ABSTRACT

Cytopathic "stealth-adapted" viruses bypass the cellular immune defenses mechanisms because of the deletion of crucial antigen coding genes. Stealth viruses establish persistent, systemic virus infection that can involve the brain. The terms multi-system stealth viral infection with- and multi-system stealth viral infection without- encephalopathy (MSVIE and MSVI, respectively), are suggested to help distinguish stealth virus infected patients presenting with a clearly identified brain illness (MSVIE), from viral infected patients with no or only minimal symptoms referable to the brain (MSVI). Patients with MSVIE can manifest a range of neuropsychiatric symptoms. Disregarding the potential role of viral infection as a cause of impaired brain function leads to an inappropriate categorization of patients into primary psychiatric diseases or into such vague clinical entities as the chronic fatigue syndrome (CFS). Recogition of the systemic nature of stealth virus infection justifies a multi-system, comprehensive, diagnostic evaluation of the patient's illness. The occurence of disease among family members is consistent with the potential household transmission of infection. Clinical trials on the use of anti-stealth virus therapies in stealth virus culture positive patients manifesting neuropsychiatric symptoms are warranted.

INTRODUCTION

Overview of Neurology and Psychiatry
Dysfunctional brain syndromes are erroneously viewed as comprising two distinct groups of illnesses: neurological and psychiatric. Neurologists mainly address diseases that can be attributed to discrete anatomic lesions, with readily elicited physical signs pertaining to the affected region of the brain. Although the therapeutic options are usually limited, the causes of these illnesses have a rational basis in terms of well-defined neuroanatomical lesions. As opposed to neurologists, psychiatrists and other mental health personnel, mostly address diseases lacking precise anatomic localization or biologic explanation. These diseases are expressed in terms of varying degrees of altered emotions, behaviors and cognitive processes; functions that are viewed as expressions of the "mind" rather than of the "organic brain." The availability of mind-altering drugs has helped shift the therapeutic emphasis for these diseases from simply trying to coerce the patient to change his or her ways (psychotherapy) to the somewhat more successful (if still empirical) psychopharmacological approach. The use of therapeutic drugs in psychiatry is predicated on the assumption that patients have a underlying disturbance in neural metabolism that can be at least partially restored pharmacologically. The etiology of the "chemical imbalance" is rarely addressed and often assumed to be a result of an inappropriate behavioral adaptation to life stressors. This article offers an alternative explanation for psychiatric illnesses; one that is based on altered brain function resulting from infections with stealth viruses.

Spatial Distribution of Normal Brain Function

The brain is unique among the body's organs in the spatial distribution of its many functions. Unlike other organs, damage to one area of the brain can not readily be compensated for by heightened activities of other brain areas. Moreover, individual components of the brain participate in complex neural networks that can subserve a variety of integrated functions. Even minimal damage to neurological tissue has the potential for profound effect compared to similar damage in extra-neural tissues. Not only is the brain tissue spatially complex, it is hampered by the inability of mature neuronal cells to replicate and to replace neurons damaged as a result of either illness or normal senescence.

Assessment of Brain Function

The brain is responsible for motor, sensory, autonomic and cognitive functions. It also determines personality, mood, self-perception and social interactions. Delirium, coma and gross deficits of sensory and motor functions are readily detected in routine neurological examinations. Depression, anxiety, personality change, attention defiocits and psychoses are also symptoms of a dysfunctioning brain. when unaccompanied by marked alterations in other brain functions, they are considered pychiatric rather than neurological in nature. Much of this false distinction rests with the relative insensitivity of clinical testing methods and the impractical nature of more sophisticated tests. Office testing for subtle sensory and motor changes, and for possible derangements of the autonomic nervous system are rarely employed by psychiatrists. Such tests have also been disregarded by many neurologists as providing inconsequential "soft signs." Complex assays, such as tilt-table testing for orthostatic hypotension, can provide a quantitative measure of a specific autonomic function, but are unsuitable for everyday clinical practice. Neuroimaging techniques, such as computerized EEG, PET scans and functional MRI, can also provide measures of brain function, but they, too, are unsuitable for routine psychiatric practice. Furthermore, the etiological foundations for the subtle changes that may be seen in psychiatric patients are not yet established. Neuropsychiatric testing for minor personality disorders and for mild cognitive impairments requires an in depth knowledge of the individual's pre-illness performance; information which is not generally available. One-time testing will usually not reveal the early changes in personality or cognitive abilities that patients themselves or their friends may perceive.

Diagnostic Labeling of Psychiatric Illnesses

In spite of the shortcomings in assessments of many brain functions, psychiatrists have managed to categorize psychiatric illnesses into distinct clinical entities by grouping symptoms into a variety of syndromes. These groupings obscure the fact that many symptoms are common to various disease categories. Moreover, the naming of an illness tends to overlook the considerable variability that can exist in the actual symptoms, and especially their relative severity between patients and even in a single patient over time. The lack of true diagnostic precision in reflected in such terms as "co-morbidity" and "borderline condition." The assumption that different syndromes have different underlying etiologies has also hampered efforts to find common causes of mental illnesses.

Etiology of Psychiatric Illnesses

In a similar way that diagnostic labels have tended to artificially sub-divide a spectrum of neuropsychiatric illnesses, the proponents of various etiologic theories have also tended to be exclusive rather than inclusive. The notion that organic brain illness has to be either genetic, infectious, auto-immune or toxic, precludes the known interactions between all of these components. The aging process itself can slowly erode the limited functional reserves that may have survived an earlier insult, leading to a delay in the clinical expression of an illness years after the initiating event has occurred. Of the four etiologic categories listed above, an infectious cause has the promise of being the most readily targeted for therapy, as well as the added concern of being potentially transmissible between individuals. Viral infections of the brain could present in many different ways depending simply on its localization to different regions of the brain and on the varying levels of the various capacities for various brain functions, that the patient had prior to becoming infected. It could also render an individual susceptible to normally tolerated environmental factors and other stressors of brain function.

Viruses and Psychiatric Illnesses

The digression of psychiatry from basic molecular biology is seen in the minimal attention currently given to the potential role of viral infections in psychiatric illnesses. Historically, such conditions as encephalitis lethargica, subacute sclerosing panencephalitis, multifocal leukoencephalopathy and general paresis of the insane, were belatedly accepted as infectious. The reality of AIDS dementia is also now unquestioned. On the other hand early attempts to detect viruses in patients with schizophrenia (schizoviruses) and other major psychiatric illnesses, failed to provide convincing and readily reproducible findings. In spite of the availability of more sensitive technologies , such as the polymerase chain reaction (PCR), few psychiatrists are intellectually poised to consider viral infections as a likely cause of their patients' illnesses.

The prevailing model of a viral brain infection is that of Herpes simplex virus (HSV) encephalitis. Typically the patient will present with an acute onset (<2 weeks from the initial symptoms to severe illness); have a progressively diminishing level of consciousness; show localizing signs, often to the temporal lobes, on clinical, radiologic and EEG examinations; and have a marked CSF pleocytosis with increased protein levels. Relatively mild meningitis/encephalitis-like illnesses are also commonly encountered in General Practice. If pursued vigorously, serological assays, changes in CSF and stool cultures will sometimes indicate enteroviral infection. The illnesses are considered to be short lasting without sequella. The notion of a persisting, sub-acute, non-inflammatory viral encephalopathy is rarely considered clinically or tested for using either viral cultures or molecular probe based assays.

VIRUSES

Virus Classification
One reason for the lack of consideration of viruses in psychiatric illnesses is the plethora of different viruses that in many ways seem unconnected to each other. Emphasizing differences rather than similarities has impeded a clear overview of molecular virology in much the same way that the over categorization of dysfunctional brain syndromes has confounded, rather than simplified, psychiatry. A working model to help bypass the complex viral classifications schemes that are currently in place can be arrived at through the simple principle that viruses must replicate. While larger, more complex DNA viruses code their own DNA dependent DNA polymerase, smaller DNA viruses need to make use of either one of the cell's own DNA polymerases, or alternatively the polymerase of a larger DNA virus. Many of the very small DNA viruses, such as parvoviruses, which lack their own polymerase will only replicate within either an already dividing cells, or cells co-infected with a virus that has a DNA polymerase. Some small DNA viruses (e.g. papovaviruses) replicate through the activation of cellular proliferation. With the exception of hepatitis D virus (an RNA virus that the cell misreads as DNA), conventional RNA viruses generally need to provide their own polymerase. Negative single-stranded RNA viruses encode their own RNA dependent RNA polymerase, which is packaged along with the viral genome. Positive single-stranded (ss) RNA viruses and most double stranded (ds)RNA viruses, synthesized their polymerase soon after infection occurs. Retroviruses are negative strand RNA viruses which encode a reverse transcriptase RNA dependent DNA polymerase which can replicate its RNA into ds DNA. Integration of the ds DNA into the cellular genome, allows for reformation of ss RNA through the action of cellular DNA dependent RNA polymerase. DNA copies of ss RNA viral sequences could be similarly replicated by cells in which endogenous retroviral genes, containing a functional RNA dependent DNA polymerase, were activated.

Viral survival also depends on the ability to spread to other cells. Simple viruses merely rely on passive uptake or hitching-a-ride within other viruses. The survival of viruses between cells is generally achieved by enclosing the viral geome within an insoluble protein structure formed by the self-assembly (aggregation) of proteins, giving rise to the viral capsid or coat. Many plant viruses establish tubular structures formed by the ordered assembly of so called "movement proteins." These tubes penetrate between cells and act as conduits for the intercellular transfer of viral nucleic acids. Complex animal viruses may incorporate sequences coding for molecules which become embedded into a cellular membrane surrounding the viral capsid. This viral envelope enables the viral particle to more effectively interact with the surface of cells destined to become infected. The actual genes encoding the capsid, polymerase and envelope proteins can exist on a single nucleic acid molecule or, as cooperative genetic elements within the same viral particle (segmented viruses) or different viral particles (bipartate and even tripartate viruses). Complex viruses may possess additional protein components within the virus particle, which serve to facilitate their metabolic interactions with the host cell. These nature of these interactions are more readily understood in terms of the specific relatedness of the viral genes to their cellular counterparts, rather than viewing the viral genome as totally foreign to its host. The involvement of multiple viral-host gene interactions can help explain much of the restricted host species, and even cell type, specificity exhibited by many viruses. Specific gene interactions can also account for the distinctive cytopathic effects (CPE) manifested by certain viruses, beyond those simply attributed to metabolic competition.

Viral Pathogenesis

All viruses have the potential to mediate cellular changes by altering the normal metabolic balance within the cell through over utilization of the cell's energy resources. While this can eventually lead to cell death, an earlier cost can be the failure of the cell to perform all of its normal functions. Continued metabolic drain on the cell can lead to a loss of essential components such as ATP required to maintain mitochondrial energy generation. These cells can show foamy vacuolization, swelling and intercellular fusion. Some viruses trigger a more active form of cellular death, called apoptosis, characterized by shrinkage and condensation of cellular components. While herpesviruses, especially HSV and human cytomegaloviruses (HCMV), adenoviruses, influenza and certain enteroviruses are cytopathic in cultures, many of the human viruses are essentially incapable of inducing a readily discernable CPE in viral cultures on human cells. For example, rubella; hepatitis A, B, C and D; HTLV; Borna and Hartaan viruses are non-cytopathic. Moreover, primary clinical isolates of measles, mumps and polioviruses induce far less CPE on human compared to animal cell lines. For many non-cytopathic, disease-associated, human viruses, the in vivo tissue damage is a consequence of immune activation.

Viral Immunity

The immune system can also both reduce and enhance the extent of viral damage. Antibodies can provide an effective blockade preventing viruses from gaining access to normally permissive cells. In particular, antiviral antibodies can help prevent viruses passing from the blood to the brain. Cellular immunity can reduce viral load by destroying infected cells prior to the release of infectious viral particles. On the other hand, cellular immunity against viral antigens or against modified or inappropriately expressed cellular antigens can lead to immune damage of a cell beyond that achieved by the virus itself.

Viruses have evolved various mechanisms to help evade the immune system. One such mechanism is the deletion of the genes coding for the major antigens recognized by the cellular immune system. This mechanism of bypassing the cellular immune defenses has been referred to as a "stealth adaptation."

STEALTH VIRUSES

Stealth Viruses
A corollary of the clonal selection theory of immunology is that to be effectively recognized, a viral infected cell must restrict the number of different viral antigens presented to the cellular immune system. Even with large complex viruses, relatively few viral components actually serve as effective targets for cellular immune defenses. For certain viruses, e.g. HCMV, experimental studies suggest that deletion (or mutation) of genes coding for the major viral components recognized by the cellular immune system, would simply yield a defective, non-replicating , non-cytopathic viral sequence. One could have, however, a potential building block towards the evolution of a cytopathic non-immunogenic "stealth virus." Potentially, the downsized gene-depleted virus could form a synergy with a replicating non-cytopathic virus and/or incorporate certain cellular genes by recombination, to yield an atypically structured cytopathic virus. These concepts are embodied in the following definition of stealth viruses:

Molecularly heterogeneous grouping of atypically structured, cytopathic viruses, that cause persistent systemic infection, often with neuropsychiatric manifestations, in the absence of significant anti-viral inflammation. Stealth viruses induce a vacuolating cytopathic effect (CPE) in a range of human and animal cells. The formation, progression, and/or host range of the CPE distinguish stealth viruses from traditional human cytopathic viruses, including herpesviruses, enteroviruses, and adenoviruses. Additional distinctions can be made on the basis of electron microscopy, serology, and molecular-based studies

Origins and Replication of Stealth Viruses

Certain stealth viruses contain genetic sequences which are nearly identical to sequences found in African green monkey simian cytomegalovirus (SCMV). Other regions of these viruses are clearly different from SCMV. Genetic sequences related to other human and animal associated viruses, and additional sequences more closely related to various cellular genes, have been detected in the DNA and/or RNA fractions of stealth viral infected cultures. Electron microscopy has also revealed differences between stealth viral cultures in terms of the types and relative abundance of distinctive accumulations of viral-like materials within cells showing the characteristic vacuolated CPE. An interesting observation is the apparent genetic instability and fragmentation of a stealth viral DNA genome.

Possible Vaccine Origins of Stealth Viruses

While stealth adapted viruses have presumably existed for a long time, the increasing incidence of many of the diseases referred to above, suggests an additional recent source of these viruses. DNA sequence data on the stealth virus isolated from a patient with acute encephalopathy following a 4 year history of a manic-depressive illness, indicate an origin from African green monkey simian cytomegalovirus (SCMV). Short term kidney cell cultures from African green monkeys have been used since the early 1960's to produce live polio virus vaccines. The probable presence of SCMV in polio vaccines was largely ignored even though in 1972, all 11 monkey kidney culture tested using sensitive indicator cell lines, showed the presence of SCMV. Only 4 of these isolates would have been detected using the standard detection procedures that remained in place despite of the above finding.

Other stealth viruses also appear by electron microscopy to have a relatedness to herpesviruses, but so far their sequence data have yet to be linked to that of known human or animal viruses. Fresh animal tissues have been used for a variety of human live viral vaccines, including dog and duck kidney cells for rubella vaccines. SV-40 virus was present in many of the polio vaccines lots produced in kidney cultures from Rhesus monkeys. A diverse array of animal cell lines have also been used for the many animal vaccines that have been developed. It is not unreasonable to suggest that the vaccine viruses may have contributed genetic elements to contaminating herpes and other viruses to facilitate the emergence of replicating, non-immunogenic (stealth-adapted) viruses. Once within the human population, stealth viruses can be passed via direct human to human and human to animal and back to human transmission routes.

Detection of Stealth Viruses

Not only have stealth-adapted viruses evaded the cellular immune system, but they have also gone unnoticed by investigators relying on an inflammatory response as a sign of infection, or on virus cultivation methods used in routine diagnostic laboratories. Modified virus culture methods can, however, provide a reliable method for detecting the diversity of stealth viruses. Specifically, the patient's mononuclear cells are co-cultured with a variety of indicator cell types. The cultures are refed frequently and observed for the induction of a transmissible CPE. Typically, rhesus monkey kidney cells and a human fibroblast cell line such as MRC-5 cells are inoculated with the patient's mononuclear cells and observed for 1-4 weeks. Frequent refeeding of the cultures can help promote the development of the CPE. It is quite unusual (<10%) to observe a rapidly developing CPE in blood samples from randomly selected hospital outpatients. Conversely, it is unusual not to observe a strong positive CPE in cultures from patients with otherwise unexplained neurological or behavioral disorders.

The stealth virus CPE is best characterized by the formation of foci of enlarged, rounded cells, often with the suggestion of syncytia. Proliferation foci of affected cells can occasionally be seen. The actual appearance of the CPE differs between cultures and is best followed by repeated examination of individual cultures by the same observer. The CPE can be transferred to fresh cultures. Positive cultures can be further examined by staining cell smears or sectioned cell pellets. These analyses can include the use of the patient's and/or other sera in immunostaining procedures. This is because, although, the cellular immune system can be indifferent to stealth viruses, some of the viral antigens still provide targets for antibody responses. Biocemically and/or immunologiocally detectable products of both viral and cellular origens can also be screen for in the virus culture supernatants. Electron microscopic studies can also provide useful confirmation of cytopathology and reveal various patterns of accumulated cellular and/or viral products. Cell derived DNA and RNA can also be used for molecular characterization. A series of PCR primer sets based on previously characterized stealth viruses can be used to screen for virus-derived DNA and RNA sequences. The primers can also be used to test for DNA and RNA dependent polymerases. Finally, the viral cultures can be used to test the effects of various anti-viral therapies.

As noted above, stealth viral infections are not necessarily confined to the brain and indeed blood samples are routinely used for stealth viral cultures. Other serological signs of viral infections can include unusually high levels of anti-herpesvirus antibodies. This may reflect the presence of the stealth virus or the two-way cross stimulation that can be seen between stealth and conventional herpesviruses. Broadly reactive herpesviral primers can also be used in low stringency PCR based assays on DNA and RNA directly isolated from the patient's blood. Other primer sets have been shown to cross react with several stealth virus isolates in low stringency PCR assays. Cloning and sequencing of the PCR products can be used to design more specific primer sets. The possible role of stealth adapted herpesviruses in secondary activation of parvo- and papovaviruses, including monkey-derived SV40, can also be assessed using serological and molecular probe based assays for these agents.

Stealth Viral Infection

Stealth viruses have been isolated from blood and cerebrospinal fluid of patients with a spectrum of illnesses with neurological and neuropsychiatric manifestations. The clinical diversity seen in stealth viral infected patients may relate to the predominant areas of the brain that are infected as well as the timing and intensity of the infection. The clinical diagnoses have included autism and attention deficit learning disorders in children, chronic fatigue, fibromyalgia, Gulf war syndrome and depression in adults, and dementia in the elderly. Severe acute encephalopathy and major psychotic reactions have also been associated with stealth viral infections. Brain biopsies have been available from several patients with very severe illness. The predominant histological characteristic is the presence of occasional cells with distinctly vacuolated cytoplasm and distorted abnormal nuclei. The affected cells may show varying granules positive with periodic acid Schiff stain. Significant vasculitis was present in one of the biopsies. Major inflammation was not present within the parenchyma of the several biopsies examined. Because they bypass effective cellular immunity, stealth viral infections can cause persistent illnesses subject to reactivation over a course of several years.

Animal Transmission

Stealth viruses from humans have induced acute neurobehavioral diseases in experimental cats and mice, accompanied by similar histogical and electron microscopic changes as seen in brain biopsies of infected humans. Illness has also been seen in naturally infected cats, as well as in cats inoculated with stealth viruses obtained from infected humans. The animal studies confirmed that the cellular changes were not confined to the brain but that signs of infection could be found in various organs. The predominant clinical manifestations in the animals were, as expected, neurobehavioral, consistent with the unique susceptibility of the brain to limited degrees of viral damage.


Examples of Stealth Virus Positive Patients with Psychiatric Illnesses

Manic-Depression: One of the earliest isolates of a stealth virus came from a patient with a 4 year history of a psychotic bi-polar manic depression. Her condition deteriorated acutely in January, 1991 with what appeared clinically to be a viral encephalitis. The absence of significant cellular changes in the cerebrospinal fluid led to a revised diagnosis of a attempted suicide from drugs complicated by cerebral anoxia from a transient cardiac arrest. This patient has remained in a vegetative state since this episode.

Schizophrenia: Adult patients have unwittingly contributed to their diagnosis of a psychotic disorder by desperately trying to explain symptoms unfamiliar to their physicians. For example a diagnosis of schizophrenia was suggested when one patient described her headache as "a large screw boring into the back of my head." Another patient confronted his physician with the idea that his illness was like "a number of men inside my head not knowing what the others are doing." Unsuspecting patients present themselves as being outside the limits of accepted medical diagnoses, and are offended when this leads to talk of a serious psychiatric disease. One culture positive patients labeled as schizophrenic come from family in which both parents were diagnosed as having CFS and a grand parent as having an atypical Parkinson's disease.

Autism: Because of the possibility of the developing brain repairing viral induced damage, the presence of stealth viruses in children labeled as autistic has been of special concern. The incidence of autism has increased significantly since it was first described in 1942. All but 1 of 40 autistic children referred for stealth viral testing have shown positive stealth viral cultures. Stealth viral infections have also been linked to abrupt onset of severe learning disorders with attention deficit, poor memory and oppositional defiant behavior.

Dementia: Cellular genes can be incorporated into the replicative mechanisms used by stealth viruses. Stealth viruses are likely to pick up sequences from the organs in which infection is occurring. An increasing number of neurodegenerative diseases have been linked to excessive accumulations of self-aggregating proteins. These include Alzheimer's disease (pre-senilin protein) and spongiform encephalopathy (prion protein). The incorporation of sequences coding such genes could help explain these illnesses.

Personality Disorders, Drug Addiction and Suicide: Culture positive patients, labeled CFS and/or FMS, not uncommonly exhibit mild psychiatric symptoms. These individuals have been forced to choose between the social stigma and limited medical and disability insurance coverage of a psychiatric diagnosis versus the uphill battle of trying to convince physicians and friends of the reality of a nebulous medical illness. Some patients resort to illicit drug use both as an attempt at self medication and as an excuse in thinking that their problems are secondary to the drugs, rather than a "weak mind". More tragic is resorting to suicide to escape the frustration, disordered thought processing and actual pain experienced by patients.

Non-Neurological Clinical Manifestations in Stealth Virus Infected Patients

Stealth virus infected patients, whether presenting with a psychiatric or neurological illness, will commonly show signs and symptoms consistent with a systemic viral infections involving various organs, including the liver, salivary glands, thyroid and genital organs. Autoimmune damage, probably evoked in response to viral induced cellular changes, may account for the prevalence of anti-nuclear and anti-thyroid antibodies seen in many stealth viral infected patients. Immune system abnormalities resulting from infection of the lymphoid system may destabilize the body defenses against other infectious agents, possibly accounting for the reported detection using sensitve PCR based assays of low levels of mycoplasma and chlamydia related sequences in the blood of some patients with chronic fatigue. There is no evidence that these agents contribute to the clinical manifestations of chronic fatigue. Indeed, the reported findings may simply reflect primer cross reaction with modified stealth virus or cellular sequences.

Since brain damage is essentially additive patients with a viral encephalopathy are particularly susceptible to environmental neurotoxins. These include many of the toxic chemicals and even certain pharmaceutical products, used for medical, veterinary and agricultural use. Multiple chemical sensitivity can be especially severe if infection of the liver and gastrointestinal tract can alter their detoxification and barrier functions allowing a greater exposure of the brain to various xenobiotics. In some patients, including a patient who died from his illness, a cerebral vasculitis component was present, possibly resulting from direct viral infection of blood vessels. Milder forms of vasculitis could alter the normal blood brain barrier further enhancing susceptibility to circulating toxic components.

Stealth Virus Associated Malignancy:

Pathology resulting from damage even to an individual cell can be severe if it leads to malignant transformation. The potential to capture, amplify and mutate cellular genes provides a mechanism whereby stealth viruses could transmit oncogenic information between cells. Stealth viruses have been recovered from patients with various malignancies, including multiple myeloma, lymphoma and salivary gland tumors. The potential association between stealth viruses and malignancy should be considered in any cancer patient with a history of a dysfunctional brain syndrome

Transmission of Stealth Viral Infections

The lack of a consistent clinical picture and the protracted, slowly erosive nature of most stealth viral infections, do not fit easily into the current epidemiology models of acute infectious diseases. Even when apparent outbreaks exist, it is all too easy to dismiss individual cases as resulting from non-infectious causes. With the development of reliable stealth virus culture methods, it is possible to approach this problem from a laboratory standpoint. Cultures have confirmed a recent outbreak of stealth virus infection in the Mohave Valley region of the United States. Both as part of this epidemic and elsewhere, there have been examples of multiple family members, and even household pets, succumbing to an illness that they recognize as having common features Salivary gland swelling, pharyngeal "crescent," mild gingivitis and mouth ulcers, have pointed to possible oral transmission. This opinion has been supported by positive stealth virus throat cultures. Congenital infection is supported by positive cultures in neonates, some of whom have presented with intracerebral choroidal hemorrhages. Occupational exposure probably accounts for the positive cultures seen in health care workers, and in school teachers. Blood products, including gamma globulin preparations, are potential sources of infection, as may be viral vaccines.

Therapy for Stealth Viruses

The molecular heterogeneity between stealth viruses will undoubtedly pose a problem with their therapy. An important in vitro observation, however, is that viral growth is promoted by regular refeeding of the cultures. This has been equated with the accumulation of inhibitory component(s) of possible therapeutic use. The term "Epione" has been applied to these putative inhibitors. Some stealth viral isolates have responded in vitro to alpha interferon, and some physicians have tried with partial success to achieve clinical remission with this approach. A small number of virus culture positive patients, including some children, have been given oral Acyclovir with suggestive improvement. More recently, oral and intravenous ganciclovir have been tried in individual patients with apparent, if modest, beneficial effect. Neither Acyclovir or ganciclovir is likely to be effective in arresting replicating RNA viral genomes. Inhibitors of RNA dependent polymerases warrant in vitro, and if effective, in vivo testing.

Knowledge of the stealth virus induced metabolic derangements should lead to appropriate nutritional therapies. In attempting metabolic resuscitation, it is important to consider the potential adverse effects that could result if one were to merely "feed the virus," rather than restoring normal cellular function. The in vitro cultures provide a valuable system to evaluate this possible dilemma.

A number of psychological and psycho-pharmacologic approaches can be taken to support patients with damaged brains. Because of the enormous diversity between patients, there is no single prescription that applies to most patients but the therapy has to be individually tailored to each patient. The following principles can generally be applied. First, the brain functions in response to stimulation of the senses and a detailed history can often help identify those stimuli that aggravate the patient's symptoms. These should, as far as possible, be avoided. This can include minimizing contact with environmental chemicals and even certain food products and odors that evoke unpleasant sensations. Patients are generally advised to limit undertaking multiple simultaneous tasks, or to engage in unresolvable conflicts, which appear to overwhelm the capacity of the brain to maintain ordered function. Certain stimuli, however, including self-directed efforts to maximize so called placebo effects, can benefit certain patients and can be constructively utilized. Second, brain activity can be regulated pharmacologically and a trial and error approach with various medications can sometimes prove useful in providing symptomatic relief. Third, the actual cognitive deficits exhibited by the patient can be addressed by specific training. Fourth, aspects of brain dysfunction, as well as effects of a systemic viral infection, can cause multiple manifestations outside of the nervous system. When detected, each of these effects will need to be therapeutically addressed.

SUMMARY
Stealth viral encephalopathy could account for many psychiatric illnesses currently attributed to functional derangements of the mind. Psychiatric patients are generally not adequately tested for clinical evidence of organic brain disease. Detailed clinical examination focusing on more subtle changes in brain functions can help establish a diagnosis of encephalopathy. Patients with objective neurological signs should have stealth viral cultures and should also be tested for other manifestations of systemic viral infection. Viral isolates should also be characterized in terms of their composition, replication strategy and origin. Culture positive patients should be assigned to anti-viral treatment groups and should also receive other supportive therapies.

Acknowledgment: The work was supported in part by the Theodore and Valda Stanley Foundation.