without the adverse effects often associated with NSAID therapies.
The psychostimulants d-amphetamine and methylphenidate are thought to be the most effective treatment in children, adolescents, and adults with attention deficit-hyperactivity disorder (ADHD) because they potentiate both dopamine (DA) and norepinephrine (NE) at the synaptic cleft. These medications are not free from side effects and controversy. Newer effective and safe treatments are needed.
S-Adenosyl-L-methionine (SAM), the active form of methionine, acts as a methyl donor and is involved in many metabolic pathways. It has beta adrenergic and DA receptor agonist activity. We have been using oral SAM in a sample of well-diagnosed adults with ADHD, residual state (RS) in a 4-week open trial to establish SAM effectiveness and safety and in a 9-week, double-blind, placebo-controlled crossover trial. Preliminary data from the open trial reveal that 75 percent (6 out of 8 male) patients improve on it. The 2 who did not improve had not improved on methylphenidate trial. Improvement ranged from moderate to marked, with minimal and transient side effects that did not interfere with functioning.
Environmental Change May Be Boosting Diseases - UN Mon Feb 21, 2005 11:44 AM ET
By C. Bryson Hull
NAIROBI (Reuters) - Environmental changes wrought by population movement, destruction of habitats and other factors may be behind a resurgence of infectious diseases, a United Nations study says.
A rise in cases of diseases such as malaria and dengue fever, and the recent crossover to humans of others such as the Nipah virus, are linked to a host of changes that create more favorable conditions for their spread, according to a report by the U.N. Environmental Programme (UNEP) issued on Monday.
Deforestation, unplanned urban sprawl, poor waste management, pollution, building of roads and dams and rising temperatures are among the aggravating factors.
Infectious diseases cause about 15 million deaths annually, or about a quarter of all fatalities, UNEP says. In Southeast Asia and Africa, they account for two-thirds of all deaths, with the majority of them children and young adults.
The environmental roots of the rise in infectious diseases is one of the "emerging challenges" listed in UNEP's annual Global Environmental Outlook.
"What is good for the environment is good for health, and what is good for health is good for development," UNEP health and environment expert Hiremagalur Gopalan told a news conference.
The often fatal Nipah virus, normally found in Asian fruit bats, is believed to have crossed over to humans as the bats lost their habitats through forest fires in Sumatra and the clearance of land for palm plantations.
As the bats searched for fruit, they were brought into contact with pigs, which in turn passed the disease to their human handlers in the late 1990s, the report says.
Dengue fever, which was present in only nine countries in the 1970s, is now found in more than 100, most likely the result of increasing urban populations, the report says.
Since much urban growth occurs without planned sanitation, water treatment and sewerage, increased exposure to mosquitoes, rodents and other vermin provides more opportunities for diseases such as malaria, dengue, tuberculosis and hantavirus.
Mining, the damming of rivers and increased irrigation for agriculture also give mosquitoes more standing water in which to breed, the report says.
In the United States, cases of the tick-borne Lyme disease in New York and Connecticut have surged as humans have moved into forested areas where the deer that carry the ticks thrive, the report says.
UN Report Links Infectious Disease Outbreak in Congo to Environment By Cathy Majtenyi Nairobi 21 February 2005
A United Nations' environment official Monday said the recent outbreak of pneumonic plague in the Democratic Republic of Congo could be linked to environmental conditions. This is one example of what experts note is a growing link between environmental degradation and the rise in infectious diseases.
The head of the environment and health unit at the United Nations Environment Program, Hiremagalur Gopalan, told reporters in Nairobi exposure to mercury and overcrowded living conditions likely played a major role in the recent outbreak of pneumonic plague among miners in the Democratic Republic of Congo.
"They [miners] are also immuno-compromised," he said. "There is mining activity. They're also exposed to mercury. Mercury is known to reduce the immune activity. And they also live close together. This pneumonic plague is [transmitted] through breathing, through aerosols. So it's possible that it is linked to the environment in which they live."
The World Health Organization (WHO) said last Friday at least 61 miners in Ituri district had died of pneumonic plague. The organization and several health groups are investigating the outbreak, which is believed to have started December 21.
The pneumonic plague outbreak is a recent example of what environmental experts are saying is a rise in new and previously suppressed infectious diseases because of changes people have made to the environment. These include clearing land for agriculture or urban sprawl, or dumping pollutants into the air, water, and land.
This is one of the findings of the U.N.'s Global Environment Outlook Yearbook, released during UNEP's governing council meeting in Nairobi this week.
The deputy director of the United Nations Environment Program's early warning and assessment division, Marion Cheatle, described to reporters how environmental changes have encouraged the breeding of mosquitoes, which, in turn, spread dengue fever and malaria.
"I think all of us are aware of how mosquitoes can be encouraged in areas where we've disturbed the environment, where we've left litter around, where we changed the course of the water system to provide irrigation and big dams, and where there are more breeding places for these insects," she said.
Ms. Cheatle said the incidence of dengue fever and malaria have risen dramatically over time because of urban sprawl and other changes in land-use and human settlement patterns.
She said in the 1970s, there were only about nine countries worldwide that suffered from this disease. Today, dengue has spread to over 100 countries. Similarly in eastern and southern Africa, the proportion of under-five deaths from malaria doubled between the 1980s and 1990s.
Other diseases experts say are linked to the environment include: lyme disease, schistosomiasis, tuberculosis, bubonic plague and cholera.
Hombre de dios (Fernando)
Veo que tambien estas helado.
Ultimamente llevo el equivalente en ropa al que se lleva a un
ochomil.
Abajo, basico y mas importante, de forma permanente, camiseta de
manga larga ceñida con cuello alto ajustado con cremallera.
Tengo dos, de quita y pon, iguales. Las compre en decatlon, son las
que llevan los escaladores y los montañeros, esquiadores, etc.
Son de poliester transpirable 100 % y no me las quito ni para ir a
la cama.
Luego viene el forro polar ultrajustado o la chaqueta de cremallera
siempre de cuello alto, ni camisas ni jerseys "de vestir".
Luego viene la chupa tambien de alta montaña con cuello altisimo,
relleno, cutretex (goretex pero en barato).
Como ves toneladas de poliester transpirable de cuello alto. Armazon
contra el frio y para proteger el poco calor, hasta dudo que
ninguno, que genera el cuerpo.
No he encontrado ropa "de vestir" que ni siquiera se le acerque, por
muchas capas que te pongas.
Tres o cuatro capas y todas de decatlon y similares, ropa de deporte
discreta, para no hacer ni deporte ni absolutamente nada.
Botas, calcetines tambien de lana-poliester, de poliester doble,
termico es la unica palabra que acepto en mi armario, lo que no
quita que siempre este helado.
Para dormir, tambien por supuesto forro polar y calcetines, ademas
de plumas, manta y la manta electrica de vez en cuando para el dolor
y el entumecimiento.
Cualquiera me podria confundir con un habitante de Alaska, Reijavik,
Vladivostok o la Patagonia, pero es que estoy ya no helado sino
paralizado y malo del frio.
El mejor descubrimiento y la mejor inversion este año (un poco
caras) han sido las camisetas negras manga larga cuello ajustado con
cremallera de decatlon.
No me las he quitado ni un solo dia en los ultimos tres meses.
No me atrevo.
Ademas todo este cochino poliester tiene la INMENSA ventaja de que
no hay que plancharlo y se seca con solo mirarlo.
¿Quien me iba a decir a mi que iba a acabar disfrazado de ochomil
cuando no puedo andar ni a la vuelta de la esquina?
Venga cuidaros del frio y recordad lo de las camisetas de petroleo,
un gran invento.
Javier
--- En lyme_y_otras_zoonosis_cronicas_espanol@yahoogroups.com,
Fernando Almazán Gil <fernandoalmazn@y...> escribió:
> Querida Asun, es que no me encuentro, por eso no aparezco mucho.
He estado pasando unos días en casa de mi hermana, en Murcia, con
mis dos sobrinos, Jorge y Edu. Aquí hace mucho frio y llevo unos
días realmente enfermo. Una vez en Murcia, con el clima más benigno
la cosa no ha mejorado mucho, todo lo contrario. El cambio de
ubicación siempre lo noto mucho, siempre me lleva tres o cuatro días
adecuarme al nuevo entorno climático. Todo eso me afecta mucho. Como
el primer día que ponen la calefacción. Desde que me levanto, han de
transcurrir tres o cuatro horas hasta que puedo abrir bien los ojos;
días hay que los paso enteros totalmente cerrado, muy mal. Siento
estar tan quejicoso ....
>
> Estuve para que me sacaran sangre para la IgM del WesternBlot de
borrelia, y tuve sus más y mis menos con la doctora del centro.
Había dormido dos escasas horas y prácticamente no podía articular
palabra. Ya lo hube previsto, así que llevé cuatro folios con
mensajes del foro de Lyme, de Miguel Ángel, debidamente
seleccionados, en donde se explicaban las razones para realizarse
sobretodo esa IgM y como debía de realizarse. Quedé con la doctora
en que me llamaría una vez se leyera todas las notas, pero he estado
fuera y no sé si ha llamado. Me han dado un mes para volver a
recoger los análisis, el doble de tiempo que la primera vez para lo
mismo.
>
> Mañana a las diez y media tengo visita a la MAZ para el estudio
del sueño. Me han dicho que me lleve un pijama. Por si acaso me voy
a llevar una manta y cuatro o cinco parejas de calcetines de
acampada. También me tendría que llevar somníferos (no tomo, ni eso
ni nada, y además no me harían efecto), pues mucho me temo que me
van a dar las tantas y no voy a poder dormirme.
>
> También me parece muy mal que ahora te dediques a robar perros.
Eso está feo, Asun. Tu sabrás que es lo que haces ....
>
> Besos,
> Fernando
>
>
>
>
>
>
> ----- Original Message -----
> From: roquebusqueros
> To: lyme_y_otras_zoonosis_cronicas_espanol@yahoogroups.com
> Sent: Wednesday, February 16, 2005 6:01 PM
> Subject: [lyme_y_otras_zoonosis_cronicas_espanol] Mi pequeña
Anap y mi pequeño Fer
>
>
>
> A ver, pequeños míos, si llego a saber que la historia negra de
mi
> familia os causa tal horror que no volvéis a escribir, no la
cuento.
> Comprendo que historias como esta y la de la noche del kimono
verde os
> hagan huir, pero ya, ¿no? Es hora de que volváis. Seré buena. No
sé si
> recordáis una película de Henry Fonda, muy antigua, ya ves, de
Henry
> Fonda joven, puff, años, de dos familias de granjeros
enfrentadas. La
> América profunda, Puerto Hurraco. De veras que no somos los
O´Timmy ni
> los Izquierdo. Un poco extravagantes, un mucho locos, pero no
malos
> del todo.
>
> He pasado una semana de vértigo. Recordáis la película de David
Lynch
> "Blue velvet", pues he estado en el mundo de la oreja, caí
> directamente en él. Y todo porque encontré perdido un schnauzer
> miniatura sin chip, sin collar y muy muy sucio. Lo llevé al
> veterinario, lo desparasité, le compré una correíta y un arnés
> preciosos, le puse la pipeta para protegerlo de pulgas y
garrapatas y
> luego me fui a poner carteles. Esto ya lo he hecho otras veces.
> No os contaré detalles, pero cuando apareció aquel hombre de
melena
> larga a la altura de los hombros y negra, ancho bigote y
medallón en
> el pecho colgando de un grueso cordón de oro creí morir. Decía
que
> había puesto dos personas para vigilarme. ¡Pero si yo había
puesto
> carteles! ¿no sabían leer? ¡si lo sabían todos los veterinarios
de
> jerez! Si yo ya tengo una golden, no quiero más. Ha sido
terrible. Al
> final me dieron hasta las gracias, pero es duro intentar hablar
con
> neandertales, muy, muy duro.
> Pero ya veo que no os importa lo que me pase.
>
> Hasta pronto,
> Asun
>
>
>
>
>
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correo-e a:
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>
>
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Querida Asun, es que no me encuentro, por eso no aparezco mucho. He estado pasando unos días en casa de mi hermana, en Murcia, con mis dos sobrinos, Jorge y Edu. Aquí hace mucho frio y llevo unos días realmente enfermo. Una vez en Murcia, con el clima más benigno la cosa no ha mejorado mucho, todo lo contrario. El cambio de ubicación siempre lo noto mucho, siempre me lleva tres o cuatro días adecuarme al nuevo entorno climático. Todo eso me afecta mucho. Como el primer día que ponen la calefacción. Desde que me levanto, han de transcurrir tres o cuatro horas hasta que puedo abrir bien los ojos; días hay que los paso enteros totalmente cerrado, muy mal. Siento estar tan quejicoso ....
Estuve para que me sacaran sangre para la IgM del WesternBlot de borrelia, y tuve sus más y mis menos con la doctora del centro. Había dormido dos escasas horas y prácticamente no podía articular palabra. Ya lo hube previsto, así que llevé cuatro folios con mensajes del foro de Lyme, de Miguel Ángel, debidamente seleccionados, en donde se explicaban las razones para realizarse sobretodo esa IgM y como debía de realizarse. Quedé con la doctora en que me llamaría una vez se leyera todas las notas, pero he estado fuera y no sé si ha llamado. Me han dado un mes para volver a recoger los análisis, el doble de tiempo que la primera vez para lo mismo.
Mañana a las diez y media tengo visita a la MAZ para el estudio del sueño. Me han dicho que me lleve un pijama. Por si acaso me voy a llevar una manta y cuatro o cinco parejas de calcetines de acampada. También me tendría que llevar somníferos (no tomo, ni eso ni nada, y además no me harían efecto), pues mucho me temo que me van a dar las tantas y no voy a poder dormirme.
También me parece muy mal que ahora te dediques a robar perros. Eso está feo, Asun. Tu sabrás que es lo que haces ....
Subject: [lyme_y_otras_zoonosis_cronicas_espanol] Mi pequeña Anap y mi pequeño Fer
A ver, pequeños míos, si llego a saber que la historia negra de mi familia os causa tal horror que no volvéis a escribir, no la cuento. Comprendo que historias como esta y la de la noche del kimono verde os hagan huir, pero ya, ¿no? Es hora de que volváis. Seré buena. No sé si recordáis una película de Henry Fonda, muy antigua, ya ves, de Henry Fonda joven, puff, años, de dos familias de granjeros enfrentadas. La América profunda, Puerto Hurraco. De veras que no somos los O´Timmy ni los Izquierdo. Un poco extravagantes, un mucho locos, pero no malos del todo.
He pasado una semana de vértigo. Recordáis la película de David Lynch "Blue velvet", pues he estado en el mundo de la oreja, caí directamente en él. Y todo porque encontré perdido un schnauzer miniatura sin chip, sin collar y muy muy sucio. Lo llevé al veterinario, lo desparasité, le compré una correíta y un arnés preciosos, le puse la pipeta para protegerlo de pulgas y garrapatas y luego me fui a poner carteles. Esto ya lo he hecho otras veces. No os contaré detalles, pero cuando apareció aquel hombre de melena larga a la altura de los hombros y negra, ancho bigote y medallón en el pecho colgando de un grueso cordón de oro creí morir. Decía que había puesto dos personas para vigilarme. ¡Pero si yo había puesto carteles! ¿no sabían leer? ¡si lo sabían todos los veterinarios de jerez! Si yo ya tengo una golden, no quiero más. Ha sido terrible. Al final me dieron hasta las gracias, pero es duro intentar hablar con neandertales, muy, muy duro. Pero ya veo que no os importa lo que me pase.
Hasta pronto, Asun
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425 INCIDENCIA DE ENFERMEDADES TRANSMITIDAS POR GARRAPATAS EN UN AREA SANITARIA DE LA ZONA DE LEVANTE
A. Guerrero, F. Gimeno, J. Colomina y M. Molina Servicio de Microbiología, Área de Diagnóstico Biológico, Hospital de La Ribera, Alcira-Valencia.
Objetivos: Las enfermedades transmitidas por garrapatas en España incluyen: fiebre botonosa mediterránea, fiebre recurrente endémica, tularemia, babesiosis, borreliosis de Lyme, ehrlichiosis, y una nueva enfermedad denominada DEBONEL/TIBOLA, siendo las tres últimas las consideradas como emergentes. Existen pocos datos epidemiológicos regionales sobre la incidencia de cada una de ellas. Por ello, el objetivo de este estudio fue conocer la incidencia de las enfermedades transmitidas por garrapatas en un área sanitaria de la zona de Levante.
Materiales y métodos: El estudio se realizó en el Area Sanitaria 10 de la Comunidad Valenciana, con un población dependiente de 235.000 habitantes. Se analizaron retrospectivamente los 5 últimos años, durante los cuales se detectaron 675 pacientes con sospecha clínica de enfermedades tra nsmitidas por garrapatas. Se aceptó como criterios diagnósticos de dichas enfermedades: sospecha o documentación de picadura de garrapata, con clínica y analítica compatible, junto con exclusión razonable de otras enfermedades. Para establecer el diagnóstico microbiológico, se emplearon técnicas serológicas, cultivos bacterianos, frotis de sangre periférica o PCR según el agente etiológico a estudio. Se revisaron las historias clínicas de todos aquellos pacientes con hallazgos microbiológicos.
Resultados: De los 380 pacientes estudiados para borreliosis de Lyme solo 22 mostraron serología positiva para Borrelia burgdorferi, aunque ninguno de ellos cumplió los criterios diagnósticos del Grupo Español de Trabajo de Borreliosis de Lyme. De los 110 pacientes estudiados serológicamente para la fiebre botonosa mediterránea solo 6 mostraron serología IgG positiva para Ricketsia conorii. De ellos, solo uno reunía criterios diagnósticos (presencia de fiebre, mancha negra y/o erupción cutánea). Un paciente de 9 años cumplía los criterios diagnósticos de la nueva enfermedad DEBONEL/TIBOLA (picadura de garrapata en cuero cabelludo con escara periférica, adenopatía regional y alopecia residual). No se documento ningún caso de fiebre recurrente, tularemia, babesiosis o ehrlichiosis.
Conclusiones: Nuestros datos sugieren que la incidencia de enfermedades transmitidas por garrapatas en el Levante es muy baja. Sin embargo este dato de incidencia puede estar en parte condicionado por una baja concienciación del clínico ante estas enfermedades.
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426 DETECCIÓN DE VARIANTES NO PATÓGENAS DE ANAPLASMA PHAGOCYTOPHILUM EN IXODES RICINUS DE LA PENÍNSULA IBÉRICA
A. Portillo*, A.S. Santos**, S. Santibáñez*, J.R. Blanco*, V. Ibarra*, F. Bacellar** y J.A. Oteo* *Hospital General de La Rioja, Logroño, La Rioja, España. **Centro de Estudos de Vectores e Doenças Infecciosas. Instituto Nacional de Saúde Dr. Ricardo Jorge, Águas de Moura, Portugal.
Introducción: La anaplasmosis humana (AH) (antigua ehrlichiosis humana granulocítica) es una zoonosis emergente transmitida por garrapatas. Estudios previos han detectado una alta prevalencia de infección por Anaplasma phagocytophilum (anteriormente, Ehrlichia phagocytophila) en Ixodes ricinus del Norte de España (La Rioja y País Vasco). Sin embargo, hasta la fecha, en la Península Ibérica sólo se han comunicado casos esporádicos de AH. Estos hechos podrían explicarse por diferencias en la virulencia de distintas variantes de A. phagocytophilum.
Objetivo: Identificar posibles variantes de A. phagocytophilum en I. ricinus recogidos en La Rioja mediante la detección de mutaciones en el gen ARNr 16S de Anaplasma.
Material y métodos: Se analizaron 90 ejemplares de I. ricinus (84 adultos y 6 ninfas) recogidos de vacas en Villoslada de Cameros (La Rioja) en noviembre de 2003. El ADN se extrajo individualmente de cada garrapata. Se amplificó por PCR el gen ARNr 16S de A. phagocytophilum de las muestras agrupadas (cebadores GE9f y GE10r). Cuando el resultado fue positivo, se repitió la PCR con ADN de ejemplares individuales. Los amplicones obtenidos (919 pb) se secuenciaron en ambos sentidos y por duplicado. En todos los casos se incluyeron controles positivos y negativos adecuados.
Resultados: Mediante PCR se obtuvo una banda del tamaño esperado correspondiente al ADN mezcla proveniente de las 6 ninfas agrupadas de I. ricinus. La PCR posterior de cada muestra individual demostró la presencia de A. phagocytophilum en una ninfa. El análisis de la secuencia de esta muestra mostró dos mutaciones puntuales en los nucleótidos 76 y 84 (G y A, respectivamente) con respecto a la secuencia del agente de la AH (nº acceso en GenBank U02521). Estos cambios corresponden a la variante 1 (AP-variante 1) descrita en EE.UU. por Massung y cols. Dichas mutaciones no se evidenciaron en el control positivo.
Conclusiones: Se ha detectado por primera vez en la Península Ibérica la presencia de AP- variante 1 de A. phagocytophilum en I. ricinus. Dicha variante no se ha asociado por el momento con AH, por lo que su presencia puede justificar la escasa incidencia de casos clínicos en la Península, en contraste con la alta prevalencia de infección por A. phagocytohilum en I. ricinus.
Agradecimientos: Financiado en parte con ayudas FIS PI021810 y G03/057, M. Sanidad y Consumo, España.
429 DETECCIÓN DE ANTICUERPOS FRENTE A RICKETTSIA SLOVACA EN PERROS Y ZORROS EN LA PROVINCIA DE SORIA
L. Lledó, J.L. Serrano*, M.I. Gegúndez, J.V. Saz, A. González y M. Beltrán Dpto. Microbiología y Parasitología, Facultad de Medicina, Universidad de Alcalá. *Servicio Territorial de Sanidad y Bienestar Social de Soria.
Objetivos: Rickettsia slovaca, miembro del grupo de las fiebres exantemáticas, produce un cuadro clínico denominado TIBOLA. Se transmite desde los reservorios al ser humano por la picadura de garrapatas del género Dermacentor (D. marginatus, D. reticulatus). Los cánidos, tanto domésticos como salvajes, tienen un papel importante en la epidemiología de muchas enfermedades infecciosas, como en el caso de ciertas rickettsiosis (Rickettsia conorii). El objetivo de este estudio es investigar la presencia de anticuerpos frente a R. slovaca en perros y zorros de la provincia de Soria.
Material y métodos: Durante los años 1993 a 2000, se obtuvieron 313 muestras de sangre de zorro mediante cacerías, y 73 de perros que acudieron a clínicas veterinarias en la provincia de Soria. La sangre se transportó refrigerada a 4ºC al laboratorio y tras la separación del suero, éste se conservó a -20ºC hasta su análisis. La técnica utilizada en el estudio fue la inmunofluorescencia indirecta (IFI). El antígeno empleado fueron células Vero E6 (ATCC 1586) infectadas con R. slovaca (cepa 246 CDC), y como conjugado suero anti Ig G perro (SIGMA). Los sueros con títulos iguales o superiores a 1:40 se consideraron positivos.
Resultados: se detectó la presencia de anticuerpos específicos frente a R. slovaca en 21 zorros y en 10 perros, lo que representa una prevalencia del 6.7% y del 13.7% respectivamente (diferencias estadísticamente significativas entre ambos p < 0,05). Los títulos oscilaron entre 1:40 y 1:320 en los zorros, y entre 1:80 y 1:1280 en los perros.
Conclusiones: Se demuestra la existencia de infección por R. slovaca en cánidos domésticos y salvajes de la provincia de Soria. El relevante número de ejemplares (sobre todo perros) con anticuerpos, sugiere que el contacto humano con dichos animales puede suponer un factor de riesgo para adquirir esta infección. Estos datos obligan a seguir investigando para poder establecer la importancia de estos animales en el ciclo epidemiológico de esta bacteria en nuestro país.
430 APROXIMACIÓN AL AGENTE ETIOLÓGICO DE UNA NUEVA ENFERMEDAD TRANSMITIDA POR GARRAPATAS (DEBONEL)
V. Ibarra*, A. Portillo*, S. Santibañez*, J.R. Blanco*, A. Orduña** y J.A. Oteo* *Hospital de La Rioja. **Universidad Valladolid.
Introducción: En los últimos años venimos observando en La Rioja (al igual que en otras zonas europeas), una afección transmitida por garrapatas:DEBONEL/TIBOLA, con características epidemiológicas, de vector, clínicas y microbiológicas diferentes a las previamente descritas. Esta afección aparece en los meses fríos del año y está transmitida por Dermacentor marginatus. Los rasgos clínicos más destacados son la presencia de necrosis y eritema en la zona de la picadura y la existencia de linfadenopatías regionales dolorosas. Hasta el momento no se ha podido establecer de forma definitiva el agente etiológico, si bien se ha implicado a una rickettsia del grupo de las fiebres manchadas (SFG): Rickettsia slovaca.
Objetivo: Investigar, mediante técnicas de biología molecular (PCR y secuenciación) las especies de rickettsia presentes en D. marginatus retiradas de pacientes que desarrollaron DEBONEL.
Material y métodos: Entre Enero de 2001 y Enero de 2004, 20 pacientes acudieron a la consulta con las manifestaciones clínicas anteriormente descritas (DEBONEL). De ellos 8 adjuntaban la garrapata que les había picado. Las 8 fueron identificadas como D. marginatus adultos. Todos los ejemplares se procesaron individualmente. Tras la extracción del DNA, se amplificaron por PCR los fragmentos de los genes de Rickettsia sp.:rOmpA (PCR semianidada), glta y 16SrRNA (PCR convencional). Posteriormente se secuenciaron los productos amplificados para determinar la especie.
Resultados: En todos los ejemplares estudiados se detectó infección por rickettsias del SFG. Tras la secuenciación del gen rOmpA se obtuvo en 5 muestras una secuencia con un 100% de identidad con el mismo gen de R. slovaca, y en las 3 restantes se evidenció máxima identidad (98%) con el fragmento del gen rOmpA de Rickettsia sp. RpA4, DnS14 y DnS28.
Conclusiones: Todos los D. marginatus retirados de personas que dearrollan DEBONEL están infectados por rickettsias del SFG. Hemos identificado R. slovaca y Rickettsia sp. RpA4, DnS14 y DnS28. Estos hallazgos sugieren la implicación de más de una especie de rickettsia en la etiología de la enfermedad.
Financiado en parte con ayudas FIS PI021810 y G03/057. M. Sanidad y Consumo, España.
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431 SEROPREVALENCIA DE LA INFECCIÓN POR BORRELIA BURGDORFERI EN CIERVOS DE LOS MONTES DE TOLEDO (CASTILLA LA MANCHA)
J. Ledesma, M.I. Gegúndez, L. Lledó, J.V. Saz y M. Beltrán Dpto. Microbiología y Parasitología, Facultad de Medicina, Universidad de Alcalá
Objetivos: La infección producida por Borrelia burgdorferi (agente etiológico de la enfermedad de Lyme) es una zoonosis que se transmite desde sus reservorios (principalmente roedores) a través de vectores (garrapatas del género Ixodes). Las formas adultas de estas garrapatas suelen encontrarse en animales de tamaño medio-grande como perros, ciervos, cabras..., pudiendo, por tanto, participar en la epidemiología de esta infección. El objetivo de este estudio es investigar la presencia de anticuerpos frente a B. burgdorferi en ciervos de los Montes de Toledo.
Material y métodos: Durante los años 1997 y 1998 se obtuvieron sueros de 107 ciervos (Cervus elaphus) mediante cacerías. Se recogieron datos de sexo, edad, peso y localización geográfica de los ejemplares. Los sueros se estudiaron mediante inmunofluorescencia indirecta, utilizando como antígeno B. burgdorferi (cepa B31) cultivada en medio BSK II. Como conjugado se empleó un suero de ratón anti Ig G de oveja (SIGMA). Se consideraron positivos títulos mayores o iguales a 1:64.
Resultados: Se detectaron 42 sueros con anticuerpos específicos frente a B. burgdorferi, lo que representa una prevalencia del 39,25% (23.35% para machos, 15,89% para hembras). No se encontraron diferencias estadísticamente significativas ni por sexo, edad, peso ni localización geográfica. Los títulos de los seropositivos oscilaron entre 1:64 y 1:256.
Conclusiones: Se demuestra la presencia de infección por B. burgdorferi en ciervos de los Montes de Toledo. La elevada prevalencia encontrada, superior a la hallada en otros estudios para estos animales y otros como suidos y lagomorfos, sugiere que el contacto humano con estos animales puede suponer un factor de riesgo para ciertos colectivos como cazadores, campesinos o turistas de la zona.
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Sábado 1 Diciembre 2001. Volumen 19 - Número 10 p. 509 - 513
Preguntas y respuestas
¿Podemos prevenir las enfermedades transmitidas por garrapatas?
José A. Oteoa José R. Blancoa Valvanera Ibarraa
aServicio de Medicina Interna y Enfermedades Infecciosas. Hospital de La Rioja Logroño.
Can we prevent tick-borne transmitted disease?
Enferm Infecc Microbiol Clin 2001; 19: 509 - 513
¿Qué son las garrapatas?
Las garrapatas son artrópodos hematófagos presentes en todo el mundo, que parasitan diferentes especies de mamíferos, aves y reptiles. A esta capacidad parasitaria se une la propiedad de ser huéspedes intermediarios de diferentes procesos bacterianos, víricos y protozoarios de gran importancia en Salud Pública1,2 .
Conocemos dos grandes familias de garrapatas capaces de producir enfermedad en el hombre, las Ixodidae o «garrapatas duras», y las Argasidae, «chinchorros» o «garrapatas blandas» que transmiten la fiebre recurrente endémica. Existe una tercera familia, Nuttalliellidae, pero ésta se encuentra confinada en el sudeste de África y, como tal, no tiene transcendencia en nuestro medio1,2 .
En la actualidad, las garrapatas duras se han convertido en los principales vectores de enfermedades infecciosas en el mundo industrializado, superando en este papel a mosquitos, pulgas y piojos2,3 y de éstas serán de las que nos ocupemos en esta revisión.
A efectos prácticos debe conocerse que durante el ciclo vital de estas garrapatas, que pasan por tres estadios (larva, ninfa y adulto), el hombre pude ser atacado y sufrir alguna de las enfermedades que son capaces de transmitir; el estadio que más ataca al hombre es el de ninfa.
Para que se produzca una determinada afección transmitida por picadura de garrapatas en una determinada zona, al menos deben concurrir tres factores:
1. Debe existir la especie de garrapata competente para la transmisión de la enfermedad en ese medio (especificidad de vector).
2. La garrapata debe estar infectada por el agente causal, para lo cual es necesario la presencia del reservorio de la enfermedad (pequeños roedores, aves, etc.).
3. Como en el resto de las enfermedades infecciosas, la víctima (paciente) debe ser susceptible al agente causal (o neurotoxina)2 .
¿Qué garrapatas existen en España?
En España existe una amplia variedad de garrapatas duras entre las que se incluyen al menos 23 especies correspondientes a los géneros Ixodes, Rhipicephalus, Dermacentor, Haemaphysalis, Hyalomma y Boophilus. Éstas son responsables de la transmisión de un variado espectro de enfermedades que afectan a los animales y al hombre produciendo además grandes pérdidas económicas (anemización del ganado)2,4,5 . Con relación al espectro de afecciones transmitidas por garrapatas presentes en la Península Ibérica debemos citar la fiebre botonosa o exantemática mediterránea6 , babesiosis7 , tularemia8 , parálisis neurotóxica9 , ehrlichiosis10,11 y una nueva enfermedad denominada DEBONELTIBOLA12 . No obstante, la borreliosis de Lyme (BL) es la que más impacto provoca, dada su alta incidencia y la posibilidad de desarrollar formas graves y secuelas de evolución crónica13,14 .
En la práctica clínica no es raro que se nos consulte porque un paciente ha sido picado por una garrapata o es portador del artrópodo. Cuando esto ocurre, una serie de dudas se nos pasan por la mente. ¿Desarrollará una enfermedad? ¿Debo ofrecerle profilaxis antibiótica? ¿Cómo debo extraer la garrapata? Además, en muchas ocasiones el paciente presenta una elevada carga de ansiedad y habrá que explicarle los riesgos y cómo prevenir una nueva picadura.
¿Cómo evitar las picaduras de garrapatas?
La medida profiláctica más eficaz para la prevención de las enfermedades transmitidas por garrapatas (ETG) consiste en evitar la picadura de las mismas. A este respecto debemos conocer que las actividades ocupacionales y recreativas (paseo por el campo, senderismo, caza, pesca, acampada, etc). suponen el principal riesgo para sufrir las ETG13-19 . Así, sería conveniente señalar las áreas de mayor riesgo y realizar campañas publicitarias en las que se advierta del riesgo de ser picado por garrapatas (no tenemos constancia de que en ningún lugar de nuestra geografía existan tales advertencias).
Existen medidas de protección personal que resultan de utilidad si queremos evitar las picaduras de estos artrópodos:
1. En primer lugar se aconseja llevar ropas claras en las salidas al campo que permiten la identificación del artrópodo antes de que se ancle a la piel.
2. En las actividades al aire libre se debe exponer la menor superficie corporal al artrópodo (pantalones dentro de los calcetines, camisa dentro de los pantalones, camisa de manga larga y gorro).
3. Administración de repelentes. El repelente ideal, entre otras características, debe ser efectivo frente a diversos artrópodos, no irritante en la piel tras su administración tópica o en los tejidos, inodoro o de olor agradable, perdurable tras los lavados y económico20 . Frente a las garrapatas, uno de los más efectivos es la permetrina, que es insecticida y repelente, y presenta una absorción cutánea mínima20 .
4. Desparasitación de los animales de compañía para evitar la presencia de garrapatas en el hogar y/o casas de campo21 .
5. Con el fin de disminuir las poblaciones de garrapatas, se deben controlar las poblaciones de roedores, y eliminar la hojarasca y cuidar las zonas boscosas alrededor de las viviendas22,23 .
6. Con independencia de los mecanismos de protección empleados, se considera imprescindible realizar una inspección cuidadosa de las ropas, piel y cuero cabelludo, tras las salidas al campo en busca de garrapatas. A este respecto se debe conocer que en el caso de la BL hace falta que transcurra un mínimo de 48-72 horas de alimentación de la garrapata para que se inoculen espiroquetas. Así, si retiramos el artrópodo antes de que transcurra este tiempo podremos evitar la transmisión de las mismas24-27 . Por desgracia esta medida no resulta tan eficaz en la prevención de otras enfermedades transmitidas por garrapatas como las ehrlichiosis y las rickettsiosis del grupo de las fiebres manchadas27 .
¿Cómo debemos retirar las garrapatas?
Una vez que se ha producido la picadura de la garrapata se debe proceder a la extracción de la misma. Existen numerosos métodos populares para extraer las garrapatas (aceite, vaselina, quemarlas con cigarrillos, alcohol, gasolina, etc.). No se debe confundir la forma en que mejor se desprenden las garrapatas, con cuál es el modo de extracción de las mismas que se asocia a un menor riesgo infeccioso. En la literatura no existen estudios diseñados para dar respuesta a esta última cuestión, salvo el realizado por nuestro grupo de trabajo15 . En él se demuestra que la extracción de garrapatas con pinzas protege de forma significativa del desarrollo de complicaciones derivadas de la picadura (p < 0,005) y de la infección por microorganismos transmitidos por garrapatas ( p< 0,05) con independencia de otras variables. Los expertos también coinciden en que la retirada cuidadosa con pinzas es el método de elección28 . Así, y aunque todos los métodos son eficaces para la extracción y/o suelta de las garrapatas de la piel, la manipulación, la impregnación en aceite o la extracción manual se asocian a un mayor riesgo de complicaciones.
La extracción de la garrapata se debe realizar con pinzas finas, con borde liso (sin dientes), introduciendo la pinza entre la cabeza y la piel. Posteriormente se debe aplicar una tracción constante y firme de forma perpendicular a la piel hasta que se extraiga el artrópodo. Si después de la extracción quedara alguna parte de la garrapata dentro de la piel, se debe realizar una biopsia del punto de inoculación ya que existe el riesgo de que se produzca una parálisis neurotóxica al quedar las glándulas salivares y la neurotoxina en el paciente9 . Tras la extracción se debe aplicar un desinfectate local (povidona yodada).
¿Debemos administrar profilaxis antibiótica tras la picadura de garrapatas?
La mayoría de las picaduras de garrapata no se acompañan de ningún tipo de complicación, a no ser del desarrollo de reacciones inflamatorias pruriginosas locales y leves (pápula eritematosa y pruriginosa en el punto de la picadura) de corta duración.
Dada la posibilidad del desarrollo de secuelas tardías, la mayoría de los estudios realizados para dar respuesta a la cuestión planteada han sido diseñados para prevenir la BL. A este respecto Warshafsky et al29 publicaron un metaanálisis en el que incluyeron tres estudios prospectivos, randomizados y doble ciego (amoxicilina, penicilina o tetraciclina), y en el que se investigaron más de 600 personas picadas por garrapatas competentes en la transmisión de Borrelia burgdorferi en zonas de alta endemicidad para la BL. En sus conclusiones estiman que por cada 83 pacientes que recibían profilaxis, únicamente se prevenía un caso de BL. Además, dependiendo del antibiótico empleado ( por ejemplo, amoxicilina), de cada diez pacientes tratados, uno desarrrollaría una reacción cutánea (urticaria) que podría ser de gravedad. Los autores concluyen que los efectos adversos serían mayores que los beneficios.
Los Centros de Control de Enfermedades y Prevención de Atlanta (CDC) no recomiendan el uso rutinario de profilaxis antibiótica para la profilaxis de las infecciones transmitidas por garrapatas30 . Además, hace aproximadamente un año, un panel de expertos de enfermedades infecciosas de la Sociedad Americana de Enfermedades Infecciosas (IDSA) recomendó que los pacientes que sufrían una picadura de garrapatas no recibieran de forma rutinaria antibioterapia profiláctica31 .
No obstante, existen trabajos que apuntan la idoneidad del tratamiento profiláctico con antibióticos. En un estudio de coste-efectividad realizado por Magid et al32 sobre una cohorte ficticia de 100.000 individuos picados por garrapatas (objetivo: disminución de las complicaciones tardías de la BL) concluyen que el tratamiento empírico con doxicilina durante dos semanas estaría indicado si la probabilidad de infección por B. burgdorferi fuera >= 3,6%, dependiendo este resultado del porcentaje de garrapatas infectadas en cada medio. Este artículo fue muy debatido y criticado sin que se llegara a un consenso. En todo caso, opinamos que el conocimiento del porcentaje de infección del vector en cada medio es una herramienta que puede ayudar a la toma de decisiones 19,33 .
Por otro lado, y tal y como hemos comentado con anterioridad, a la hora de administrar una antibioterapia profiláctica, algunos autores también recomiendan considerar el tiempo que ha estado alimentándose la garrapata o el grado de engorde de la misma ya que al parecer se necesita un tiempo mínimo de alimentación del artrópodo sobre la víctima para que se produzca el paso de espiroquetas. Así, el riesgo de infección por B. burgdorferi es mayor cuando la garrapata se está alimentando durante más de 48-72 horas24-27 . No obstante, creemos que esta recomendación es poco práctica, ya que en una gran mayoría de los casos no es posible valorar bien estos aspectos, y aún menos reconocer la especie de artrópodo. Además en Europa el período de incubación de la BL parece ser más corto que en América. Por otro lado y como también hemos señalado, otras infecciones como las provocadas por Ehrlichia (agente de la ehrlichiosis humana granulocítica) o infecciones por rickettsias del grupo de las fiebres manchadas, pueden transmitirse de forma precoz (en horas)27 , por lo que el concepto no es extensible a la profilaxis universal de las ETG.
En el caso de que se decida la administración de un antibiótico para la profilaxis de la BL, éste debería administrarse en las primeras 48 horas de producirse la picadura, ya que éste es el tiempo mínimo que permanece la espiroqueta en la puerta de entrada en el modelo animal34 . En este mismo año, la revista New England Journal of Medicine publica un original de Nadelman et al en el que e valúan la eficacia de una dosis única de 200 mg de doxiciclina para la profilaxis de la BL en una zona hiperendémica en los Estados Unidos de América35 . Se trata de un ensayo clínico aleatorio, doble ciego y controlado con placebo en pacientes que presentaban una garrapata adherida durante más de 72 horas. La eficacia del tratamiento con doxicilina fue del 87%. Además, esta pauta evitó la aparición de complicaciones relacionadas con la BL como eritema migratorio (p <0,04). No obstante, esta actuación no estuvo exenta de complicaciones, siendo las más frecuentes las náuseas y los vómitos tras la administración de doxiciclina (p <0,001). El artículo motivó un editorial en el que se apuntaba la posibilidad de la administración tópica de antibióticos para la prevención de la BL36 . A este respecto, nuestro grupo de trabajo realizó hace años un estudio controlado, randomizado y doble ciego, con el objetivo de valorar la eficacia de la administración tópica de oxittraciclina al 2% en una zona endémica para la BL. En él comparábamos su administración tópica (dos aplicaciones durante dos días) frente a vaselina, realizando un seguimiento clínico y serológico a los 30 y 60 días. Los pacientes que recibieron el antibiótico tópico no desarrollaron infección o enfermedad relacionada con la picadura de garrapata (BL, fiebre botonosa y/o infección por sus respectivos agentes causales), observándose diferencias significativas (p=0,0113 test exacto de Fisher [TEF]). Además, ningún paciente desarrolló efectos adversos relacionados con la administración del placebo o terramicina tópica (no publicado). Estos datos no han sido corroborados y el pequeño tamaño de la muestra no permite realizar una recomendación en regla (seguimos trabajando).
En nuestro Centro no aconsejamos la profilaxis generalizada de las ETG con antibióticos. En principio los datos de eficacia de la profilaxis con doxiciclina de Nadelman et al35 no son extrapolables a Europa, en donde habría que realizar un estudio multicéntrico para demostrar la efectividad de la profilaxis antibiótica. Otra cuestión es si los resultados de este hipotético estudio pudiesen ser aceptados por todas las regiones de Europa, ya que existen grandes diferencias climáticas, de fauna y flora entre las mismas. En todo caso, somos de la opinión de ofrecer profilaxis con doxiciclina cuando la garrapata haya sido manipulada15 , la garrapata se encuentre repleta (varios días de alimentación) o cuando el paciente presente un alto grado de ansiedad. En la práctica diaria preferimos avisar de las posibles complicaciones (labor formativa que venimos realizando en los Centros de Salud de nuestra Comunidad) y realizar un seguimiento del paciente detectando de forma precoz la aparición de signos y/o síntomas relacionados con la picadura y actuando en consecuencia. Tampoco somos de la opinión de realizar un seguimiento serológico ya que éste resulta caro y molesto para el paciente.
¿Qué importancia tienen las vacunas en la prevención de las enfermedades transmitidas por garrapatas?
En los Estados Unidos de América se dispone de una vacuna eficaz frente a BL (vacuna frente a la OspA). La decisión de administrar esta vacuna está en función del riesgo individual, de la prevalencia de BL en la zona y del contacto que el individuo presenta con las garrapatas (duración, estacionalidad). Por otro lado, esta vacuna sólo ofrece protección frente a la BL no frente a otras zoonosis que sabemos que pueden coinfectar a las mismas garrapatas (babesia, ehrlichia), por lo que a pesar de la existencia de una vacuna se han de continuar aplicando las medidas antes comentadas.
No existen datos de eficacia de esta vacuna en Europa, por lo que de momento no está justificado su uso, sin que por ello dejemos de exponer aquí alguna de las características de esta vacuna y algunos de los datos publicados37-45 .
En primer lugar hay que señalar que la administración de esta vacuna es segura y eficaz tanto en animales como en seres humanos38-42 . Se administra vía intramuscular (30 µg), aconsejándose tres dosis para una mayor efectividad. Existen dos posibles pautas. Una de administración en los meses 0, 1 y 12; y otra en los meses 0, 1 y 2. En esta última se aconseja que la tercera dosis se administre en el mes de abril con el fin de obtener un título de anticuerpos suficientes durante el verano42-44 . El título de anticuerpos obtenidos con ambas pautas es similar42 . En un análisis sobre la intención de tratar, la eficacia definitiva de la vacuna frente a la BL (presencia de eritema migrans, o de manifestaciones neurológicas, músculo-esqueléticas, o cardiovasculares de la BL, junto a confirmación microbiológica mediante cultivo, (reacción en cadena de la polimerasa [PCR] positiva o seroconversión medida mediante western-blot) tras administrar dos dosis fue del 49% (IC 95%: 15-69) y tras una tercera dosis del 76% (IC 95%: 58-86)43 . La eficacia en la protección de los pacientes infectados pero sin clínica (pacientes asintomáticos pero con seroconversión) fue del 83% durante el primer año (IC 95%: 32-97) y del 100% en el segundo año (IC 95%: 26-100).
En el otro estudio, realizado por Sigal et al44 (no comparable al anterior por su diferencia metodológica), la eficacia al año tras administrar dos dosis fue del 68%, logrando a los dos años tras la administración de la tercera dosis una eficacia del 92%. En este sentido, aunque no existen recomendaciones oficiales37 , para evitar el descenso del título de anticuerpos, se aconseja una revacunación cada año o cada tres años, si bien la revacunación anual aumenta el coste-efectividad de la misma44,45 . Los efectos adversos más frecuentes son locales con enrojecimiento, dolor y edema en el punto de inyección de la vacuna. Puede aparecer un cuadro pseudo-gripal con fiebre, escalofríos y mialgias42-44 . De forma anecdótica, en el estudio de Sigal et al44 se observó un aumento de la incidencia de otitis externas. A pesar de que se ha señalado la posibilidad del desarrollo de cuadros de artritis resistentes asociados a la respuesta inmune frente a la OspA, la frecuencia en los vacunados no aumenta respecto del grupo placebo. No se conoce con certeza la efectividad del uso de esta vacuna en mujeres embarazadas, en inmunodeprimidos, ni en pacientes menores de 15 años o mayores de 70 años. Tampoco se ha evaluado la efectividad en zonas no endémicas para la BL41 .
Según los estudios referidos, los pacientes que deben ser vacunados son aquellos entre 15 y 70 años que residen en zonas endémicas, y aquellos que por su actividad, deben acudir a estas zonas de riesgo (forestales, etc)37,41,42,44 .
Que nosotros sepamos, no existen vacunas para la prevención de otras ETG presentes en nuestro medio. No obstante en Centroeuropa una de las garrapatas presentes en España (Ixodes ricinus) es el vector de la Encefalitis Centro-Europea de PrimaveraVerano (familia de los flavivirus)46,47 . Para su prevención existe una gammaglobulina que puede administrarse pre o postexposición al vector (siempre en una zona endémica) antes de que transcurran cuatro días47-49 . En poblaciones de alto riesgo o en individuos que visitan con regularidad zonas con alto riesgo para contraer esta enfermedad también se aconseja la administración de vacunas. La pauta recomendada se basa en la inyección de una primera dosis de vacuna (basal), seguida de una segunda dosis entre el primer y tercer mes, y otra tercera dosis entre nueve y doce meses de la segunda47,48,50 .
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Abstract book of the 6th International Congress for Infectious Diseases. Prague (Czech Republic) 1994; A660. 9. Oteo JA, Maraví E, Martínez de Artola V, Antuñano P. Parálisis por mordedura de garrapata. Med Clin (Barc) 1990; 94: 275-276. 10. Oteo JA, Blanco JR, de Artola VM, Ibarra V. First report of Human Granulocytic Ehrlichiosis from Southern Europe (Spain). Emerg Infect Dis 2000; 6: 430-431. 11. Oteo JA, Gil H, Barral M, Pérez A, Jiménez S, Blanco JR, et al. Presence of granulocytic ehrlichia in ticks and serological evidence of human infection in La Rioja. Spain. Epidemiol Infect 2001; 127:353. 12. Oteo JA, Ibarra V. Dermacentor Borne Necrosis Eritema Linfadenopatía (DEBONEL). ¿Una nueva enfermedad transmitida por garrapatas? Enferm Infecc Microbiol Clin (en prensa). 13. Guerrero A, Escudero R, Martí-Belda P, Quereda C. Frecuencia de las manifestaciones clínicas de la borreliosis de Lyme en España. Enferm Infecc Microbiol Clin 1996; 14: 72-79. 14. Oteo Revuelta JA, Blanco Ramos JR, Martínez de Artola V, Grandival García R, Ibarra Cucalón V, Dopereiro Gómez R. Eritema migratorio (borreliosis de Lyme). Características clinico-epidemiológicas de 50 pacientes. Rev Clin Esp 2000; 200: 60-63. 15. Oteo JA, Martínez de Artola V, GómezCadiñanos R, Casa JM, Blanco JR, Rosel L. Evaluación de los métodos de retirada de las garrapatas en la ixodidiasis humana. Rev Clin Esp 1996; 196: 584-587. 16. Oteo JA, Martínez de Artola V. Borreliosis de Lyme: aspectos epidemiológicos y etiopatogenia. Enf Infecc y Microbiol Clin 1995; 13: 557-558. 17. Oteo JA, Casa JM, Martínez de Artola V. Lyme disease in outdoor workers: risk factors, preventive measures and tick removal methods. Am J Epidemiol 1991; 133: 754-755. 18. Costello CM, Steere AC, Pinkerton RE, Feder HM. A prospective study of tick bites in an endemic area for Lyme disease. J Infect Dis 1989; 159: 136-139. 19. Oteo JA, EstradaPeña A. Garrapatas infectadas por Borrelia burgdorferi (enfermedad de Lyme). Estudio de 4.662 garrapatas (Ixodioidea) en la Comunidad Autónoma de La Rioja. Enferm Infecc Microbiol Clin 1992; 10 (S2): 139. 20. Brown M, Hebert AA. Insect repellents: an overview. J Am Acad Dermatol 1997; 36: 243-249. 21. Curran KL, Fish D. Increased risk of Lyme disease for cat owners. N Engl J Med 1989; 320: 183. 22. Schulze TL, Jordan RA, Hung RW. Suppression of Ixodes scapularis (Acari: Ixodidae) after remoal of leaf litter. J Med Entomol 1995; 32: 730-733. 23. Curran KL, Fish D, Piesman J. Reduction of nymphal Ixodes dammini (Acari: Ixodidae) in a residential suburban landscape by area application of insecticides. J Med Entomol 1993; 30: 107-113. 24. Piesman J, Mather TN, Sinsky RJ, Spielman A. Duration of tick attchment and Borrelia burgdorferi transmission. J Clin Microbiol 1987; 25: 557-558. 25. Sood SK, Salzman MB, Johnson BJ, Happ CM, Feig K, Carmody L, et al. Duration of tick attachment as a predictor of the risk of Lyme disease in an area in which Lyme disease is endemic. J Infect Dis 1997; 175: 996-999. 26. Piesman J. Dynamics of Borrelia burgdorferi transmission by nymphal Ixodes dammini ticks. J Infect Dis 1993; 167: 1.082-1.085. 27. Des Vignes F, Piesman J, Hefferman R, Schhulze TL, Stafford KC III, Fish D. Effect of tick removal on transmission of Borrelia burgdorferi and Ehrlichia phagocytophilia by Ixodes scapularis nymphs. J Infect Dis 2001; 183: 773-778. 28. Matuschka FR, Spielman A. The vector of the Lyme disease spirochete. N Engl J Med 1992; 327: 542. 29. Warshafsky S. Nowakowski J, Nadelman RB, Kamer RS, Peterson S, Wormser GP. Efficacy of antibiotic prophylaxis for prevention of Lyme borreliosis. J Gen Intern Med 1996; 11: 329-333. 30. Antibiotic prophylaxis of Lyme disease following recognized bite: Bacterial Zoonoses Branch, Division of Vector-Borne Diseases National Center for Infectious Diseases, Centers for Diseases Control. Con Med 1991; 55: 691-693. 31. Wormser GP, Nadelman RB, Dattwyler RJ, Dennis DT, Shapiro ED, Steere AC, et al. Practice guidelines for the treatment of Lyme disease. Clin Infect Dis 2000; 31 (S1): S1-S14. 32. Magid D, Schwartz B, Craft J, Schwartz JS. Prevention of Lyme disease after tick bites: a cost-effectiveness analysis. N Engl J Med 1992; 327: 534-541. 33. Estrada-Peña A, Oteo JA, EstradaPeña R, Gortazar C, Osácar JJ, Moreno JA, Castellá J. Borrelia burgdorferi in ticks (Acari: Ixodidae) from two different foci in Spain. Exp Acarol 1995; 19: 173-180. 34. Shih CM, Pollack RJ, Telford SR III, Spielman A. Delayed disssemination of Lyme disease spirochetes from the site of deposition in the skin of mice. J Infect Dis 1992; 166: 827-831. 35. Nadelman RB, Nowakowski J, Fish D, Falco RC, Freeman K, McKenna D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med 2001; 345: 79-84. 36. Shapiro ED. Doxycycline for tick bites not for everyone. N Engl J Med 2001; 342: 133-134. 37. Steeere AC. Lyme disease. N Engl J Med 2001; 345: 115-125. 38. Schoen RT, Meurice F, Brunet CM, Cretella S, Krause DS, Craft JE, et al. Safety and immunogenicity of an outer surface protein A vaccine in subjects with previous Lyme disease. J Infect Dis 1995; 172: 1.324-1.329. 39. Telford SR, Kantor FS, Lobet Y, Barthold SW, Spielman A, Flavell RA, et al. Efficacy of human Lyme disease vaccine formulations in a mouse model. J Infect Dis 1995; 171: 1.368-1.370. 40. Keller D, Koster FT, Marks DH, Hosbach P, Erdile LF, Mays JP. Safety and immunogenicity of a recombinant outer surface protein A Lyme vaccine. JAMA 1994; 271: 1.764-1.768. 41. Recommendations for the Use of Lyme Disease Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999; 48(RR07): 1-17. 42. Schoen RT, Sikand VK, Caldwell MC, Van Hoecke C, Gillet M, Buscarino C, et al. Safety and immunogenicitiy profile of a recombinant outer-surface protein A Lyme disease vaccine: clinical trial of a 3-dose schedule at 0, 1, and 2 months. Clin Ther 2000; 22: 315-325. 43. Steere AC, Sikand VK, Meurice F, Parenti DL, Fikrig E, Schoen RT, et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. N Engl J Med 1998; 339: 209-215. 44. Sigal LH, Zahradnik JM, Lavin P, Patella SJ, Bryant G, Haselby R, et al. A vaccine consisting of recombinant Borrelia burgdorferi outersurface protein A to prevent Lyme disease. N Engl J Med 1998; 339: 216-222. 45. Meltzer MI, Dennis DT, Orloski KA. The cost effectiveness of vaccinating against Lyme disease. Emerging Infect Dis 1999; 5: 321-328. 46. Heinz FX, Mandl CW. The molecular biology of tickborne encephalitis virus. Review article. APMIS 1993; 101: 735745. 47. Kunz C. Tickborne encephalitis in Europe. Acta Leidensia 1992; 60: 1-14. 48. Barrett PN, Dorner F. Tickborne encephalitis vaccine. En: Plotkin SA, Mortimer EA, eds. Vaccines. Second Edition. Philadelphia: WB Saunders Company, 1994; 715-727. 49. Waldvogel K, Bossart W. Huisman T, Boltshauser E, Nadal D. Severe tick-borne encephalitis following passive immunization. Eur J Pediatr 1996; 155: 775-779. 50. Kunz C. The impact of a mass vaccination campaing on tick-borne encephalitis in Austria. En: 2nd International Symposium on Tick-borne encephalitis. Baden/Viena 6th- 7th June,
620 ANTICUERPOS FRENTE AL PÉPTIDO C6 (VlsE) DE BORRELIA BURGDORFERI S.L. UNA EVALUACIÓN PRELIMINAR
B. Vilar, M.J. López de G. y J. Pérez-Irezábal
Introducción: La reciente caracterización del péptido C6, una fracción altamente conservada e inmunógena de una proteina variable de la superficie de la borrelia (VlsE), y presente en las 3 genoespecies implicadas en la Borreliosis de Lyme (BL) en Europa, se perfila como una alternativa prometedora para el diagnóstico serológico de las diversas formas de la BL.
El Objetivo de la presente comunicación es realizar una valoración preliminar de un ELISA basado en la demostración de anticuerpos frente al péptido C6.
Material y métodos: 66 muestras (62 de suero y 4 LCR) pertenecientes a 54 pacientes, fueron obtenidos de nuestra seroteca (congeladas a -20ºC, de los años 2001-03); 20 muestras de 13 pacientes con diagnóstico clínico y serológico de BL (Inmunoblot IgG o/y IgM positivo, grupo I.); 23 muestras (20 pacientes) con clinica compatible y serología convencional positiva (ELFA, IFI), pero inmunoblot negativo ó indeterminado (gr.II), y por último 23 muestras de 21 pacientes con otra patología infecciosa: neumonia por Chlamydia (2 pacientes),Fiebre Q (2), F.botonosa (2), Lues (5), Enfermedad por arañazo de gato (EAG, 5), Toxoplasmosis (2) e infección por EBV (3). Todas las muestras fueron procesadas para la demostración de anti-C6 según indicaciones del fabricante (QuickELISA C6 Borrelia kit. Immunetics, LETI)
Resultados: Muestras de 11 de los 13 pacientes (84,6%) del gr.I (4 ECM, 8 neuroborreliosis y 1 artritis), y de 2 de 20 del gr.II (concordancia: 90%) mostraron reactividad sérica frente al antígeno peptídico C6 (los 2 pacientes positivos tuvieron inmunoblot indeterminado). Solamente un paciente del grupo III (con EAG) fué positivo (E:95%)
Conclusiones: Dada la buena sensibilidad (84,6%) y mejor especificidad (95%) obtenida, la deteción de anticuerpos anti-C6, se perfila, si se confirman estos resultados, como una alternativa superior a las técnicas de EIA convencional -e IFI- para el cribado serológico de pacientes con sospecha de BL
425 INCIDENCIA DE ENFERMEDADES TRANSMITIDAS POR GARRAPATAS EN UN AREA SANITARIA DE LA ZONA DE LEVANTE
A. Guerrero, F. Gimeno, J. Colomina y M. Molina Servicio de Microbiología, Área de Diagnóstico Biológico, Hospital de La Ribera, Alcira-Valencia.
Objetivos: Las enfermedades transmitidas por garrapatas en España incluyen: fiebre botonosa mediterránea, fiebre recurrente endémica, tularemia, babesiosis, borreliosis de Lyme, ehrlichiosis, y una nueva enfermedad denominada DEBONEL/TIBOLA, siendo las tres últimas las consideradas como emergentes. Existen pocos datos epidemiológicos regionales sobre la incidencia de cada una de ellas. Por ello, el objetivo de este estudio fue conocer la incidencia de las enfermedades transmitidas por garrapatas en un área sanitaria de la zona de Levante.
Materiales y métodos: El estudio se realizó en el Area Sanitaria 10 de la Comunidad Valenciana, con un población dependiente de 235.000 habitantes. Se analizaron retrospectivamente los 5 últimos años, durante los cuales se detectaron 675 pacientes con sospecha clínica de enfermedades tra nsmitidas por garrapatas. Se aceptó como criterios diagnósticos de dichas enfermedades: sospecha o documentación de picadura de garrapata, con clínica y analítica compatible, junto con exclusión razonable de otras enfermedades. Para establecer el diagnóstico microbiológico, se emplearon técnicas serológicas, cultivos bacterianos, frotis de sangre periférica o PCR según el agente etiológico a estudio. Se revisaron las historias clínicas de todos aquellos pacientes con hallazgos microbiológicos.
Resultados: De los 380 pacientes estudiados para borreliosis de Lyme solo 22 mostraron serología positiva para Borrelia burgdorferi, aunque ninguno de ellos cumplió los criterios diagnósticos del Grupo Español de Trabajo de Borreliosis de Lyme. De los 110 pacientes estudiados serológicamente para la fiebre botonosa mediterránea solo 6 mostraron serología IgG positiva para Ricketsia conorii. De ellos, solo uno reunía criterios diagnósticos (presencia de fiebre, mancha negra y/o erupción cutánea). Un paciente de 9 años cumplía los criterios diagnósticos de la nueva enfermedad DEBONEL/TIBOLA (picadura de garrapata en cuero cabelludo con escara periférica, adenopatía regional y alopecia residual). No se documento ningún caso de fiebre recurrente, tularemia, babesiosis o ehrlichiosis.
Conclusiones: Nuestros datos sugieren que la incidencia de enfermedades transmitidas por garrapatas en el Levante es muy baja. Sin embargo este dato de incidencia puede estar en parte condicionado por una baja concienciación del clínico ante estas enfermedades.
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426 DETECCIÓN DE VARIANTES NO PATÓGENAS DE ANAPLASMA PHAGOCYTOPHILUM EN IXODES RICINUS DE LA PENÍNSULA IBÉRICA
A. Portillo*, A.S. Santos**, S. Santibáñez*, J.R. Blanco*, V. Ibarra*, F. Bacellar** y J.A. Oteo* *Hospital General de La Rioja, Logroño, La Rioja, España. **Centro de Estudos de Vectores e Doenças Infecciosas. Instituto Nacional de Saúde Dr. Ricardo Jorge, Águas de Moura, Portugal.
Introducción: La anaplasmosis humana (AH) (antigua ehrlichiosis humana granulocítica) es una zoonosis emergente transmitida por garrapatas. Estudios previos han detectado una alta prevalencia de infección por Anaplasma phagocytophilum (anteriormente, Ehrlichia phagocytophila) en Ixodes ricinus del Norte de España (La Rioja y País Vasco). Sin embargo, hasta la fecha, en la Península Ibérica sólo se han comunicado casos esporádicos de AH. Estos hechos podrían explicarse por diferencias en la virulencia de distintas variantes de A. phagocytophilum.
Objetivo: Identificar posibles variantes de A. phagocytophilum en I. ricinus recogidos en La Rioja mediante la detección de mutaciones en el gen ARNr 16S de Anaplasma.
Material y métodos: Se analizaron 90 ejemplares de I. ricinus (84 adultos y 6 ninfas) recogidos de vacas en Villoslada de Cameros (La Rioja) en noviembre de 2003. El ADN se extrajo individualmente de cada garrapata. Se amplificó por PCR el gen ARNr 16S de A. phagocytophilum de las muestras agrupadas (cebadores GE9f y GE10r). Cuando el resultado fue positivo, se repitió la PCR con ADN de ejemplares individuales. Los amplicones obtenidos (919 pb) se secuenciaron en ambos sentidos y por duplicado. En todos los casos se incluyeron controles positivos y negativos adecuados.
Resultados: Mediante PCR se obtuvo una banda del tamaño esperado correspondiente al ADN mezcla proveniente de las 6 ninfas agrupadas de I. ricinus. La PCR posterior de cada muestra individual demostró la presencia de A. phagocytophilum en una ninfa. El análisis de la secuencia de esta muestra mostró dos mutaciones puntuales en los nucleótidos 76 y 84 (G y A, respectivamente) con respecto a la secuencia del agente de la AH (nº acceso en GenBank U02521). Estos cambios corresponden a la variante 1 (AP-variante 1) descrita en EE.UU. por Massung y cols. Dichas mutaciones no se evidenciaron en el control positivo.
Conclusiones: Se ha detectado por primera vez en la Península Ibérica la presencia de AP- variante 1 de A. phagocytophilum en I. ricinus. Dicha variante no se ha asociado por el momento con AH, por lo que su presencia puede justificar la escasa incidencia de casos clínicos en la Península, en contraste con la alta prevalencia de infección por A. phagocytohilum en I. ricinus.
Agradecimientos: Financiado en parte con ayudas FIS PI021810 y G03/057, M. Sanidad y Consumo, España.
429 DETECCIÓN DE ANTICUERPOS FRENTE A RICKETTSIA SLOVACA EN PERROS Y ZORROS EN LA PROVINCIA DE SORIA
L. Lledó, J.L. Serrano*, M.I. Gegúndez, J.V. Saz, A. González y M. Beltrán Dpto. Microbiología y Parasitología, Facultad de Medicina, Universidad de Alcalá. *Servicio Territorial de Sanidad y Bienestar Social de Soria.
Objetivos: Rickettsia slovaca, miembro del grupo de las fiebres exantemáticas, produce un cuadro clínico denominado TIBOLA. Se transmite desde los reservorios al ser humano por la picadura de garrapatas del género Dermacentor (D. marginatus, D. reticulatus). Los cánidos, tanto domésticos como salvajes, tienen un papel importante en la epidemiología de muchas enfermedades infecciosas, como en el caso de ciertas rickettsiosis (Rickettsia conorii). El objetivo de este estudio es investigar la presencia de anticuerpos frente a R. slovaca en perros y zorros de la provincia de Soria.
Material y métodos: Durante los años 1993 a 2000, se obtuvieron 313 muestras de sangre de zorro mediante cacerías, y 73 de perros que acudieron a clínicas veterinarias en la provincia de Soria. La sangre se transportó refrigerada a 4ºC al laboratorio y tras la separación del suero, éste se conservó a -20ºC hasta su análisis. La técnica utilizada en el estudio fue la inmunofluorescencia indirecta (IFI). El antígeno empleado fueron células Vero E6 (ATCC 1586) infectadas con R. slovaca (cepa 246 CDC), y como conjugado suero anti Ig G perro (SIGMA). Los sueros con títulos iguales o superiores a 1:40 se consideraron positivos.
Resultados: se detectó la presencia de anticuerpos específicos frente a R. slovaca en 21 zorros y en 10 perros, lo que representa una prevalencia del 6.7% y del 13.7% respectivamente (diferencias estadísticamente significativas entre ambos p < 0,05). Los títulos oscilaron entre 1:40 y 1:320 en los zorros, y entre 1:80 y 1:1280 en los perros.
Conclusiones: Se demuestra la existencia de infección por R. slovaca en cánidos domésticos y salvajes de la provincia de Soria. El relevante número de ejemplares (sobre todo perros) con anticuerpos, sugiere que el contacto humano con dichos animales puede suponer un factor de riesgo para adquirir esta infección. Estos datos obligan a seguir investigando para poder establecer la importancia de estos animales en el ciclo epidemiológico de esta bacteria en nuestro país.
430 APROXIMACIÓN AL AGENTE ETIOLÓGICO DE UNA NUEVA ENFERMEDAD TRANSMITIDA POR GARRAPATAS (DEBONEL)
V. Ibarra*, A. Portillo*, S. Santibañez*, J.R. Blanco*, A. Orduña** y J.A. Oteo* *Hospital de La Rioja. **Universidad Valladolid.
Introducción: En los últimos años venimos observando en La Rioja (al igual que en otras zonas europeas), una afección transmitida por garrapatas:DEBONEL/TIBOLA, con características epidemiológicas, de vector, clínicas y microbiológicas diferentes a las previamente descritas. Esta afección aparece en los meses fríos del año y está transmitida por Dermacentor marginatus. Los rasgos clínicos más destacados son la presencia de necrosis y eritema en la zona de la picadura y la existencia de linfadenopatías regionales dolorosas. Hasta el momento no se ha podido establecer de forma definitiva el agente etiológico, si bien se ha implicado a una rickettsia del grupo de las fiebres manchadas (SFG): Rickettsia slovaca.
Objetivo: Investigar, mediante técnicas de biología molecular (PCR y secuenciación) las especies de rickettsia presentes en D. marginatus retiradas de pacientes que desarrollaron DEBONEL.
Material y métodos: Entre Enero de 2001 y Enero de 2004, 20 pacientes acudieron a la consulta con las manifestaciones clínicas anteriormente descritas (DEBONEL). De ellos 8 adjuntaban la garrapata que les había picado. Las 8 fueron identificadas como D. marginatus adultos. Todos los ejemplares se procesaron individualmente. Tras la extracción del DNA, se amplificaron por PCR los fragmentos de los genes de Rickettsia sp.:rOmpA (PCR semianidada), glta y 16SrRNA (PCR convencional). Posteriormente se secuenciaron los productos amplificados para determinar la especie.
Resultados: En todos los ejemplares estudiados se detectó infección por rickettsias del SFG. Tras la secuenciación del gen rOmpA se obtuvo en 5 muestras una secuencia con un 100% de identidad con el mismo gen de R. slovaca, y en las 3 restantes se evidenció máxima identidad (98%) con el fragmento del gen rOmpA de Rickettsia sp. RpA4, DnS14 y DnS28.
Conclusiones: Todos los D. marginatus retirados de personas que dearrollan DEBONEL están infectados por rickettsias del SFG. Hemos identificado R. slovaca y Rickettsia sp. RpA4, DnS14 y DnS28. Estos hallazgos sugieren la implicación de más de una especie de rickettsia en la etiología de la enfermedad.
Financiado en parte con ayudas FIS PI021810 y G03/057. M. Sanidad y Consumo, España.
------------------------------------
431 SEROPREVALENCIA DE LA INFECCIÓN POR BORRELIA BURGDORFERI EN CIERVOS DE LOS MONTES DE TOLEDO (CASTILLA LA MANCHA)
J. Ledesma, M.I. Gegúndez, L. Lledó, J.V. Saz y M. Beltrán Dpto. Microbiología y Parasitología, Facultad de Medicina, Universidad de Alcalá
Objetivos: La infección producida por Borrelia burgdorferi (agente etiológico de la enfermedad de Lyme) es una zoonosis que se transmite desde sus reservorios (principalmente roedores) a través de vectores (garrapatas del género Ixodes). Las formas adultas de estas garrapatas suelen encontrarse en animales de tamaño medio-grande como perros, ciervos, cabras..., pudiendo, por tanto, participar en la epidemiología de esta infección. El objetivo de este estudio es investigar la presencia de anticuerpos frente a B. burgdorferi en ciervos de los Montes de Toledo.
Material y métodos: Durante los años 1997 y 1998 se obtuvieron sueros de 107 ciervos (Cervus elaphus) mediante cacerías. Se recogieron datos de sexo, edad, peso y localización geográfica de los ejemplares. Los sueros se estudiaron mediante inmunofluorescencia indirecta, utilizando como antígeno B. burgdorferi (cepa B31) cultivada en medio BSK II. Como conjugado se empleó un suero de ratón anti Ig G de oveja (SIGMA). Se consideraron positivos títulos mayores o iguales a 1:64.
Resultados: Se detectaron 42 sueros con anticuerpos específicos frente a B. burgdorferi, lo que representa una prevalencia del 39,25% (23.35% para machos, 15,89% para hembras). No se encontraron diferencias estadísticamente significativas ni por sexo, edad, peso ni localización geográfica. Los títulos de los seropositivos oscilaron entre 1:64 y 1:256.
Conclusiones: Se demuestra la presencia de infección por B. burgdorferi en ciervos de los Montes de Toledo. La elevada prevalencia encontrada, superior a la hallada en otros estudios para estos animales y otros como suidos y lagomorfos, sugiere que el contacto humano con estos animales puede suponer un factor de riesgo para ciertos colectivos como cazadores, campesinos o turistas de la zona.
Subject: [lyme_y_otras_zoonosis_cronicas_espanol] SFC y western blot para Borrelia
Esto es información del congreso internacional de SFC de hace 10 años:
..."El western blot para Borrelia mostró 3 o más bandas de IgG específicas en 54 de 131 pacientes (41.2 %)...
Si las bandas son específicas no es necesario tener 3 bandas, una o dos bandas se considera un resultado positivo, además no tienen en cuenta la IgM que como hemos visto es más sensible. Si hubieran tenido esto en cuenta seguramente la mayoría de los pacientes serían positivos para Borrelia. No parece que hayamos avanzado mucho en 10 años, por no decir que seguimos exactamente igual.
FIRST WORLD CONGRESS ON CHRONIC FATIGUE SYNDROME AND RELATED DISORDERS Brussels, November 9-11, 1995
CHRONIC FATIGUE SYNDROME: EVALUATION OF A 30-CRITERIA-SCORE AND CORRELATION WITH IMMUNE ACTIVATION - A. HILGERS, J. FRANK
Institut for angewandte Immunologie und Umweitmedizin, Duesseldorf, Germany
505 patients with no other definitive diagnosis and suspicion of chronic fatigue syndrome were checked by an 45-criteria-score. 15 criteria corresponded with the criteria of the Centers of Disease Control and were fulfilled by 385 patients. These 385 patients showed significant difference to 53 healthy controls in 40 of the 45 criteria (p < 0.001, twitches and food allergies p < 0.05). Furthermore sensitivity, specificity and precision of every criterion was calculated. The 15 CDC criteria were all significant (p < 0.001), 15 other significant criteria of descending precision were added : respiratory infections, palpitations, dizziness, dyspepsia, dryness of mouthleyes, allergies, nausea, paresthesia, loss of hair, skin alterations, lack of coordination, chest pain, personality changes, eczema, general infections, twitches, urogenital infections (precision of the 30 criteria: 95.7% down to 36.3%). Correlation (Spearman rank-correlation-coefficient rs ties corrected) between this 30-criteria- score and immunological parameters could be evaluated in 472 of the 505 patients. Significant positive correlation to the 30-criteria-score was found in: CD8+-T-Iymphocytes (rs = 0.083, p = 0.036),DR+-T-Iympho-cytes (rs, = 0.085, p = 0.032), gamma globulin (rs = 0.099, p = 0.016), IgM (rs= 0.145, p = 0.001), IgG (rs = 0.087, p = 0.029), and the number of types of autoantibodies (mainly ANA, ACA, thyreoidal and parital antibodies) (rs = 0.1274, p = 0.003); significant negative correlation was found in albumin-globulin-ratio (rs = -0.102, p = 0.014), eosinophils (rs = -0.106, p = 0.011) and IgE (rs, = -0.126, P = 0.020). Most of these parameters did also correlate with one another.
On the other hand in the group of the 505 patients serological tests of the following pathogens were striking: HHV-6-IgG in 243 of 487 patients (49.9 %), EBV-EA in 170 of 480 (35.4 %), HSV-KBR in 135 of 462 (29.2 %), CMV-KBR in 49 of 390 (12.5 %), Chlamydia-IgA in 142 of 406 (35.0 %). ****Borrelia western blot showed 3 or more specific IgG-bands in 54 of 131 patients (41.2 %)****. In single special cases infection with EBV, HHV-6 and CMV, respectively, was confirmed by DNA-PCR-test.
CONCLUSIONS : In more and more larger groups of patients with CFS and related disorders we often see clinical signs and longer history of other symptoms beside the classical criteria of CFS, specially a high prevalence of local and general susceptibility to infections and prolonged inflammatory processes. Together with other results published by us and other investigators the data further confirm the hypothesis that a reduced or unstable immune control or delayed immune reaction to persisting viruses or bacterial intracellular pathogens can - triggered by common infections or other environmental factors - lead to a chronic neuro-immune activation state and auto-immune disorders. Hypersensitivity symptoms of the patients might not be mediated by classical allergy with IgE and eosinophils.
Saludos,
Miguel
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Esto es información del congreso internacional de SFC de hace 10 años:
..."El western blot para Borrelia mostró 3 o más bandas de IgG específicas en 54 de 131 pacientes (41.2 %)...
Si las bandas son específicas no es necesario tener 3 bandas, una o dos bandas se considera un resultado positivo, además no tienen en cuenta la IgM que como hemos visto es más sensible. Si hubieran tenido esto en cuenta seguramente la mayoría de los pacientes serían positivos para Borrelia. No parece que hayamos avanzado mucho en 10 años, por no decir que seguimos exactamente igual.
FIRST WORLD CONGRESS ON CHRONIC FATIGUE SYNDROME AND RELATED DISORDERS Brussels, November 9-11, 1995
CHRONIC FATIGUE SYNDROME: EVALUATION OF A 30-CRITERIA-SCORE AND CORRELATION WITH IMMUNE ACTIVATION - A. HILGERS, J. FRANK
Institut for angewandte Immunologie und Umweitmedizin, Duesseldorf, Germany
505 patients with no other definitive diagnosis and suspicion of chronic fatigue syndrome were checked by an 45-criteria-score. 15 criteria corresponded with the criteria of the Centers of Disease Control and were fulfilled by 385 patients. These 385 patients showed significant difference to 53 healthy controls in 40 of the 45 criteria (p < 0.001, twitches and food allergies p < 0.05). Furthermore sensitivity, specificity and precision of every criterion was calculated. The 15 CDC criteria were all significant (p < 0.001), 15 other significant criteria of descending precision were added : respiratory infections, palpitations, dizziness, dyspepsia, dryness of mouthleyes, allergies, nausea, paresthesia, loss of hair, skin alterations, lack of coordination, chest pain, personality changes, eczema, general infections, twitches, urogenital infections (precision of the 30 criteria: 95.7% down to 36.3%). Correlation (Spearman rank-correlation-coefficient rs ties corrected) between this 30-criteria- score and immunological parameters could be evaluated in 472 of the 505 patients. Significant positive correlation to the 30-criteria-score was found in: CD8+-T-Iymphocytes (rs = 0.083, p = 0.036),DR+-T-Iympho-cytes (rs, = 0.085, p = 0.032), gamma globulin (rs = 0.099, p = 0.016), IgM (rs= 0.145, p = 0.001), IgG (rs = 0.087, p = 0.029), and the number of types of autoantibodies (mainly ANA, ACA, thyreoidal and parital antibodies) (rs = 0.1274, p = 0.003); significant negative correlation was found in albumin-globulin-ratio (rs = -0.102, p = 0.014), eosinophils (rs = -0.106, p = 0.011) and IgE (rs, = -0.126, P = 0.020). Most of these parameters did also correlate with one another.
On the other hand in the group of the 505 patients serological tests of the following pathogens were striking: HHV-6-IgG in 243 of 487 patients (49.9 %), EBV-EA in 170 of 480 (35.4 %), HSV-KBR in 135 of 462 (29.2 %), CMV-KBR in 49 of 390 (12.5 %), Chlamydia-IgA in 142 of 406 (35.0 %). ****Borrelia western blot showed 3 or more specific IgG-bands in 54 of 131 patients (41.2 %)****. In single special cases infection with EBV, HHV-6 and CMV, respectively, was confirmed by DNA-PCR-test.
CONCLUSIONS : In more and more larger groups of patients with CFS and related disorders we often see clinical signs and longer history of other symptoms beside the classical criteria of CFS, specially a high prevalence of local and general susceptibility to infections and prolonged inflammatory processes. Together with other results published by us and other investigators the data further confirm the hypothesis that a reduced or unstable immune control or delayed immune reaction to persisting viruses or bacterial intracellular pathogens can - triggered by common infections or other environmental factors - lead to a chronic neuro-immune activation state and auto-immune disorders. Hypersensitivity symptoms of the patients might not be mediated by classical allergy with IgE and eosinophils.
Como 8 bandas quizá sean pocas y 20 demasiadas, creo que estas son las 12 que realmente merecen la pena. Como podréis apreciar es un artículo demasiado conservador sobre el diagnóstico del Lyme.
En la tabla que copio a continuación, además de las 12 bandas viene su reactividad cruzada, cuanto menor sea ésta más específica es la proteína de B.b..
--------------------------------------------- CONTENTS --------------------------------------------- THE UNDERDIAGNOSIS OF NEUROPSYCHIATRIC LYME DISEASE IN CHILDREN AND ADULTS
Brian A. Fallon 1 MD, MPH Janice M. Kochevar 2 NP Andrea Gaito 3 MD Jenifer A. Nields 4 MD
1 Department of Psychiatry, Columbia University Medical Center and the Lyme Disease Research Program New York, New York (BAF) 2 private practice Armonk, New York (JMK) 3 Department of Medicine, Seton Hall University, and private practice Basking Ridge, New Jersey (AG) 4 Department of Psychiatry, Yale University School of Medicine New Haven, Connecticut (JAN) ------------------------------------------------------------------------ Address reprint requests to Brian A. Fallon, MD, MPH The NYS Psychiatric Institute Lyme Disease Research Program 722 West 168th Street, #13 New York, NY 10032 ------------------------------------------------------------------------ This work has been supported by the Lyme Disease Association of New Jersey and the Betz Family.
Lyme disease is a tick-borne illness caused by the spirochete Borrelia burgdorferi. Reported throughout the United States, the greatest incidence of Lyme disease occurs in certain areas, such as the Northeast, the upper Midwest, and the Pacific Coastal states. It has been dubbed "The New Great Imitator" because, like another spirochetal illness neurosyphilis--the original Great Imitator, Lyme disease has a vast array of multisystem manifestations, including neuropsychiatric ones. [18] Failure to recognize Lyme disease early in its course can result in the development of a chronic illness that is only temporarily or partially responsive to antibiotic therapy. The goal of this article is to present the typical and atypical manifestations of Lyme disease in children and adults in order to help the clinician more rapidly unmask the correct diagnosis behind the puzzling presentations of some patients.
THE DIAGNOSTIC PROBLEM
Whenever a disease exists for which serologic tests are unreliable in determining the presence or absence of the disease process, frustration and anxiety rise among both patients and doctors. When controversy exists even among the leading academic researchers as to the validity and reliability of these tests, a battleground is then set in which doctors dispute amongst themselves over the diagnosis while the patient is left with an uncertain clinical syndrome in which treatment recommendations vary widely depending on the physician chosen. If this particular disease process also has psychiatric manifestations that lower the patient's frustration tolerance, increase irritability, and impair cognitive functioning, then the stage is set for a referral to a psychiatrist to address a presumed psychogenic or functional disorder. Such is the situation when dealing with Lyme disease. For example, in 1991, an essay appeared in a major medical journal entitled, From the Centers for Fatigue Control (CFC) Weekly Report. Lime disease-- United States, in which patients with unexplained persistent fatigue were mocked for wondering whether or not they had Lyme disease, suggesting that they were clinging to a stylish diagnosis unable to accept that they actually suffered from a fictitious "Lime Disease." [14] This sarcastic essay resulted perhaps from a sense that the medical scientific community had full knowledge about this disease. Such was (and is) clearly not the case. The observation that fatigue after Lyme disease is a significant problem, that many of these patients would meet clinical criteria for chronic fatigue syndrome (CFS), and that a substantial portion of these patients appear to have signs in experimental CSF studies of persistent infection with B. burgdorferi has led the National Institute of Health to fund major research studies investigating the extent to which ongoing symptoms are due to persistent infection versus a "post-Lyme" syndrome.
Overdiagnosis of Lyme disease has been reported in rheumatology clinics. In 1990, a report [20] summarizing a chart review of 100 patients referred to a New Jersey Lyme Clinic indicated that only 25% had a history explicitly suggestive of Lyme disease. The most common other diagnosis was fibromyalgia. In 1993, an article [21] describing a retrospective case survey of 788 patients referred to another Lyme disease center revealed that only a minority (23%) of the patients met diagnostic criteria for active Lyme disease. An additional 20% of the 788 patients had confirmed previous Lyme disease with concurrent or residual symptoms and an additional 45% of the patients who were determined not to have ever had Lyme disease had negative serologic results in the authors' laboratory, but had had positive serologic results in other laboratories. Patients with fibromyalgia or CFS constituted the majority of cases of presumed misdiagnosis. Given that the symptoms of fatigue, myalgia, arthalgia, sleep disturbance, and persistent headaches are common during active Lyme disease and that both CFS and fibromyalgia are thought by some researchers to be triggered and perhaps perpetuated by infectious agents, excluding CFS and fibromyalgia as aspects of the syndrome of active Lyme disease seems premature in the history of our understanding of this illness.
Data to support the clinical speculation that many persistently symptomatic Lyme disease patients have one disease process and not multiple concomitant diseases was provided in 1994 by the results of a case-controlled community epidemiologic study. [19] Compared to controls, patients with a history of previously treated well-defined Lyme disease had significantly increased frequency of fatigue, arthralgias, paresthesias, poor coordination, inattention, emotional lability, and sleep disturbances. Less than half of these patients at follow-up were seropositive for Lyme disease. Among the 10 persistently symptomatic patients who were retreated, five improved. Although not a placebo-controlled study, the latter finding suggests that neuropsychiatric symptoms may persist in some patients despite prior therapy and that retreatment with antibiotics may result in further gains.
Possible misdiagnosis of Lyme disease and failure to identify another concurrent disease need to be considered seriously among patients who do not have a typical profile, whose tests are equivocal, or who are not responding to antibiotic treatment. In certain Lyme endemic areas, for example, approximately 10% of patients with Lyme disease may be coinfected with babesiosis, a comorbid infection which worsens the course of Lyme disease resulting in more frequent symptoms (fatigue, headaches, sweats, chills, anorexia, emotional lability, nausea) and a longer duration of illness. [13] Patients with major depression alone may have prominent fatigue, anorexia, emotional lability, myalgias, and insomnia, all symptoms that overlap with Lyme disease but by themselves do not make the diagnosis. Because a medical diagnosis is more socially acceptable, disabling major depression may go untreated for years. One patient, who consulted with one of the authors, with a prior history of Lyme disease was given long courses of antibiotic treatment for a constellation of symptoms, among which were prominent panic attacks and agoraphobia. After treatment with pharmacotherapy and behavior therapy, her panic attacks and medical condition dramatically improved. Although panic attacks and severe anxiety may be a symptom of untreated Lyme disease, when the Lyme disease has been treated but the anxiety persists physicians should suspect that an underlying Lyme-triggered or unrelated-but-concomitant psychiatric disorder exists.
Underdiagnosis of Lyme disease, however, is also a problem, particularly when the symptoms are primarily neuropsychiatric. In a survey of 193 patients with seropositive chronic Lyme disease, [7] patients reported having been sick for approximately 1 year and having had to consult with a mean of two doctors before the diagnosis of Lyme disease was made. Prior to diagnosis, 42.5% of these seropositive patients were thought to have had only a psychiatric disorder. Although this survey sample undoubtedly included some seropositive patients who may not have had Lyme disease, the results do suggest that neuropsychiatric problems are common in chronic Lyme disease, and that mental health professionals can play a critical role in the initial diagnosis.
In this article, the authors describe the typical clinical profile of Lyme disease and the tests that exist to support the diagnosis. They conclude with case studies of three patients who were initially thought to have other diagnoses: attention deficit disorder (ADD), depression, and multiple sclerosis (MS).
CLINICAL MANIFESTATIONS
In the early phase of infection after being bitten by an infected ixodes scapularis tick, common signs and symptoms include an erythematous annular rash (erythema migrans) followed by mild to severe flu-like symptoms. Hematogenous dissemination of the spirochete can occur within days to weeks of the tick bite. The organism may then lodge within the heart, eyes, joints, muscles, or central and peripheral nervous system. Although manifestations of target organ involvement may occur early, B. burgdorferi may remain quiescent for months to years before producing symptoms. Because of the potentially long latency period before disease onset, the fact that approximately one third of patients do not recall the tick-bite or rash, and the nonspecific nature of the early flu-like syndrome, infection by B. burgdorferi may not be recognized until long after the initial tick bite.
Approximately 15% to 40% of patients with Lyme disease develop neurologic problems. [4] Initially patients may complain of a bad headache without any signs of inflammation in the CSF. Early neurologic Lyme disease may be manifest thereafter by meningitis, encephalitis, cranial neuritis, and motor or sensory radiculitis. Patients with meningitis often complain of a headache and stiff neck while the patients with encephalitis may have mood lability, irritability, confusional states, and poor sleep. Involvement of the seventh cranial nerve should automatically lead the clinician to test for Lyme disease, however only 5% to 10% of patients with neurologic Lyme disease have a Bell's palsy. Peripheral neuropathies (motor or sensory) may result in sharp shooting or stabbing pains, burning pains, paresthesias, weakness, or fasciculations. Later stage neurologic Lyme disease may result in a chronic encephalopathy (see below) or an encephalomyelitis. Encephalomyelitis, markedly less common, may be characterized by spastic paraparesis, transverse myelitis, cerebellar syndromes, hemiparesis, or movement disorders. Rarely patients with neurologic Lyme disease may have strokes, seizures, or severe dementia.
Lyme encephalopathy is characterized by subtle to severe disturbances in cognition, affecting primarily short-term memory, verbal fluency, attention and concentration, and processing speed. Patients may complain that their brains are "in a fog" or that their reaction time is slower. Recitation of their history may be very disorganized because these patients have a hard time keeping track of their thoughts. Some of these patients are so distractible that they may appear to have new- onset attention deficit disorder. Although memory storage is often not impaired, patients may have a hard time retrieving information. Word transpositions are not uncommon, such that a patient might say, "I put the microwave in the dinner" instead of "I put the dinner in the microwave." Other concomitant symptoms associated with late Lyme disease include profound fatigue, sleep disturbance, photophobia, hyperacusis, periods of geographic disorientation, and disturbances of mood.
The plethora of psychiatric problems associated with Lyme disease were first reviewed in 1990 in the European medical literature by Drs. Kohler [12] and Omasits. [17] Kohler attempted to categorize the psychiatric symptoms by stage, listing depressive mood in early disease, organic personality disorders in mid-stage disease, and organic psychoses, dementia, and anorexia in the later phase of the illness. Omasits stated that psychiatric manifestations can be predominant and that the clinical spectrum of Lyme disease ranges from agitated depressive states with suicidal ideas to the clinical picture of dementia. A review of the medical literature [8] revealed that, in addition to the disorders listed by Kohler and Omasits, Lyme disease appear to be capable of causing syndromes which manifest as personality change, depersonalization, mania, hallucinations (auditory, visual, and olfactory), paranoia, catatonia with stupor and mutism, somatization disorder, obsessive compulsive disorder, violent outbursts, panic attacks, and disorientation.
In children and adolescents with neurologic Lyme disease, behavioral or mood disturbances are the second most frequently reported symptom. [1] Common neuropsychiatric symptoms include headaches, fatigue, difficulty with concentration in school, irritability, oppositional behavior, and new onset anxiety disorders. When the onset of illness is not dramatic, but characterized by gradually increasing fatigue, disinterest, and inattention, children may begin to label themselves as incompetent as they realize they can no longer keep up with the rest of their classmates academically. While developmental and family issues always need to be considered when there is a change in a child's behavior or mood, in endemic areas Lyme disease should be considered as well, particularly because delays in diagnosis are associated with greater chronicity.
DIAGNOSTIC TOOLS
When Lyme disease is suspected clinically, the clinician should order a Lyme ELISA and a Lyme Western Blot, both indirect serologic tests that detect the presence of antibodies against B. burgdorferi. Whereas the ELISA is a less expensive screening test, it is less specific (and perhaps less sensitive) than the Western blot, resulting in false positives among patients infected with other spirochetal conditions, such as syphilis or periodontal disease. Because patients can have a negative ELISA but a positive Western blot, polymerase chain reaction (PCR) assay, or culture, and both an ELISA and Western blot should be ordered. [11] [16] The test should be sent to a laboratory with established reliability in conducting Lyme assays. The Centers for Disease Control (CDC) guidelines currently used by many commercial laboratories for the interpretation of the Western blot are overly restrictive in that patients with active Lyme disease may not have the requisite 5 of 10 specific bands. In addition, certain bands not listed as specific such as the 31 Kd (Osp A) and 34 kD (Osp B) bands are in fact highly specific, the former being used to create the new Lyme vaccines. Other tests that may be helpful include more direct tests such as the PCR assay that detects the presence of the DNA of the spirochete and antigen detection assays (in urine or cerebrospinal fluid [CSF]) which detect pieces of the spirochete itself. These tests are stronger indications that the organism may in fact be present; however, they do not necessarily indicate that the spirochete is alive. The best and most definitive test is based on culture, although this test has a very low yield in late Lyme disease.
Overutilization of Lyme serologic tests can lead to a higher likelihood of false positive results. When tests are used as an indiscriminate screen, ordered without regard for clinical presentation, risk factors, and history, one report indicates that the positive predictive value of a test falls to 7%. [10] When tests are ordered for patients with a typical clinical history of Lyme disease, the positive predictive value rises to over 96%. The clinical history therefore is extremely important.
A recent FDA Public Health Advisory statement [3] on assays for Lyme disease warned: "A positive result does not necessarily indicate current infection with B. burgdorferi, and patients with active Lyme disease may have a negative test result." For example, in early Lyme disease with erythema migrans, patients are expected to have negative serologies because detectable levels of borrelia-specific antibodies have not yet been produced. In later chronic Lyme disease, among patients who were treated early in their illness, negative or equivocal serologies may result presumably because the early antibiotic treatment abrogated the immune response. In one recent study, [15] of 8 patients with late Lyme encephalopathy who had CSF evidence of active central nervous system (CNS) infection, half of the patients had equivocal serologic results and one quarter were seronegative. This study, in addition to demonstrating the presence of seronegative Lyme disease, points out the importance of spinal fluid assays among patients with suspected central nervous system involvement.
Other tests that are a key part of the evaluation include neuropsychologic testing, CSF studies, and structural and functional imaging. Neuropsychologic tests of memory, attention, processing speed, and verbal fluency can detect objective evidence of cognitive dysfunction that may not be immediately observable on clinical exam. The most common problems are in memory retrieval and attention. CSF tests in early neurologic Lyme disease may demonstrate intrathecal antibody production, although in later Lyme disease the results of CSF antibody studies may be negative up to 43% of the time. [5] More commonly the CSF may reveal a mild increase in protein or a pleocytosis. Because a normal CSF may be seen in 20% of patients with active central nervous system infection with B. burgdorferi, this test cannot be used to exclude the diagnosis of Lyme disease. MRI scans may reveal T2 weighted white matter hyperintensities similar to the demyelinating lesions associated with MS. Functional imaging may reveal a diffuse pattern of heterogeneous uptake, resembling patients with vasculitides. [9] [15] In late neurologic Lyme disease, SPECT and PET imaging appear to be more sensitive in detecting objective abnormalities than MRI scans. Neuropsychiatrists therefore may find functional imaging particularly helpful in the effort to tease out whether a patient's problems are primarily psychiatric or owing to another more diffuse central nervous system process.
ILLUSTRATIVE CASES
Three cases are presented below, one child, one adolescent, and one adult. Each demonstrates the complexity of presentation, diagnosis, and course.
Case Study 1
Attention Deficit Disorder Versus Lyme Disease
At age 7, Susan who lived in a Lyme endemic area developed problems focusing in school. A neuropsychologist diagnosed probable ADD. Other symptoms included lethargy, irritability, forgetfulness, headaches, poor coordination, joint pain, word-finding difficulties, and light and sound sensitivity. A comprehensive medical work-up, including EEG and MRI, were within normal limits, except for a positive Lyme ELISA. Once Lyme disease was diagnosed and treated, her symptoms of attention deficit disorder resolved and her school grades returned to their pre- Lyme disease level of excellence. Her course over the subsequent 2 years appeared to be antibiotic-dependent, such that she would do well as long as she stayed on antibiotics and relapse when taken off. At age 9, she was able to come off antibiotics and remained symptom free for 3 years, performing in the A/A+ range academically. Knee pain, frequent headaches, and poor concentration re-emerged at age 12. Serologic tests revealed a positive ELISA with fully reactive IgG and IgM Western blots. A brain SPECT revealed normal perfusion. Treatment with oral cefuroxime for 2 months led to a rapid improvement in all symptoms, however within 2 weeks of stopping antibiotics her symptoms returned. During the following months, her teachers recorded a variety of problems: "trouble with consistency in day-to-day work; careless; head in the clouds; scattered and sloppy work; assignments are late, forgotten, or lost; difficult time following directions; more forgetful and disorganized." Her parents noted that Susan would go to school with homework in her bag but once there have no idea where it was or whether she had done it. Emotionally, she had become frustrated, overwhelmed, tearful, aggressive, and fearful with new onset phobias and nightmares. Physically, she had knee pain with mild swelling, paresthesias, headaches, moderate fatigue, insomnia, and trouble focusing.
On mental status examination, Susan acknowledged having problems in 6 of the 9 inattention areas identified in the DSM-IV criteria for attention deficit hyperactivity disorder (ADHD), thereby qualifying for the diagnosis. She denied significant depression or suicidal feelings but acknowledged feeling overwhelmed. Cognitive testing after being off of antibiotics for 4 months revealed that she had a very superior baseline intelligence (verbal IQ 132) but significant deficits in visual motor planning, speed of processing, visual scanning, attention, visual memory, and learning. She was diagnosed then as having a persistent encephalopathy secondary to Lyme disease and treated with additional oral antibiotics. She continues on oral cefuroxime several months later and has had a full return to her prior level of health and academic excellence, with no evidence of the prior ADHD symptoms.
Case Study 2
Depression Versus Lyme Disease
David, a 16-year-old boy who lived in a Lyme endemic area, presented complaining of long-standing depression, exacerbated recently when he stopped dating a girl after only 2 weeks because he felt too tired and not smart enough. He reported anger, frustration, insomnia, poor appetite, mild weight loss, and passive suicidal ideation: "I wish I could just die in my sleep." He was oriented to person and place, but when asked the date he said 1977 instead of 1997. He reported feeling spaced out all the time, as if in a fog.
David's recent medical history was notable for painful knees throughout much of 7th grade, such that he had to quit sports. A previous A/A- student, his grades declined to Bs. He appeared lazy because he found it hard to get out of bed in the morning and often forgot to hand in assignments that he had in fact completed. His grades declined during 8th and 9th grades such that by 10th grade he was nearly failing most of his courses. The presumed cause of his poor performance was either laziness or mild depression. When asked about his school difficulties, he reported trouble staying awake in class and trouble concentrating. When asked about his physical and cognitive status, he acknowledged severe headaches; facial fasciculations; myalgias; stiff neck; hyperacusis; episodic paresthesias of his face and hands; sudden sweating; painful joints; sore throats; palpitations; electric shock- like pains; word-finding problems such that it was hard to finish sentences; semantic paraphasias; short-term memory problems such that he could not recall conversations; and testicular pain. David had had embedded tick bites, but he could not recall ever having had an erythema migrans rash.
Given the suspicious clinical history, further testing was done. Although a Lyme ELISA was negative twice in the prior 3 months, his IgG Western blot revealed 4 of the 5 requisite CDC specific bands. Other tests, including TFTs, heterophile antibodies, and brain MRI with FLAIR sequences were unremarkable. Neuropsychologic testing revealed significant deficits in processing speed and visual spatial memory, in a young man whose premorbid intellectual capacity was estimated to be in the 85th percentile. A brain SPECT was ordered that revealed moderate to severe diffusely and heterogeneously decreased perfusion in the cortex and the central white matter, consistent with encephalitis, vasculitis, and Lyme disease. Based on these findings, a diagnosis of probable Lyme encephalopathy was made and he was treated with 12 weeks of IV ceftriaxone with excellent results physically (sleep, appetite, headaches, joint pains, distractibility, numbness), cognitively (distractibility, short-term memory), and emotionally. Anti-depressant medications had been recommended prior to IV treatment, but were not taken. The patient was no longer depressed after the IV antibiotic regimen and his school performance markedly improved. David's follow-up neuropsychologic testing revealed an improvement of 22 full-scale IQ points.
Case Study 3
Multiple Sclerosis Versus Lyme Disease
Mr. B, a 45-year-old research scientist recently diagnosed as having MS, presented asking whether any of his current symptoms might be related to a diagnosis of Lyme disease 6 years earlier. Current symptoms included headaches, arthritis, sleeping difficulties, paresthesias, tremors, fasciculations, irritability, visual problems, and short-term memory difficulties.
At age 39, shortly after two tick bites from a Lyme endemic area, the patient experienced a severe flu and myalgias, followed by marked headaches, fatigue, leg weakness, migratory lower extremity polyarthritis, paresthesias, loss of touch, and temperature sensation below the hips, and urinary sphincter dysfunction. Serologic tests were unremarkable, including a Lyme ELISA and rheumatoid factor. Although some CSF studies (including VDRL, Lyme titers, and oligoclonal bands) were within normal limits or nonreactive, he did have a pleocytosis of 7 white blood cell (WBC) count and mildly elevated myelin basic protein. A neurologist diagnosed transverse myelitis, secondary to presumed seronegative Lyme disease. He was treated with intramuscular ceftriaxone for 2 weeks followed by 4 weeks of oral doxycycline with resolution of his headaches. This was followed by oral prednisone with resolution of his leg weakness and foot drag. Although markedly improved, over the subsequent 5 years he was intermittently symptomatic with ankle pain, headaches, night sweats, fasciculations, paresthesias below the waist, insomnia, and testicular pain. The cause of these persistent symptoms was unclear.
At age 44, his symptom profile worsened: more severe headaches, slurred speech, left facial and upper extremity tingling, double-vision, poor coordination with poor postural balance, and lightheadedness. Neurologic examination revealed dysarthric speech, decreased pain, and temperature sensation and a delayed corneal reflex on the left side of his face, decreased temperature sensation in the lower extremities, and a markedly abnormal cerebellar examination. A brain MRI revealed multiple areas of focal white matter disease extending from the brain stem to the parieto-occipital lobe. Median nerve somatosensory evoked potential studies were within normal limits. Visual evoked potential studies were abnormal suggestive of optic nerve or severe retinal disease on the left and axonal optic nerve dysfunction on the right. CSF was within normal limits with no evidence of Lyme antibodies, oligoclonal bands, or elevated myelin basic protein. Despite the normal CSF, he was diagnosed clinically as having probable MS. After treatment with prednisone, he experienced improved energy and vision, but continued to have diffuse multisystemic symptoms.
Now at age 45, he presented with the symptoms identified above. Lyme serologies revealed a Western blot IgG that met full CDC criteria for reactivity. Other laboratory tests were within normal limits (including FTA, ANA, RF, ACE, anti-cardiolipin antibody) except for a mild polyclonal increase of IgM. Brain SPECT revealed decreased perfusion diffusely throughout the cortex, the white matter, and the basal ganglia bilaterally. The diagnosis of Lyme disease was made, although concurrent MS could not be excluded.
Over the subsequent 9 months, off all steroids, Mr. B was treated with high dosages of oral cefuroxime and minocycline. Although improvement occurred in all symptoms such that he was able to return to work, a return of left-sided paresthesias and weakness led to a repeat MRI which showed a worsening of demyelination in the brainstem. He was then started on a regimen of intravenous ceftriaxone (2 g IV qd) and clarithromycin (500 mg po BID), both of which he continues on now 12 months later. Since the IV antibiotics were started, serial MRI scans at the same center revealed progressive diminution in the size of all white matter lesions and the development of no new lesions. Based on the history, Lyme serologies, and antibiotic responsiveness, both his neurologist and infectious disease doctors changed their diagnosis from MS to a resolving antibiotic responsive Lyme encephalomyelitis.
Discussion
These three cases demonstrate that patients with Lyme disease may have variable neuropsychiatric presentations, equivocal or negative serologic test results, incomplete treatment response and subsequent relapses. As is true for most patients with neuropsychiatric Lyme disease, each of these patients had a history of multisystemic symptoms after exposure to a Lyme endemic area. In the absence of such a history, Lyme disease is not likely to be the correct diagnosis.
Inattention and poor mental tracking are common features of Lyme encephalopathy in both children and adults. Although impulsivity and hyperactivity may be seen, more often children with Lyme-induced ADHD meet criteria for only the inattention subtype. The initial treatment should be antibiotics, followed later by psychopharmacologic approaches to help diminish any residual problems with inattention.
The optimal duration of antibiotic treatment in chronic Lyme disease is unknown, although typically patients are initially given 4 to 6 weeks followed by longer courses if relapse occurs. [2] [6] [13A] In case 1, Susan appeared to need long courses of oral antibiotics to remain symptom free. An understanding of the microbiology of this spirochete sheds light on why Lyme disease may require longer courses of treatment. Borrelia burgdorferi has many features that are typical of organisms that are difficult to eradicate: a slow rate of growth; ability to remain dormant for long periods; intracellular invasion; and, sequestration in areas where antibiotic penetration is more difficult, such as the central nervous system or the anterior chamber of the eye. Case study 2 demonstrated that even among patients who have had Lyme disease undetected for long periods, antibiotic treatment can be helpful although perhaps not curative.
The depression associated with the earlier encephalitic phase of neurologic Lyme disease is characterized by marked irritability and mood lability. Later, in the setting of encephalopathy, the depression is often more mild, characterized primarily by anhedonia, low energy, hopelessness regarding the future, and a diminished sex drive. In case study 2, David's long-standing depressive state appeared to be a chronic dysthymia. The diagnosis of Lyme disease would have been missed had the physician not asked explicitly about specific cognitive and physical symptoms. After the initiation of antibiotic treatment, he had to be carefully educated about the fact that he had been suffering from an undiagnosed infectious illness over the last few years that had been draining his energy. Rather than being lazy and incompetent, he had been sick. With this new understanding, David was able to perceive himself in a new way and once again apply himself to his studies, working hard to make up for the years of illness.
Differentiating Lyme encephalomyelitis from MS can be difficult. Mr. B in case study 3 had many of the clinical features of MS, including double vision, optic neuritis, paresthesias in one half of the body, disturbed micturition initially, cerebellar involvement, and diffuse white matter disease. Mr. B's CSF however did not have the characteristic oligoclonal bands which are seen in over 90% of patients with MS but in fewer than 5% of patients with neurologic Lyme disease. Nor did his CSF demonstrate the common finding in MS of a marked elevation in myelin basic protein. The negative CSF results for MS, the positive serologic tests for Lyme disease, clinical improvement with antibiotics, and progressive diminution of MRI hyperintensities together confirmed the diagnosis of Lyme encephalomyelitis.
Although none of the three patients in this report took psychiatric medications, psychopharmacology can be very valuable adjunctively for patients dealing with persistent or severe neuropsychiatric symptoms. For example, carbamazepine may help to reduce paroxysmal pain or hyperacusis. Bupropion may help to diminish depression and enhance attention.
In conclusion, in endemic areas, although Lyme disease may be an overdiagnosed disorder in rheumatology clinics, it may be an underdiagnosed disorder in child and adults psychiatry clinics. Although none of the currently available tests for Lyme disease other than direct culture definitively indicates active infection, the clinical presentation and the multiplicity of tests taken together can serve as guideposts for the clinician.
References
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