W. John Martin, M.D., Ph.D.
Center for Complex Infectious Diseases
Rosemead CA 91770
The entity called chronic fatigue syndrome (CFS) simply refers to a loose grouping of certain symptoms that are part of a much wider spectrum of the clinical manifestations of viral induced organic brain damage. The preferred term for the underlying organic brain disease is viral encephalopathy (viral pathology of the brain). The term CFS should be discarded.
The viruses that are associated with CFS are termed "stealth" because, although, they cause significant cellular damage, they do not typically evoke an anti-viral inflammatory response. They are best viewed as "derivatives" or as "down-sized" conventional viruses. They include but are not limited to derivatives of human and animal herpesviruses. The "stealth adaptation" consists primarily of the deletion of the genes coding for the major antigenic components normally targeted by the cellular immune system. Stealth viruses do not grow as efficiently as conventional viruses, but have a striking advantage over conventional viruses in not having to confront the body's cellular immune defense mechanisms. They can, therefore, create persistent ongoing infections in spite of an individual's intact immune system. This is different from a latent infection seen with many human herpesviruses in which the virus is essentially inactive except for brief transient periods of viral activation, rapidly controlled by the body's immune mechanisms..
Both in cell cultures and in infected tissues, viral infection can lead to the development of foamy vacuolated cells, which may form syncytia. The cellular changes can be readily seen using electron microscopy. With most conventional viruses, the formation of intact viral particles precedes the induction of major cytopathic effects. The appearance of intact fully formed viral particles is much less of a feature in stealth viral infections. Typically one may merely see accumulations of viral like components, possibly with incomplete virus-like structures, in a cell which displays intense cytopathic effects.
The types of viral products that accumulate in stealth viral infected cells can differ between different stealth viral isolates. In some cultures the predominant material may be coarse nucleocapsid-like materials, in others there may be collections of fine granular deposits, still other cultures may show an over expression of viral envelope structures. A common feature, however, is the apparent metabolic disruption expressed as mitochondrial damage, lipid accumulation, extensive cytoplasmic vacuolization, and altered nuclei. Infected cells are metabolically impaired because various energy and other resources are diverted towards the synthesis of viral components at the expense of normal functions. Severe defects in energy generating metabolic pathways are apparent in the marked mitochondrial disruption that is prominent in electron micrographs of viral infected cells.
An important observation concerning the development of the in vitro cytopathic effect is that it can be inhibited by substances that accumulate in the media of infrequently fed cultures. These substances can be removed by frequently replacing the tissue culture medium. They also hold promise in the potential therapy of stealth viral infection. The inhibitor(s) in tissue culture supernatants has been termed "Epione" after the wife of Ascepius, the Greek God of medicine. Epione was reputed to have skills in soothing pain.
Stealth viral infected patients have a systemic viral illness. Although the infection and resulting cellular disruption is systemic, many of the symptoms experienced by infected patients relate to dysfunction of the brain. This merely reflects the unique susceptibility of the brain to localized viral induced damage. Significant viral damage to other organs, such as the bowel, liver, thyroid, adrenal, etc., can, however, add to the neurological dysfunction resulting from viral infection within the brain.
The clinical diversity of neuropsychiatric symptoms seen in patients labeled with various neurological, psychiatric, rheumatological and behavioral problems is probably determined by the localization of the brain infection, as well as by genetically and environmentally determined differences in predisposition to various symptoms. Additionally, the extent of viral damage to other organs can impact on the overall clinical presentation.
Potential complications of viral infection include the induction of auto-immunity, antigen-antibody complex formation, ischemia resulting from viral vascular damage, breakdown of both the physical barriers and the cellular clearance mechanisms operative against common bacteria, transactivation of other viruses, and finally the induction of malignancy.
The primary therapeutic approach is aimed at suppressing viral expression and the further spread of viral infection. In several cases partial success has been seen using intravenous and/or oral ganciclovir. Next are efforts that can augment cellular metabolic function. In principle one is faced with the quandary of not wanting to "feed the virus" by giving nutritional supplements. To help avoid this possibility, one should take advantage of the cover provided by anti-viral agents to restore metabolic health. Another important therapeutic goal is to attempt, through adjustments to sensory inputs, followed if necessary by low dose therapy with neuromodulating agents, to promote normal brain function. Activities which aggravate the patient's symptoms should be avoided, while those that ameliorate symptoms should be employed. The pharmacological approach is largely one of trying different medications and the patient observing what effects, if any, occur. The patient should be willing to maximize the potential placebo effects of prescribed medications and other adjustments while at the same time remain objective when comparing medications. The physician prescribing the medication also needs to remain objective and sensitive to the potential side effects of neuroactive medicines.
Non-neurological illness, especially those that can indirectly affect neuronal function, for example leaky bowel with impaired liver detoxification, hypo- or hyperthyroidism, adrenal insufficiency, etc., need to be addressed on an individual basis. Finally, the patient should be encouraged to relearn cognitive skills to the extent possible.
The issues of potential contagiousness of a stealth viral infection is relevant within the context of family and friends of patients, work environment especially educational personnel dealing with infected children, health care workers, and recipients of blood products and viral vaccines produced in primary cultures of animal tissues.
A major goal of clinical research is the application of standardized approaches to measure and to monitor deficits in brain functions associated with stealth viral infections. The use of labels such as CFS, fibromyalgia, gulf war syndrome, depression, dementia, attention deficit, autism, etc., etc., obscure the major overlaps that can be seen in stealth viral infected individuals. To address this, a series of simple but objective clinical tests are being devised to more efficiently document the scope and severity of brain dysfunction in all stealth viral infected patients. These tests, along with repeat viral cultures can form the basis of evaluating and optimizing various therapeutic approaches.
The primary goal is to isolate and characterize the inhibitory component(s) present in stealth viral culture medium. The second goal is to develop and apply serological assays to determine if an individual is at risk for infection with a particular stealth viruses. The results will help in counseling family members as to their potential risks. Similar studies can be applied to household pets. The possibility of vaccination of household pets and family members will also need to be addressed.
Physicians interested in enrolling patients into therapeutic trials are asked to contact CCID at 3328 Stevens Avenue, Rosemead CA 91770. Suggestions as to possible alternative approaches to therapy are welcomed. A computerized data base is being established to help allocate patients to various treatment options and to rapidly validate the efficacy of promising therapies. Patients in whom the disease has spread to family members or to household pets are asked to contact CCID directly by calling (626) 572-7288. Similarly, families in which an array of differing illnesses have occurred among family members should contact CCID. Written reports of these illnesses or of other outbreaks can be sent to CCID via FAX at (626) 572-9288.
Funding and Support:
A tax deductible donation of $210.00 for a single day's support of CCID's operations, or a larger donation to expedite the development of Epione, is being requested from all interested persons. A grant has been submitted to the U.S. Army for studies on the Gulf War Syndrome. Details of the Epione Development Fund will be provided to potential contributors. Of several additional unmet needs, the following listing are of high priority.
Specific Funding Requests:
Address for Donations:
3328 Stevens Avenue
Rosemead CA 91770
Arrangements can be made to receive visitors within the laboratory and to identify the uses to which donated fund will be applied.
References Relating to Stealth Viruses:
1. Martin W.J. Viral infection in CFS patients. in "The Clinical and Scientific Basis of Myalgic Encephalomyelitis Chronic Fatigue Syndrome." Byron M. Hyde Editor. Nightingdale Research Foundation Press. Ottawa Canada pp 325-327, 1992.
2. Martin W.J. Detection of viral related sequences in CFS patients using the polymerase chain reaction.in "The Clinical and Scientific Basis of Myalgic Encephalomyelitis Chronic Fatigue Syndrome." Byron M. Hyde Editor. Nightingdale Research Foundation Press. Ottawa Canada pp 278-283, 1992.
3. Martin WJ, Zeng LC, Ahmed K, Roy M. Cytomegalovirus-related sequences in an atypical cytopathic virus repeatedly isolated from a patient with the chronic fatigue syndrome. Am. J. Path. 145: 441-452, 1994.
4. Martin W.J. Stealth viruses as neuropathogens. College of American Pathologist's publication "CAP Today" 8 67-70, 1994
5. Martin WJ. Stealth virus isolated from an autistic child. J. Aut. Dev. Dis. 25:223-224,1995
6. Martin WJ, Ahmed KN, Zeng LC, Olsen J-C, Seward JG, Seehrai JS. African green monkey origin of the atypical cytopathic 'stealth virus' isolated from a patient with chronic fatigue syndrome. Clin. Diag. Virol. 4: 93-103, 1995.
7. Martin WJ. Severe stealth virus encephalopathy following chronic fatigue syndrome-like illness: Clinical and histopathological features. Pathobiology 64:1-8, 1996.
8. Martin WJ. Stealth viral encephalopathy: Report of a fatal case complicated by cerebral vasculitis. Pathobiology 64:59-63, 1996.
9. Martin WJ. Simian cytomegalovirus-related stealth virus isolated from the cerebrospinal fluid of a patient with bipolar psychosis and acute encephalopathy. Pathobiology 64:64-66, 1996. 10. Gollard RP, Mayr A, Rice DA, Martin WJ. Herpesvirus-related sequences in salivary gland tumors. J. Exp. Clin. Can. Res. 15: 1-4, 1996.
11. Martin WJ. Genetic instability and fragmentation of a stealth viral genome. Pathobiology 64:9-17, 1996. 12. Martin WJ, Glass RT. Acute encephalopathy induced in cats with a stealth virus isolated from a patient with chronic fatigue syndrome. Pathobiology 63: 115-118, 1995.
13. Martin WJ. Detection of RNA sequences in cultures of a stealth virus isolated from the cerebrospinal fluid of a health care worker with chronic fatigue syndrome. Pathobiology (in press)
14. Martin WJ Anderson D. Stealth Virus Epidemic in the Mojave Valley: I. Initial report of virus isolation. Pathobiology (in press)
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