Chapter 33. Viral Infections of the Nervous System, Chronic Meningitis, and Prion Diseases

A number of viruses share the unique tendency to primarily affect the human nervous system. Included in this group are the human immunodeficiency viruses (HIV-1 and HIV-2), herpes simplex viruses (HSV-1 and HSV-2), herpes zoster or varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), poliovirus, rabies, and several seasonal arthropod-borne viruses (Flaviviruses). Some of these are neurotropic, exhibiting an affinity for certain types of neurons: for example, poliomyelitis viruses and motor neurons, VZV and peripheral sensory neurons, and rabies virus and brainstem neurons. Yet others attack nonneuronal supporting glial cells; JC virus causing progressive multifocal leukoencephalopathy is the prime example. For many of the rest, the affinity is less selective in that all elements of the nervous system are involved. Herpes simplex, for example, may devastate the medial parts of the temporal lobes, destroying neurons, glia cells, myelinated nerve fibers, and blood vessels; and HIV may induce multiple foci of tissue necrosis throughout the cerebrum. These relationships and many others, which are the subject of this chapter, are of wide interest in medicine. In some conditions, the systemic effects of the viral infection are negligible; it is the neurologic disorder that brings them to medical attention.

Pathways of Infection

Viruses gain entrance to the body by one of several ways. Mumps, measles, and VZV enter via the respiratory passages. Polioviruses and other enteroviruses enter by the oral–intestinal route, and HSV enters mainly via the oral or genital mucosal route. Other viruses are acquired by inoculation, as a result of the bites of animals (e.g., rabies), ticks, mites, or mosquitoes (arthropod-borne or arbovirus infections). The fetus may be infected transplacentally by rubella virus, CMV, and HIV. In all these cases, viremia is an intermediate step to seeding the brain or CSF.

Another pathway of infection is along peripheral nerves; centripetal movement of virus is accomplished by the retrograde axoplasmic transport system. HSV, VZV, and rabies virus utilize this peripheral nerve pathway, which explains why the initial symptoms of rabies occur locally, at a segmental level corresponding to the animal bite. It has been shown experimentally that HSV may spread to the CNS by involving olfactory neurons in the nasal mucosa; the central processes of these cells pass through openings in the cribriform plate and synapse with cells in the olfactory bulb (CNS). Another potential pathway is the trigeminal nerve and gasserian ganglion, however, the role of these pathways in human infection is not certain. Of the different routes of infection, the hematogenous one is by far the most important for the majority of viruses.

Additionally, VZV resides in the sensory ganglia and becomes reactivated later in life, causing shingles decades after the primary infection that produces chicken pox. The JC virus also is latent in tissues, possibly the kidney and bone marrow, only to reemerge under conditions of immunosuppression, to infect the brain.

Mechanisms of Viral Infections

Viruses, once they invade the nervous system, have numerous clinical and pathologic effects. One reason for this diversity is that different cell populations within the CNS vary in their susceptibility to infection with different viruses. To be susceptible to a viral infection, the host cell must have on its cytoplasmic membrane specific receptor sites to which the virus attaches. Thus, some infections are confined to meningeal cells, enteroviruses being the most common, in which case the clinical manifestations are those of aseptic meningitis. Other viruses involve particular classes of neurons of the brain or spinal cord, giving rise to the more serious disorders such as encephalitis and poliomyelitis. The virus or its nucleocapsid must be capable of penetrating the cell, mainly by the process of endocytosis, and of releasing its protective nucleoprotein coating. For viral reproduction to occur, the cell must have the metabolic capacity to transcribe and translate virus-coated proteins, to replicate viral nucleic acid, and, under the direction of the virus's genome, to assemble virions. Certain agents depend on cell-surface receptors to ingress into the cell; these relationships have potential therapeutic interest as, for example, the use of serotonin receptor for entry of the JC virus into oligodendrocytes.

The pathologic effects of viruses on susceptible cells vary greatly. In acute encephalitis, neurons are invaded directly by virus and the cells undergo lysis. There is a corresponding glial and inflammatory reaction. Neuronophagia (phagocytosis of affected neurons and their degenerative products by microglia) is a mark of this phenomenon. In progressive multifocal leukoencephalopathy (PML), there is a selective lysis of oligodendrocytes, resulting in foci of demyelination. In certain congenital infections, e.g., measles and rubella, the virus persists in nervous tissue for months or years. In still other circumstances, a viral infection may exist in the nervous system for a long period before exciting an inflammatory reaction (e.g., subacute sclerosing panencephalitis, SSPE); in these cases the disease may be so indolent as to simulate a degenerative disease.

Differentiating cells of the fetal brain have particular vulnerabilities, and viral incorporation may give rise to malformations and to hydrocephalus; an example is mumps virus with ependymal destruction and aqueductal stenosis.

In experimental animals cerebral neoplasms can be induced when certain viral genomes are incorporated into the DNA of the host cell. There is suggestive evidence of such a mechanism relating to EBV in B-cell lymphoma of the brain. The prions have yet other means of affecting cells that do not conform to the traditional concepts of infection and are discussed in a later section of this chapter.

A large number of viruses are able to affect the nervous system. Among the enteroviruses alone, nearly 70 distinct serologic types are associated with CNS disease, and additional types from this family of viruses and others are still being discovered. There is no need, however, to consider them individually, as there are only a limited number of ways in which they express themselves clinically: (1) acute aseptic ("lymphocytic") meningitis; (2) a less-common recurrent meningitis; (3) acute encephalitis and meningoencephalitis; (4) ganglionitis (herpes zoster); (5) chronic invasion of nervous tissue by retroviruses, i.e., HIV and tropical spastic paraparesis (TSP); (6) acute anterior poliomyelitis; (7) chronic viral infections including the agent causing PML and subacute sclerosing panencephalitis (SSPE) and (8) the prion agents that are discussed later in the chapter.

The term aseptic meningitis was first introduced to designate what was thought to be a specific disease—"aseptic" because bacterial cultures were negative. The term is now applied to a symptom complex that is produced by any one of a number of infective agents, the majority of which are viral but a few of which are bacterial (mycoplasma, Q fever, other rickettsial infections). Because aseptic meningitis is rarely fatal, the precise pathologic changes are uncertain but are presumably limited to the meninges. Conceivably, there may be some minor changes in the underlying brain itself, but these are of insufficient severity to cause neurologic symptoms and signs or to show changes on imaging studies.

In outline, the clinical syndrome of aseptic meningitis consists of fever, headache, signs of meningeal irritation, and a predominantly lymphocytic pleocytosis in the spinal fluid with normal glucose. Usually the onset is acute and the temperature is elevated, from 38 to 40°C (100.4 to 104°F). Headache that is more severe than that associated with other febrile states is the most frequent symptom. A variable but usually mild degree of lethargy, irritability, and drowsiness may occur. Photophobia and pain on movement of the eyes are common additional complaints. Stiffness of the neck and spine on forward bending attests to the presence of meningeal irritation (meningismus), but at first it may be so slight as to pass unnoticed. Here the Kernig and Brudzinski signs help little, for they are often absent in the presence of manifest viral meningitis. When there are accompanying neurologic signs, they too tend to be mild or fleeting: paresthesia in an extremity, or wavering Babinski signs.

Systemic symptoms and signs aside from fever are infrequent and depend mainly on the more mundane effects of the invading virus; these include sore throat, nausea and vomiting, vague weakness, pain in the back and neck, conjunctivitis, cough, diarrhea, vomiting, rash, petechia, hepatitis, adenopathy, or splenomegaly. The childhood exanthems associated with meningitis and encephalitis (varicella, rubella, mumps) produce well-known eruptions and other characteristic signs. An erythematous papulomacular, nonpruritic rash, confined to the head and neck or generalized, may also be a prominent feature, particularly in children, of certain echoviruses and Coxsackie viruses. An enanthem (herpangina), taking the form of a vesiculoulcerative eruption of the buccal mucosa, may also occur with these viral infections.

In milder cases, in the first hours or day of the illness, there may be no abnormalities of the spinal fluid, and the patient may erroneously be thought to have migraine or a headache induced by a systemic infectious illness. Microorganisms cannot be demonstrated by conventional smear or culture. As a rule, the glucose content of the CSF is normal; but infrequently, mild depression of the CSF glucose (never below 25 mg/dL) occurs with the meningitis caused by mumps, HSV-2, lymphocytic choriomeningitis, or VZV.

Causes of Acute Aseptic Meningitis

Aseptic meningitis is a common occurrence, with an annual incidence of approximately 20 cases per 100,000 population (Beghi et al; Ponka and Pettersson). Most are caused by viral infections. Of these, the most common are from enterovirus—mainly echovirus and Coxsackie virus. These make up 80 percent of cases in which a specific viral cause can be established. HSV-2 is perhaps next in frequency in adults, followed by varicella, HIV, mumps in children, lymphocytic choriomeningitis (LCM), HSV-1, and adenovirus infections. The next most frequent group comprise EBV (infectious mononucleosis), CMV, leptospira, HSV-1, and the bacterium Mycoplasma pneumoniae (see Chap. 32), and in some parts of the world, tick-borne encephalitis virus and Borrelia, including the Lyme agent (Kupila et al), or during local outbreaks anywhere, arboviruses. Influenza virus, adenoviruses, and numerous sporadic and otherwise innocuous agents are at times isolated from the spinal fluid in cases of aseptic meningitis. The California and West Nile viruses, which are arthropod-borne viruses ("arboviruses" in the family of Flaviviruses) are responsible for a small number of cases; they usually cause an encephalitis or meningoencephalitis in brief regional outbreaks as discussed further on.

It is also recognized that infection with HIV may present as acute, self-limited aseptic meningitis with an infectious mononucleosis-like clinical picture. While HIV has been obtained from the CSF in the acute phase of the illness, seroconversion occurs only later, during convalescence from the meningitis (see further on). HSV-1 has been isolated from the CSF of patients with recurrent bouts of benign aseptic meningitis (so-called Mollaret meningitis), but this finding has not been consistent (Steel et al). As discussed in Chap. 47, it is now believed that this virus also underlies many if not most cases of what has been traditionally considered idiopathic Bell's palsy.

Two other aspects of the virology of aseptic meningitis should be noted: first, in most published series of cases from virus isolation centers, a specific cause cannot be established in one-third or more of cases of presumed viral origin; second, most agents capable of producing aseptic meningitis also sometimes cause encephalitis.

Differential Diagnosis of the Cause of Viral Meningitis

Clinical distinctions between the many viral causes of aseptic meningitis cannot be made with high reliability, but useful clues can be obtained by attention to certain details of the clinical history and physical examination. Inquiry should be made regarding recent respiratory or gastrointestinal symptoms, immunizations, past history of infectious disease, family outbreaks, insect bites, contact with animals, and areas of recent travel. The presence of a local epidemic, the season during which the illness occurs, and the geographic location, are other helpful data.

Because the common enteroviruses, including polio, grow in the intestinal tract and are spread mainly by the fecal–oral route, family outbreaks are usual and the infections are most common among children. A number of echovirus and Coxsackie virus (particularly group A) infections are associated with exanthemata and may be associated with the grayish vesicular lesions of oral herpangina. Pleurodynia, brachial neuritis, pericarditis, and orchitis are characteristic of some cases of group B Coxsackie virus infections and there are certainly other causes. Pain in the back and neck and in the muscles should suggest poliomyelitis or dengue. Lower motor neuron weakness may also occur with echo, West Nile, and Coxsackie virus infections, but it is usually mild and transient in nature. The peak incidence of enteroviral infections is in August and September.

Mumps meningitis occurs sporadically throughout the year, but the highest incidence is in late winter and spring. Males are affected three times more frequently than females. Other manifestations of mumps infection—parotitis, orchitis, mastitis, oophoritis, and pancreatitis—may be, but most often are not, present. It should be noted that orchitis is not specific for mumps but occurs occasionally with group B Coxsackie virus infections, infectious mononucleosis, and lymphocytic choriomeningitis. A definite past history of mumps aids in excluding the disease as an attack confers lifelong immunity.

The natural host of the LCM virus is the common house mouse, Mus musculus. Humans acquire the infection by contact with infected hamsters or with dust contaminated by mouse excreta. Laboratory workers who handle rodents may be exposed to LCM. The meningitis may be preceded by respiratory symptoms, sometimes with pulmonary infiltrates. The infection is particularly common in late fall and winter, presumably because mice enter dwellings at that time.

Parvovirus causes fifth disease in young children, characterized by high fever and markedly flushed cheeks but not associated with neurologic symptoms beyond irritability and sometimes, febrile seizures. However, when contracted from the child by an adult, various neurologic manifestations such as brachial neuritis can occur. There have also been reports of encephalitis and meningitis with the B-19 strain, particularly in children and sometimes in individuals with altered immunity. By a difficult to understand complication, some patients have had strokes as discussed in the review by Douvoyiannis and colleagues.

HSV and HIV meningitis may be associated with a cauda equina neuritis. In the case of HSV, there is often a preceding genital infection with the virus (see Chap. 46). The presence of sore throat, generalized lymphadenopathy, transient rash, and mild icterus is suggestive of infectious mononucleosis caused by EBV or, at times, CMV infection. Icterus is a prominent manifestation of viral hepatitis and some serotypes of leptospirosis and, at times, of Q fever. Among the bacterial and spirochetal cause of an aseptic meningitis syndrome, leptospirosis, M. pneumoniae, and Lyme borreliosis are notable as discussed in the previous chapter.

Certain forms of encephalitis occur particularly in individual who are immunosuppressed from HIV, chemotherapy for neoplasm, organ transplantation, or hematologic and lymphoid malignancy. The manifestation is usually encephalitis but aseptic meningitis is known to occur. The main causative organisms in this group are HHV-6, CMV, and VZV.

Laboratory findings suggest certain organisms as the cause of aseptic meningitis. Most cases of infectious mononucleosis can be identified by the blood smear and specific serologic tests (heterophil or others). LCM should be suspected if there is an intense lymphocytic pleocytosis. Counts above 1,000 cells/mm3 in the spinal fluid, particularly if the cells are all lymphocytes, are most often due to LCM but may occur occasionally with mumps or echovirus 9. In the last of these agents, neutrophils may predominate in the CSF for a week or longer. Slightly depressed glucose in the spinal fluid is consistent with mumps meningitis and with the viruses mentioned earlier, but it is more often indicative of bacterial or fungal infection.

Liver function tests are abnormal in many patients with EBV infection and leptospiral infections; the hepatitis viruses are not known to produce meningitis. In the majority of patients with M. pneumoniae infections, cold agglutinins appear in the serum toward the end of the first week of the illness.

Panels of serologic tests for the main viruses that cause aseptic meningitis are available; most use complement fixation or enzyme-linked immunosorbent assay (ELISA) techniques; an infection is demonstrated by a fourfold increase in titer from acute to convalescent serum drawn at least 10 days apart, but these, of course, do no more than confirm the diagnosis after the illness has mostly passed. In some instances, elevation of specific IgM antibody directed at an infectious agent is useful. Serologic reactions of CSF for syphilis should be interpreted with caution, because inflammation of many types, including infectious mononucleosis, can produce a false-positive reaction. In the last few years, the polymerase chain reaction (PCR) has been applied to the diagnosis of viral infections of the nervous system, among them being CMV and HSV. The test is most sensitive during the active stage of viral replication, in contrast to serologic tests, which are more accurate later in the course of the infection. There are numerous false-negative and fewer false-positive PCR tests for CMV, but they are nonetheless useful in some circumstances, such as the early diagnosis of fulminant CMV infection in AIDS patients (see later in this chapter). For the most part, neither serologic nor PCR testing is required in clinical practice.

Nonviral Causes of Aseptic, Chronic, and Recurrent Meningitis

In addition to the aforementioned bacterial infections that can cause meningitis, several other categories of disease may cause a sterile, predominantly lymphocytic or mononuclear reaction in the leptomeninges: (1) foci of bacterial infection lying adjacent to the meninges, such as spinal or cranial epidural abscess (parameningeal infection); (2) partially treated bacterial meningitis; (3) meningeal infections in which the organism is difficult or impossible to isolate—fungal and tuberculous meningitis are at times in this category and parasitic infections are in this group; (4) neoplastic invasion of the leptomeninges (lymphomatous and carcinomatous meningitis); (5) granulomatous, vasculitic, or other inflammatory diseases such as sarcoidosis, Behçet disease, and granulomatous angiitis; and (6) acute or chronic recurrent inflammatory meningitides as a result of chemical irritation, drug-induced allergic reactions, including an aseptic chemical meningitis incited by rupture of a craniopharyngioma or other cystic structure containing proteinaceous fluid. These are described further on under "Chronic Persistent and Recurrent Meningitis." (7) Rarely, children with scarlet fever or streptococcal pharyngitis develop meningeal signs and slight pleocytosis, the result of a sterile serous inflammation that does not involve invasion of the meninges by organisms. The same occurs in bacterial endocarditis.

An idiosyncratic, presumably immunologic meningitis may result from the use of nonsteroidal antiinflammatory drugs, intravenous immune globulin (due probably to a carrier chemical in the solution), and, rarely, from other drugs, including certain antibiotics. Individuals with systemic lupus erythematosus have an increased risk of aseptic meningitic reactions to antiinflammatory medications.

In respect to the first two categories, parameningeal and partially treated bacterial infections, smoldering paranasal sinusitis or mastoiditis may produce a CSF picture of aseptic meningitis because of epidural or subdural extension into the intracranial compartments; it is infrequent that the entire syndrome of meningitis is present. Uncomplicated sinusitis alone does not cause a meningeal reaction.

Antibiotic therapy given for a systemic or pulmonary infection may suppress a bacterial meningitis to the point where mononuclear cells predominate, glucose is near normal, and organisms cannot be cultured from the CSF although they may still be evident by Gram stain. Careful attention to the history of recent antimicrobial therapy permits recognition of these cases.

Syphilis, cryptococcosis, and tuberculosis are the important members of the third group that cause aseptic meningitis and in which the organism may be difficult to culture, as detailed in Chap. 32. Tuberculous meningitis, in its initial stages, may masquerade as innocent aseptic meningitis and the diagnosis may be delayed. Similarly, the diagnosis of cryptococcosis, other fungal infection, or nocardiosis is occasionally missed because the organisms may be present in such low numbers as to be overlooked in smears, especially in AIDS patients. Brucellosis (Mediterranean fever, Malta fever) is a rare disease that may present as an acute meningitis or meningoencephalitis, with the CSF findings of aseptic meningitis. The diagnosis depends on the detection of high serum antibody titers and Brucella-specific immunoglobulins, using the ELISA or serum agglutination testing.

In the neoplastic group, leukemias and lymphomas are the most common sources of meningeal infiltrations. In children, leukemic "meningitis" with cells (lymphoblasts or myeloblasts) in the CSF numbering in the thousands may occur. In leptomeningeal metastases (carcinomatous meningitis), neoplastic cells extend throughout the leptomeninges and involve cranial and spinal nerve roots, producing a picture of meningoradiculitis with normal or low CSF glucose values. Lymphocytic meningitis that is accompanied by cranial-nerve palsies may prove to be tuberculous if the patient is febrile and the CSF glucose is low (or even without these signs in an endemic area); it is likely to be neoplastic if the patient is afebrile and the CSF glucose is normal or mildly decreased. Concentrated cytologic preparations usually permit identification of the tumor cells. Chapter 31 discusses neoplastic meningitis in detail.

Occlusion of many small cerebral blood vessels by cholesterol emboli may also excite a reaction in meningeal vessels and a pleocytosis that includes eosinophils.

See Table 33-1.

Chronic and recurrent meningitides always pose diagnostic problems. Such patients may have a low-grade fever, headache of varying severity, stiff neck, and a predominantly mononuclear pleocytosis, sometimes with slightly raised CSF pressure. There may be limited focal neurologic signs such a slight pronator drift or Babinski sign. A viral or some other type of infective inflammation is always suspected, but a search by culture methods and serology usually yields negative results. Herpesvirus has been demonstrated to be the cause of a few cases, as in the recurrent Mollaret type of meningitis noted later. The process often improves without identification of the cause over a period of months or a year or more; in other cases, the cause is eventually found. Only a few end fatally.

In a group of such patients studied at the Mayo Clinic, 33 of 39 underwent a natural resolution and 2 died; 14 were still symptomatic at the time of the report (Smith and Aksamit). In another series from New Zealand of 83 patients, Anderson and colleagues ultimately found tuberculosis to be the most common identifiable cause, a smaller number being accounted for by neoplastic and cryptococcal meningitis; in fully one-third of the patients, no cause could be established. Charleston and colleagues reported a subgroup of these patients who were responsive to steroids; in only 7 of 17 patients could medication eventually be withdrawn without recurrence; 4 required treatment indefinitely; and the remaining 6 died after many months or years. The outcome and response to steroids in our patients have been much the same. These series excluded chemical or irritative meningitis, which should be considered if there had been spinal surgery or infusion of even apparently innocuous substances into the spinal space.

The special problem of chronic neutrophilic meningitis has been mentioned in the preceding chapter in relation to Nocardia, Aspergillus, Actinomyces, or certain Mycobacterium species; other causes include coccidioidomycosis, histoplasmosis, and blastomycosis, (see Peacock, cited in Chap. 32).

A reasonable approach in patients with chronic meningitis is to repeat the lumbar puncture several times to obtain all cultures including for fungi and cytology of CSF, using markers to detect uniform populations of B and T lymphocytes and tumor cells, biochemical tests that are sensitive to neoplastic meningitis (such as β2-microglobulin, lactate dehydrogenase [LDH]), and PCR amplification of herpesviruses, serologic tests mainly for HIV, syphilis, coccidioidomycosis, Brucella, and Lyme disease. MRI of the brain and spinal cord with gadolinium should also be performed to detect parameningeal collections. If hydrocephalus develops, it should be managed along the lines described in Chap. 30.

A trial of antiviral agents and broad-spectrum antibiotics may be justified, although we have had limited success with them in our last several patients. We resort to a biopsy of the meninges over the frontal convexity or at a site that demonstrates infiltration or marked enhancement if the diagnosis has not been clarified in 6 to 12 months or if febrile meningitis persists for more than several weeks, but examination of this tissue has also proved to be of limited value. In Anderson's (1995) series, mentioned earlier, biopsy yielded a diagnosis in 5 of 25 patients. Finally, if bacterial infection has been reasonably excluded, corticosteroids are administered for several weeks and then tapered while observing the patient and resampling the CSF.

The CSF formula in a number of other chronic or acutely recurring meningitides corresponds to that of aseptic meningitis. These include (1) the Vogt-Koyanagi-Harada syndrome, which is characterized by combinations of iridocyclitis, depigmentation of a thick swath of hair (poliosis circumscripta) and of the skin, vitiligo, around the eyes, loss of eyelashes, dysacusis, and deafness (the pathologic basis of the syndrome is not known); and (2) Mollaret recurrent meningitis, many instances of which have been associated with HSV-1 (Steel) and others (perhaps most) with HSV-2 infection (Cohen et al). The syndrome is characterized by episodes of acute meningitis with severe headache and sometimes low-grade fever, lasting for about 2 weeks, and recurring over a period of several months or years. In a few patients of ours, in whom no virus could be identified in the CSF, antiviral therapy met with some success, although corticosteroids seemed to reduce the severity of acute episodes. A proportion of these cases follow bouts of genital herpes and individual cases have been reported with EBV, herpes-6 in children, and other viruses. A special syndrome that has been associated with HSV-2 is that of aseptic meningitis and bladder failure and vaginal or vulvar pain after a bout of genital herpes (Elsberg syndrome as reviewed by Ellie and colleagues); (3) In some patients, the recurrent attacks are associated with encephalopathy and headache; this is probably identical to the illness called "pseudomigraine with temporary neurological symptoms" by Gomez-Aranda and described earlier by Bartleson. The entity, also known as HaNDL syndrome ("headache neurologic deficit and lymphocytic pleocytosis") is allied more closely with the headache syndromes as discussed and cited in Chap. 10. (4) Allergic or hypersensitivity meningitis, in the past occurring in the course of serum sickness and now more commonly of autoimmune diseases such as lupus erythematosus, and in relation to certain medications such as nonsteroidal antiinflammatory drugs and intravenously administered immunoglobulin. (5) Behçet disease, which is an important acute, recurrent inflammatory CNS disease, particularly in individuals of Middle Eastern origin. It is essentially a diffuse inflammatory disease of small blood vessels that has several other characteristic features such as oral and genital ulcers and is more appropriately considered with the vasculitides in Chap. 34.

In summary, the temporal history of the illness, associated clinical findings, and laboratory tests usually provide clues to the diagnosis of nonviral and chronic forms of aseptic meningitis. It is useful to keep in mind the possibility of neoplasia, HIV, tuberculosis, cryptococcosis, sarcoidosis, syphilis, borreliosis, parameningeal collection, and inadequately treated bacterial meningitis—each of which presents an urgent diagnostic problem.

From the foregoing discussion it is evident that the separation of the clinical syndromes of aseptic meningitis and encephalitis is not always clear. In some patients with aseptic meningitis, mild drowsiness or confusion may be present, suggesting cerebral involvement. Conversely, in some patients with encephalitis, the cerebral symptoms may be mild and meningeal symptoms and CSF abnormalities predominate. The common practice is to assume that viral meningitis causes only fever, headache, stiff neck, and photophobia; if any other CNS symptoms are added, the condition is generally called meningoencephalitis. As has been emphasized, the same spectrum of viruses gives rise to both meningitis and encephalitis. It is our impression that many cases of enteroviral and practically all cases of mumps and LCM encephalopathy are little more than examples of intense meningitis in which the subpial surface of the brain is inflamed. Rarely have they caused demonstrable postmortem cerebral lesions, and surviving patients have no residual neurologic signs. Conversely, several agents, notably the arboviruses, may cause encephalitic lesions with only mild meningeal symptoms.

The core of the encephalitis syndrome consists of an acute febrile illness with evidence of various combinations of seizures, delirium, confusion, stupor or coma; aphasia, hemiparesis with asymmetry of tendon reflexes and Babinski signs, involuntary movements, ataxia, and myoclonic jerks; and nystagmus, ocular palsies, and facial weakness. The meningitic component may be intense, have mild manifestations such as headache, or be entirely inapparent. The spinal fluid invariably shows a cellular reaction and the protein is slightly elevated. Imaging studies of the brain are most often normal but may show diffuse edema or enhancement of the cortex and, in certain infections, subcortical and deep nuclear involvement as well as, in the special case of HSV encephalitis, selective damage of the inferomedial temporal and frontal lobes.

Differentiation of Viral from Postinfectious Encephalitis (See also Chap. 36)

The acute encephalitis syndrome described above may take two forms: the more common direct invasion of brain and meninges (true viral encephalitis) and a postinfectious encephalomyelitis that is presumably based on an autoimmune reaction to the systemic viral infection but in which virus is not present in neural tissue. The distinction between postinfectious encephalomyelitis and infectious encephalitis may be difficult, especially in younger patients who have a proclivity to develop the postinfectious variety with fever. The latter, termed acute disseminated encephalomyelitis (ADEM), occurs after a latency of several days, as the infectious illness is subsiding. It is expressed by a low-grade fever and cerebral symptoms such as confusion, seizures, coma, or ataxia. The spinal fluid shows slight inflammation and elevation of protein—sometimes a more intense reaction, and there are usually characteristic confluent, scattered, bilateral lesions in the white matter in imaging studies, findings that differ from those of viral encephalitis. When there is no coexistent epidemic of encephalitis to suggest the diagnosis, or the preceding systemic illness is absent or obscure, a differentiation between the two may not be possible on clinical grounds alone. The fever is generally higher in the infectious type but even this difference does not always hold in young children with ADEM. The encephalitis that follows certain childhood exanthems (postexanthematous) and vaccinations at any age (postvaccinal) are essentially forms of ADEM.

Because ADEM is predominantly an inflammatory and demyelinative process, we mention it here but discuss its clinical features and imaging more fully in Chap. 36, with the other demyelinating diseases such as multiple sclerosis, with which it shares some features. We also place in special categories further on the now rare Reye syndrome of postinfectious acute encephalopathy with hepatic failure that follows influenza, and other viral infections and postinfectious cerebellitis.

Etiology

Whereas numerous viral, bacterial, fungal, and parasitic agents are cited as causes of the encephalitis syndrome, only the viral ones are considered here, for they are the most common and it is to these that one usually refers when the term encephalitis is used. The nonviral forms (mycoplasmal, rickettsial, Lyme, etc.) are considered in Chap. 32, under "Encephalitis Caused by Bacterial Infections," and should be reviewed with this section.

According to the Centers for Disease Control and Prevention, approximately 20,000 cases of acute viral encephalitis are reported annually in the United States. Death occurs in 5 to 20 percent of these patients and residual signs, such as mental deterioration, amnesic defect, personality change, recurrent seizures, and hemiparesis, are seen in approximately another 20 percent. However, these overall figures fail to reflect the widely varying incidence of mortality and residual neurologic abnormalities that follow infections by different viruses. In herpes simplex encephalitis, for example, approximately 50 percent of patients die or are left with some impairment, and in eastern equine encephalitis, the figures are even higher. On the other hand, death and serious neurologic sequelae have been observed in only 5 to 15 percent of those with western equine and West Nile infections and in even fewer patients with Venezuelan, St. Louis, and La Crosse encephalitides.

The types of viral encephalitis that occur with sufficient frequency to be of clinical importance are relatively few. HSV is by far the most common sporadic cause of encephalitis and has no seasonal or geographic predilections. Its age distribution is slightly skewed and biphasic, affecting persons mainly between ages 5 and 30 years and those older than age 50 years. Many other viruses, exemplified by the arboviral encephalitides, have a characteristic geographic and seasonal incidence. The most important of these is the Japanese encephalitis serogroup (Flaviviruses), of which the now common West Nile virus is a member. In recent outbreaks in the United States, the West Nile virus has been more frequent than any of the other arboviruses and has had a wide geographic distribution (Solomon). In the United States, eastern equine encephalitis, as the name implies, is observed mainly in the eastern states and on both the Atlantic and Gulf coasts. Western equine encephalitis is fairly uniformly distributed west of the Mississippi. St. Louis encephalitis, another arthropod-borne late-summer encephalitis, occurs nationwide but especially along the Mississippi River in the South; outbreaks occur in August through October, slightly later than is customary for the other arboviruses. Venezuelan equine encephalitis is common in South and Central America; in the United States it is practically confined to Florida and the southwestern states. California virus encephalitis predominates in the northern Midwest and northeastern states. After West Nile, the La Crosse variety is perhaps the most frequent identifiable arbovirus encephalitis in the United States.

Rabies infections occur worldwide, but in the United States they are seen mostly in the Midwest and along the West Coast. Japanese B encephalitis (the most common encephalitis outside of North America), Russian spring-summer encephalitis, Murray Valley encephalitis (Australian X disease), and several less common viral encephalitides are infrequent in the United States or, as in the case of West Nile fever, have appeared only recently. With the ease and rapidity of travel, many of these will undoubtedly increase in number in North America and parts of Europe where they have not been seen hitherto.

Infectious mononucleosis, which is a primary infection with EBV, is complicated by meningitis, encephalitis, facial palsy, or polyneuritis of the Guillain-Barré type in a small proportion of cases. Each of these neurologic complications can occur in the absence of the characteristic fever, pharyngitis, and lymphadenopathy of infectious mononucleosis. The same is true of M. pneumoniae. In these two diseases there is still uncertainty as to whether they are true infectious encephalitides or postinfectious complications, as discussed in Chap. 32. Evidence from PCR testing of spinal fluid is consistent with a direct infection in some cases. Varicella zoster and CMV are other herpes-type viruses that may cause encephalitis. They are discussed in relation to the particular clinical settings in which they occur. Definite cases of "epidemic encephalitis" (encephalitis lethargica) have not been observed in acute form since 1930, although an occasional surviving patient with a residual parkinsonian syndrome is still seen in neurology clinics. However, various movement disorders, including parkinsonism, are being seen as a residua of encephalitis from the Flaviviruses. The latency from infection to these complications is brief, or may be present from the outset, quite unlike encephalitis lethargica. There may also be a postinfectious-immune variety of this midbrain encephalitis.

More recently, a sometimes overwhelming encephalitis has been recognized as a rare manifestation of influenza infection, particularly the H1N1 strain that has infected mainly children in Southeast Asian countries, but also other serotypes of influenza including mundane influenza viruses that cause yearly outbreaks. The disorder has been called an "encephalopathy" in research publications but convulsions, delirium, and coma suggest that the neurologic aspects are from encephalitis.

The relative frequency of the various viral infections of the nervous system can be appreciated from several studies. An early series from the Walter Reed Army Institute comprising 1,282 patients is particularly noteworthy in that a positive laboratory diagnosis was achieved in more than 60 percent of cases (Buescher et al)—a higher rate than in almost any subsequent study of comparable size. Aside from the poliovirus (some of the data were gathered before 1959) the common infective agents in cases of both aseptic meningitis and encephalitis were group B Coxsackie virus, echovirus, mumps virus, lymphocytic choriomeningitis virus, arboviruses, HSV, and Leptospira, in that order. In a later prospective virologic study of all children examined at the Mayo Clinic during the years 1974 to 1976, a diagnosis of aseptic meningitis, meningoencephalitis, or encephalitis was entertained in 42 cases and an infectious agent was identified in 30 of them (Donat et al). The California virus was isolated in 19 cases and one of the enteroviruses (echovirus types 19, 16, 21, or Coxsackie virus) in 8 cases; mumps, rubeola, HSV, adenovirus 3, and M. pneumoniae were detected in individual cases (several patients had evidence of combined infections). As mentioned, recent outbreaks of West Nile virus, close to 3,000 cases yearly in the United States, make it of more current import than some of the viral infections listed here. The related Japanese encephalitis virus is even more ubiquitous on a worldwide basis, causing 10,000 deaths in Asia each year.

In a more contemporary and impressively large series of viral infections of the nervous system from the United Kingdom involving more than 2,000 patients, viral identification in the CSF was attempted by means of PCR with positive results in only 7 percent, half of which were various enteroviruses (Jeffery et al). The other organisms commonly identified were HSV-1, followed by VZV, EBV, and other herpesviruses. In patients with AIDS, however, the relative frequencies of the organisms that cause meningoencephalitis are quite different and include special clinical presentations; this applies particularly to CMV infection of the nervous system, as discussed further on, under "Opportunistic Infections and Neoplasms of the CNS in AIDS." Our personal experience has been heavily biased toward HSV encephalitis, seasonal outbreaks of eastern equine or West Nile encephalitis, and AIDS-related cases.

Arboviral Encephalitis

The common arthropod-borne viruses (arboviruses) that cause encephalitis in the United States and their geographic range have been mentioned earlier. Most of the agents are in the category of Flaviviruses. There are alternating cycles of viral infection in mosquitoes and vertebrate hosts; the mosquito becomes infected by taking a blood meal from a viremic host (horse or bird) and injects virus into the host, including humans. The seasonal incidence of these infections is practically limited to the summer and early fall, when mosquitoes are biting. In the equine encephalitides, regional deaths in horses usually precede human epidemics. For St. Louis encephalitis, the urban bird or animal or possibly the human becomes the intermediate host. West Nile outbreaks are preceded by illness in common birds such as crows and jays. St. Louis, California, and La Crosse agents are endemic in the United States because of the cycle of infection in small rodents. Powassan virus from the deer tick has been added to the list of causes of Flavivirus encephalitis in North America as in the report by Tavakoli and coworkers.

The clinical manifestations of the arbovirus infections are almost indistinguishable from one another, although they do vary with the age of the patient. The incubation period after mosquito or tick bite transmission is 5 to 15 days. There may be a brief prodromal fever with arthralgia or rash (e.g., West Nile fever). In infants, there may be only an abrupt onset of fever and convulsions, whereas in older children and adults the onset is usually less abrupt, with complaints of headache, listlessness, nausea or vomiting, drowsiness, and fever for several days before medical attention is sought; convulsions, confusion, stupor, and varying degrees of stiff neck then become prominent. Photophobia, diffuse myalgia, and tremor (of either action or intention type) may be observed. Asymmetry of tendon reflexes, hemiparesis, extensor plantar signs, myoclonus, chorea, and sucking and grasping reflexes may also occur. McJunkin and colleagues described the clinical features of 127 patients with La Crosse infection seen at their medical center over a decade, and their descriptions are representative of other arboviral infections. In addition to the typical features of viral encephalitis they emphasize aspects that occur in a proportion of patients: hyponatremia, raised intracranial pressure with cerebral swelling, and, most notable to us, signal changes in the MRI that simulate herpes encephalitis.

A special syndrome of febrile, flaccid, paralytic poliomyelitis resulting from West Nile virus infection is now also well known. It evolves over several days and in a few cases is accompanied by facial paralysis (Jeha et al). A few cases have had an early extrapyramidal syndrome; any of these features may occur with the other Flaviviruses.

The fever and neurologic signs of arboviral encephalitis subside after 4 to 14 days unless death supervenes or destructive CNS changes have occurred. No antiviral agents are known to be effective; one must rely entirely on supportive measures. On occasion, brain swelling reaches a degree that requires specific therapy, as outlined in "Management of the Acutely Comatose Patient and Management of Raised Intracranial Pressure" in Chap. 17.

Of the arbovirus infections in the United States, eastern equine encephalitis (EEE) is among the most serious, as a large proportion of those infected develop encephalitis; approximately one-third die and a similar number, more often children, are left with disabling abnormalities—mental retardation, emotional disorders, recurrent seizures, blindness, deafness, hemiplegia, extrapyramidal motor abnormalities, and speech disorders. While only a small proportion of those exposed become infected, the poliomyelitis and parkinsonian syndromes of the Flaviviruses may be permanent residua as mentioned earlier (Solomon). On the other extreme, La Crosse encephalitis, which affects mostly children, has an almost uniformly benign outcome. The rate of progression from a nondescript febrile viral syndrome to encephalitis is similarly low in the arbovirus infections and mortality rate varies from 2 to 12 percent in different outbreaks.

Diagnosis

The CSF findings are much the same as in aseptic meningitis (lymphocytic pleocytosis, mild protein elevation, normal glucose values). Recovery of virus from blood or CSF is usually not possible and PCR testing is routinely only applied during local epidemics. However, antiviral immunoglobulin (Ig) M antibody is present in the serum and CSF within the first days of symptomatic disease and can be detected and quantified by means of ELISA, making it preferable to other testing for specific diagnosis. Some patients have not developed antibodies by the time of admission to the hospital and the test may have to be repeated in several days. The MRI may be normal or show signal changes and edema in the cortex, basal ganglia, or thalamus (the latter is described particularly in the Japanese B virus group, West Nile, EEE, and rabies).

Pathology

Perivascular cuffing by lymphocytes and other mononuclear leukocytes and plasma cells, as well as a patchy infiltration of the meninges with similar cells, are the usual histopathologic hallmarks of viral encephalitis. There is widespread degeneration of single nerve cells, with neuronophagia as well as scattered foci of inflammatory necrosis involving both the gray and white matter. The brainstem is relatively spared. In some cases of eastern equine encephalitis, the destructive lesions may be massive, involving the major part of a lobe or hemisphere and are readily displayed by MRI, but in the other arbovirus infections the foci are microscopic in size (Deresiewicz et al). West Nile virus may produce a regional pattern of neuronal damage that affects the anterior horn cells of the spinal cord, a poliomyelitis, as mentioned earlier. Pathologic descriptions of this process have been provided by our colleagues and by others (see Asnis et al).

Herpes Simplex Encephalitis

Of the common viral encephalitides, this is perhaps the gravest and is by far the most common. About 2,000 cases occur yearly in the United States, accounting for approximately 10 percent of all cases of encephalitis. Between 30 and 70 percent are fatal, and the majority of patients who survive are left with serious neurologic abnormalities. HSV encephalitis occurs sporadically throughout the year and in patients of all ages and in all parts of the world. It is almost always caused by HSV-1, which is also the cause of the common herpetic lesions of the oral mucosa; only rarely, however, are the oral and encephalitic lesions concurrent. The type 2 herpesvirus may also cause acute generalized encephalitis, usually in the neonate and in relation to genital herpetic infection in the mother. Type 2 infection in the adult more typically causes an aseptic meningitis and sometimes a polyradiculitis or myelitis, again in association with a recent genital herpes infection. Exceptionally, the localized adult type of encephalitis is caused by the type 2 virus and the diffuse neonatal encephalitis by type 1.

Clinical Features

The symptoms, which evolve over several days, are in most cases like those of any other acute encephalitis—namely, fever, headache, seizures, confusion, stupor, and coma. In some patients these manifestations are preceded by symptoms and findings that betray the predilection of this disease for the inferomedial or lateral portions of the frontal and temporal lobes and the insula. The symptoms and findings include olfactory or gustatory hallucinations, anosmia, temporal lobe seizures, personality change, bizarre or psychotic behavior or delirium, aphasia, and hemiparesis. Although several seizures at the onset of illness are not an uncommon presentation, status epilepticus is rare. Disturbed memory function can often be recognized, but usually this becomes evident only later in the convalescent stage as the patient awakens from stupor or coma. Hemorrhagic swelling and herniation of one or both temporal lobes through the tentorial opening may occur, leading to coma during the first few days of the illness, a very poor prognostic sign.

The CSF is typically under increased pressure and almost invariably shows a pleocytosis (range 10 to 200 cells/mm3; infrequently greater than 500 cells/mm3). The cells are mostly lymphocytes, but there may be a significant number of neutrophils early on. In a few cases, 3 to 5 percent in some large series, the spinal fluid was normal in the first days of the illness, only to become abnormal when reexamined. The hemorrhagic nature of brain tissue destruction with this infection may be reflected in the spinal fluid. In fact, in only a minority of cases, red cells, sometimes numbering in the thousands but usually far fewer, and xanthochromia are found. The protein content is increased in most cases. Rarely, the CSF glucose levels may be reduced to slightly less than 40 mg/dL, creating confusion with tuberculous and fungal meningitides. The cerebral imaging appearance, giving highly characteristic features, is discussed later in the section on "Diagnosis."

Pathology

The lesions take the form of an intense hemorrhagic necrosis of the inferior and medial temporal lobes and the mediorbital parts of the frontal lobes. The region of necrosis may extend upward along the cingulate gyri and sometimes to the insula or the lateral parts of the temporal lobes or caudally into the midbrain but always contiguous with areas of mediotemporal lobe necrosis. The temporal lobe lesions are usually bilateral but not symmetrical. This distribution of lesions is so characteristic that the diagnosis can be made by gross inspection or by their location and appearance on imaging studies. Cases described in past years as "acute necrotizing encephalitis" and "inclusion body encephalitis" were likely to have been instances of HSV encephalitis. In the acute stages, intranuclear eosinophilic inclusions are found in neurons and glia cells, in addition to the usual microscopic abnormalities of acute encephalitis and hemorrhagic necrosis. Specific intracellular staining with antibody to various portions of the virus is perhaps the most definitive demonstration of the disease.

The characteristic localization of the lesions in this disease has been putatively explained by the virus' route of entry into the CNS. Two such routes have been suggested (Davis and Johnson). The virus may, for example, be latent in the trigeminal ganglia and, with reactivation, infect the nose and then the olfactory tract. Alternatively, with reactivation in the trigeminal ganglia, the infection may spread along nerve fibers that innervate the leptomeninges of the anterior and middle fossae. The lack of lesions in the olfactory bulbs in as many as 40 percent of fatal cases (Esiri) is a point in favor of the second pathway.

Diagnosis

Acute herpes simplex encephalitis must be distinguished from other types of viral encephalitis, from acute hemorrhagic leukoencephalitis, and from paraneoplastic and other forms of limbic encephalitis, tumor, cerebral abscess, cerebral venous thrombosis, and septic embolism (see Chap. 32). When aphasia is the initial manifestation of the illness, it may be mistaken for a stroke. The CSF findings have been mentioned and are typical of a meningoencephalitis. Spinal fluid that contains a large number of red cells may be attributed to a ruptured saccular aneurysm. The electroencephalographic (EEG) changes, consisting of lateralized periodic high-voltage sharp waves in the temporal regions and slow-wave complexes at regular 2 to 3/s intervals, are highly suggestive in the appropriate clinical context, though they are not specific for the disease and their sensitivity has not been established with certainty.

CT shows hypodensity of the affected temporal lobe areas in perhaps two-thirds of cases and MRI shows signal changes in almost all (increased signal in T2-weighted images; Fig. 33-1). T1-weighted images demonstrate areas of low signal intensity with surrounding edema and sometimes with scattered areas of hemorrhage occupying the inferior parts of the frontal and temporal lobes. The lesions almost always enhance to some degree with contrast infusion or with gadolinium, indicating cortical and pial abnormalities of the blood–brain barrier. It should be noted that these destructive lesions, and certainly their degree, are almost unique among the viral encephalitides, being seen only occasionally in other viral infections of the brain.

A rising titer of neutralizing antibodies can be demonstrated from the acute to the convalescent stage, but this is not of diagnostic help in the acutely ill patient and may not be significant in patients with recurrent herpes infections of the oral mucosa. Tests for the detection of HSV antigen in the CSF by the application of PCR have been developed and are useful in diagnosis while the virus is replicating in the first few days of the illness (Rowley et al). A refinement in this technique (a nested PCR assay described by Aurelius and coworkers) reportedly has a sensitivity of 95 percent and gives very few false-positive tests in the first 3 weeks of illness. In the experience of Lakeman and colleagues, the test was 98 percent positive in cases proven by cultures of brain biopsy material and gave 6 percent false positives. Antiviral treatment did not appear to affect the results. False-negative tests are most likely to occur in the first 48 h of febrile infection. When the clinical features are consistent with the disease and the PCR test is negative, it is advisable to repeat it in several days, perhaps in another laboratory and to obtain PCR testing for HSV-2 as well.

The only alternative way to establish the diagnosis of acute HSV encephalitis is by fluorescent antibody study and by viral culture of cerebral tissue obtained from brain biopsy. The approach to biopsy as a diagnostic test is now infrequently employed with the availability of the PCR test. We have now found it necessary to perform biopsy in only a very few cases, preferring to treat the patient with antiviral agents based on compatible clinical, radiologic, and CSF findings while awaiting serologic and PCR test results.

Treatment

Until the late 1970s, there was no specific treatment for HSV encephalitis. A collaborative study sponsored by the National Institutes of Health and also a Swedish trial indicated that the antiviral agent acyclovir significantly reduces both mortality and morbidity from the disease (Whitley et al; Sköldenberg et al). For this reason, it has become general practice to initiate treatment while confirmatory testing is being carried out. Acyclovir is given intravenously in a dosage of 30 mg/kg/d and continued for 10 to 14 days in order to prevent relapse. Acyclovir carries limited risk and can be discontinued if further clinical or laboratory features point to another diagnosis. The main problems that arise from the drug are local irritation of the veins used for infusion, mild elevation of hepatic enzymes, or transient impairment of renal function. Nausea, vomiting, tremor, or an encephalopathy that is difficult to distinguish from the encephalitis itself occurs in a very few patients.

The matter of relapse after treatment with acyclovir has been recognized, particularly in children. Several potential mechanisms have been suggested by Tiége and colleagues, including an immune-mediated inflammatory response, but treatment with too low a dose or for too brief a period is undoubtedly the main cause of the rare relapses that occur in adults. In children, a second course of acyclovir is usually successful.

When a large volume of brain tissue is involved, the hemorrhagic necrosis and surrounding edema act as an enlarging mass that requires separate attention. Coma and pupillary changes should not be attributed to the mass effect unless compression of the upper brainstem is evident on brain imaging, as the infection is capable of spreading to the mesencephalon from the contiguous deep temporal lobe, thereby causing coma by a direct destructive effect. All measures used in the management of brain edema from mass lesions are applicable here, but there are insufficient data by which to judge their effectiveness. The concern that corticosteroids may aggravate the infection has not been borne out by clinical experience, but a detrimental effect cannot be discounted and their value is uncertain. Our experience (reported by Barnett et al) and that of Schwab and colleagues have been that the presence of raised intracranial pressure early in the illness presages a poor outcome. Seizures are usually brought under control by high doses of conventional antiepileptic drugs. The use of these medications prophylactically for seizures has not been resolved.

Prognosis

The outcome of this disease, both mortality and morbidity, is governed to a large extent by the patient's age and state of consciousness, particularly at the time of institution of acyclovir therapy. If the patient is unconscious (except immediately after a convulsion), the outcome is usually poor. However, if treatment is begun within 4 days of onset of the illness in an awake patient, survival is greater than 90 percent (Whitley, 1990). Evaluation of patients 2 years after treatment showed 38 percent to be normal or nearly normal, whereas 53 percent were dead or severely impaired. The neurologic sequelae are often of the most serious type, consisting of a Korsakoff amnesic defect or a global dementia, seizures, and aphasia as described by Drachman and Adams in the era before treatment became available. If there were seizures during the acute illness, it is advisable to continue antiepileptic medications for a year or more and then judge the risk of discontinuing them on the basis of further seizures, the EEG, and the patient's exposure to situations that pose a danger, such as driving. With the exception of the rare relapsing cases mentioned earlier, the infection does not recur.

HHV-6 Encephalitis in Stem Cell Transplant

This agent, the cause of roseola (exanthema subitum), has had a controversial role in a number of acute febrile neurologic illnesses, including febrile seizures in infants and young children, subsequent temporal lobe epilepsy, cranial-nerve palsies, and other conditions. However, it is fairly firmly established as the cause of a medial temporal lobe (limbic) encephalitis in adult patients following allogenic hematopoietic stem cell bone marrow transplantation, as summarized by Seeley and colleagues. All of their patients also developed a graft-versus-host reaction. The clinical and imaging features closely resemble the paraneoplastic and anti–voltage-gated potassium channel limbic encephalitis that is discussed in Chap. 31. The prognosis is far better than in herpetic encephalitis. It is mentioned here that mundane adenoviruses can also produce a severe medial temporal lobe encephalitis in bone marrow transplant cases, in one of our patients associated with gray matter damage in the spinal cord.

The other viral agents that appear as causes of encephalitis with some regularity in stem-cell and organ transplant patients include parvovirus, CMV, EBV, adenovirus, HSV, and varicella zoster virus. Quite often, these infections are but one component of multiorgan viral infection. Some of these agents also cause manifestations of infection in peripheral and cranial nerves.

Rabies

This disease also stands apart from other acute viral infections by virtue of the latent period that follows inoculation with the virus and its stunningly distinctive clinical and pathologic features. Human examples of this disease are rare in the United States; between 1980 and 1997, only 34 instances were known to have occurred and since 1960, there have not been more than 5 or so cases in any 1 year. In some areas (Australia, Hawaii, Great Britain, and the Scandinavian peninsula), no indigenous cases have ever been reported. In contrast, in India there is a high incidence. The importance of this disease derives from the fact that it is almost invariably fatal once the characteristic clinical features appear, making survival of the infected individual dependent on the institution of specific therapeutic measures before the infection becomes clinically evident. Furthermore, each year 20,000 to 30,000 individuals are treated with rabies vaccine, having been bitten by animals that possibly were rabid, and although the incidence of complications with the newer rabies vaccination is much lower than before, a few serious reactions continue to be encountered (see further on and also Chap. 36).

Etiology

Practically all cases of rabies are the result of transdermal viral inoculation by an animal bite. In developing countries, where rabies is relatively common, the most frequent source is the rabid dog. In Western Europe and the United States, the most common rabid species are raccoons, skunks, foxes, and bats among wild animals and dogs and cats among domestic ones. Because rabid animals commonly bite without provocation, the nature of the attack should be determined. Also, the prevalence of animal rabies virus varies widely in the United States, and local presence of the disease is useful in assessing risk. Rare cases have been caused by inhalation of the virus shed by bats; a history of spelunking suggests this mode of acquiring the infection. In a few cases the source of the infection may not be identifiable. The epidemiology and public health aspects of rabies have been reviewed by Fishbein and Robinson.

Clinical Features

The incubation period is usually 20 to 60 days but may be as short as 14 days, especially in cases involving multiple deep bites around the face and neck. Tingling or numbness at the site of the bite, even after the wound has healed, is characteristic. This is thought to reflect an inflammatory response that is incited when the virus reaches the sensory ganglion.

The main neurologic symptoms, following a 2- to 4-day prodromal period of fever, headache, and malaise consist of apprehension, dysarthria, and psychomotor overactivity, followed by dysphagia (hence salivation and "frothing at the mouth"), spasms of throat muscles induced by attempts to swallow water or in rare cases by the mere sight of water ("hydrophobia"), dysarthria, numbness of the face, diplopia, and spasms of facial muscles. These features indicate the involvement of the tegmental medullary nuclei. Generalized seizures, confusional psychosis, and a state of agitation may follow. A less common paralytic form ("dumb" rabies of older writings, in distinction to the above described "rabid" form) as a result of spinal cord infection may accompany or replace the state of excitement. The paralytic form is most likely to follow bat bites or, in the past, the administration of rabies vaccination. Coma gradually follows the acute encephalitic symptoms and, with rare exceptions as noted below, death ensues within 4 to 10 days, or longer in the paralytic form.

Pathologic Features

The disease is distinguished by the presence of cytoplasmic eosinophilic inclusions, the Negri bodies. They are most prominent in pyramidal cells of the hippocampus and Purkinje cells but have been seen in nerve cells throughout the brain and spinal cord. In addition there is widespread perivascular cuffing and meningeal infiltration with lymphocytes and mononuclear cells and small foci of inflammatory necrosis, such as those seen in other viral infections. The inflammatory reaction is most intense in the brainstem. The focal collections of microglia in this disease are referred to as Babes nodules (named for Victor Babes, a Romanian microbiologist).

Treatment

Bites and scratches from a potentially rabid animal should be thoroughly washed with soap and water and, after all soap has been removed, cleansed with benzyl ammonium chloride (Zephiran), which has been shown to inactivate the virus. Wounds that have broken the skin also require tetanus prophylaxis.

After a bite by a seemingly healthy animal, surveillance of the animal for a 10-day period is necessary. Should signs of illness appear in the animal, it should be killed and the brain sent, under refrigeration, to a government-designated laboratory for appropriate diagnostic tests. Wild animals, if captured, should be killed and the brain examined in the same way.

If the animal is found by fluorescent antibody or other tests to be rabid, or if the patient was bitten by a wild animal that escaped, postexposure prophylaxis should be given. Human rabies immune globulin (HRIG) is injected in a dose of 20 U/kg of body weight (one-half infiltrated around the wound and one-half intramuscularly). This provides passive immunization for 10 to 20 days, allowing time for active immunization. Duck embryo vaccine (DEV) was previously used for this purpose and greatly reduced the danger of serious allergic encephalomyelitis from about 1 in 1,000 cases (with the formerly used equine vaccine) to 1 in 25,000 cases; it is still used in many parts of the world. The more recently developed rabies vaccine grown on a human diploid cell line (human diploid cell vaccine [HDCV]) has reduced the doses needed to just 5 (from the 23 needed with DEV); these are given as 1-mL injections on the day of exposure and then on days 3, 7, 14, and 28 after the first dose. The HDCV vaccine has increased the rate of antibody response and reduced even further the allergic reactions by practically eliminating foreign protein. A thorough trial of the new antiviral agents in patients already symptomatic has not been undertaken. Persons at risk for rabies, such as animal handlers and laboratory workers, should receive preexposure vaccination with HDCV. A preventative DNA rabies vaccine has been genetically engineered and is being tested for use in animal handlers and others at high risk.

With modern intensive-care techniques, there have been a number of survivors of the encephalitic illness, all of whom had received postexposure immunization. In addition to mechanical respiratory support, several secondary abnormalities must be addressed, including raised intracranial pressure, excessive release of antidiuretic hormone, diabetes insipidus, and extremes of autonomic dysfunction, especially hyper- and hypotension. Willoughby and colleagues were successful in treating a 15-year-old girl who had not received vaccine by using an empirical approach of induced coma with ketamine and midazolam supplemented by ribavirin and amantadine. The goal was to support the patient while her antibody response matured. At least two other cases treated in a similar manner, reported anecdotally, did not survive.

Acute Cerebellitis (Acute Ataxia of Childhood)

A comment is made here concerning a dramatic syndrome of acute ataxia that occurs in the context of an infectious illness, mainly in children. The syndrome was originally described by Westphal in 1872 following smallpox and typhoid fever in adults, but Batten is credited with drawing attention to the more common ataxic illness that occurs after common childhood infections such as measles, pertussis, and scarlet fever. Currently, acute ataxia of childhood is most often associated with chickenpox (about one-quarter of 73 consecutive cases reported by Connolly et al), but it can occur during or after any of the childhood exanthems, as well as in association with infections caused by enteroviruses (mainly Coxsackie virus), EBV, Mycoplasma, CMV, Q fever, vaccinia, a number of vaccinations, rarely following HSV, and also after nondescript respiratory infections (see Weiss and Guberman). The condition, as mentioned, is far less frequent in adults, but we encounter a case every few years in adolescents and individuals in their twenties; besides a case of varicella that we observed in a 25-year-old, the most common preceding organisms in these individuals have been EBV and Mycoplasma.

This illness, which is essentially a "meningocerebellitis," appears relatively abruptly, over a day or so, and consists of limb and gait ataxia and often, but not uniformly, dysarthria and nystagmus. Additional signs include increased limb tone, Babinski signs, or confusion. The fever of the original infection may have abated, or it may persist through the early stages of the ataxic illness. As a rule, there is a mild pleocytosis; the CSF protein is elevated or may be normal. The MRI is normal in the majority of cases but some show enhancement with gadolinium of the cerebellar cortical ribbon. Most patients make a slow recovery, but permanent residua are known to follow. Because the benign nature of the illness has precluded extensive pathologic study, there is uncertainty regarding the infectious or postinfectious nature of these ataxic illnesses. Some cases have shown an inflammatory pathology most suggestive of a postinfectious process (see Chap. 36), but the finding of fragments of VZV and Mycoplasma genomes in the spinal fluid by means of DNA amplification techniques favors a primary infectious encephalitis, at least in some instances.

Herpes zoster ("shingles," "zona") is a common viral infection of the nervous system occurring at an overall rate of 3 to 5 cases per 1,000 persons per year, with higher rates in the elderly. Shingles is distinctly rare in childhood. It is characterized clinically by radicular pain, a vesicular cutaneous eruption, and, less often, by segmental sensory and delayed motor loss. The pathologic changes consist of an acute inflammatory reaction in isolated spinal or cranial sensory ganglia and lesser degrees of reaction in the posterior and anterior roots, the posterior gray matter of the spinal cord, and the adjacent leptomeninges.

The neurologic implications of the segmental distribution of the rash were recognized by Richard Bright as long ago as 1831. Inflammatory changes in the corresponding ganglia and related portions of the spinal nerves were first described by von Barensprung in 1862. The concept that varicella and zoster are caused by the same agent was introduced by von Bokay in 1909 and was subsequently established by Weller and his associates (1958). The common agent is varicella or VZV, a DNA virus that is similar in structure to the virus of herpes simplex. These and other historical features of herpes zoster were reviewed by Denny-Brown, Adams, and Fitzgerald and by Weller, Witton, and Bell.

Pathology and Pathogenesis

The pathologic changes in VZV infection consist of one or more of the following: (1) an inflammatory reaction in several unilateral adjacent sensory ganglia of the spinal or cranial nerves, frequently of such intensity as to cause necrosis of all or part of the ganglion, with or without hemorrhage; (2) an inflammatory reaction in the spinal roots and peripheral nerve contiguous with the involved ganglia; (3) a less-common poliomyelitis that closely resembles acute anterior poliomyelitis but is readily distinguished by its unilaterality, segmental localization, and greater involvement of the dorsal horn, root, and ganglion, sometimes with necrosis; and (4) a relatively mild leptomeningitis, largely limited to the involved spinal or cranial segments and nerve roots. These pathologic changes are the substrate of the neuralgic pains, the pleocytosis, and the local palsies that may attend and follow the VZV infection. There may also be a delayed cerebral vasculitis (see further on).

As to pathogenesis, herpes zoster represents a spontaneous reactivation of VZV infection, which becomes latent in the neurons of sensory ganglia following a primary infection with chickenpox (Hope-Simpson). This mechanism is consistent with the differences in the clinical manifestations of chickenpox and herpes zoster, even though the same virus causes both. Chickenpox is highly contagious by respiratory aerosol, has a well-marked seasonal incidence (winter and spring), and tends to occur in epidemics. Zoster, on the other hand, is not communicable (except to a person who has not had chickenpox), occurs sporadically throughout the year, and shows no increase in incidence during epidemics of chickenpox. In patients with zoster, there is practically always a past history of chickenpox. Such a history may be lacking in rare instances of herpes zoster in infants, but in these cases there has usually been prenatal maternal contact with VZV.

VZV DNA is localized primarily in trigeminal and thoracic ganglion cells, corresponding to the dermatomes in which chickenpox lesions are maximal and that are most commonly involved by VZV (Mahalingam et al). The supposition is that the virus makes its way from the cutaneous vesicles of chickenpox along the sensory nerves to the ganglion, where it remains latent until activated, at which time it progresses down the axon to the skin. Multiplication of the virus in epidermal cells causes swelling, vacuolization, and lysis of cell boundaries, leading to the formation of vesicles and so-called Lipschütz inclusion bodies. Alternatively, the ganglia could be infected during the viremia of chickenpox, but then one would have to explain why only one or a few sensory ganglia become infected. Reactivation of virus is attributed to waning immunity, which would explain the increasing incidence of zoster with aging and with lymphomas, administration of immunosuppressive drugs, AIDS, and after radiation therapy.

The subject of pathogenesis of herpes zoster has been reviewed by Gilden and colleagues (2000) and in the monograph by Rentier, who describes the molecular and immune investigations pertaining to VZV.

Clinical Features

As indicated above, the incidence of herpes zoster rises with age. Hope-Simpson has estimated that if a cohort of 1,000 people lived to 85 years of age, half would have had one attack of zoster and 10 would have had two attacks. The notion that one attack of zoster provides lifelong immunity is incorrect, although recurrent attacks are rare and most localized repeated herpetic eruptions are caused by HSV. The sexes are equally affected, as is each side of the body. Herpes zoster occurs in up to 10 percent of patients with lymphoma and 25 percent of patients with Hodgkin disease—particularly in those who have undergone splenectomy or received radiotherapy. Conversely, approximately 5 percent of patients who present with herpes zoster are found to have a concurrent malignancy (about twice the number that would be expected), and the proportion appears to be even higher if more than two adjacent dermatomes are involved.

The vesicular eruption is usually preceded for several days by itching, tingling, or burning sensations in the involved dermatome, and sometimes by malaise and fever. Or there is severe localized or radicular pain that may be mistaken for pleurisy, appendicitis, cholecystitis, muscle strain, or, quite often, ruptured intervertebral disc, until the diagnosis is clarified by the appearance of vesicles (nearly always within 72 to 96 h).

The rash consists of clusters of tense clear vesicles on an erythematous base, which become cloudy after a few days (as a result of accumulation of inflammatory cells), and dry, crusted, and scaly after 5 to 10 days. In a small number of patients, the vesicles are confluent and hemorrhagic, and healing is delayed for several weeks. In most cases, pain and dysesthesia last for 1 to 4 weeks; but in the others (7 to 33 percent in different series) the pain persists for months or, in different forms, for years, and presents a difficult problem in management. Impairment of superficial sensation in the affected dermatome(s) is common, and segmental weakness and atrophy are added in approximately 5 percent of patients. In the majority of patients the rash and sensorimotor signs are limited to the territory of a single dermatome, but in some, particularly those with cranial or limb involvement, two or more contiguous dermatomes are involved.

Rarely (and usually in association with malignancy) the rash is generalized, like that of chickenpox, or it is altogether absent (zoster sine herpete) in which case, the pain is often attributed to another more mundane process such as sciatica.

In more than half of the cases, the CSF shows a mild increase in cells, mainly lymphocytes, and a modest increase in protein content (although lumbar puncture is not performed to establish the diagnosis). The herpetic nature of the eruption can be confirmed by direct immunofluorescence of a biopsied skin lesion, using antibody to VZV, or inferred by finding multinucleated giant cells in scrapings from the base of an early vesicle (Tzanck smear). The spinal fluid also contains antibodies to the virus or evidence of the organism by PCR testing in 35 percent of cases according to a prospective study by Haanpää and colleagues.

Virtually any dermatome may be involved in zoster, but some regions are far more frequent than others. The thoracic dermatomes, particularly T5 to T10, are the most common sites, accounting for more than two-thirds of all cases, followed by the craniocervical regions. In the latter cases the disease tends to be more severe, with greater pain, more frequent meningeal signs, and involvement of the mucous membranes. Another rare complication of zoster, taking the form of a subacute amyotrophy (zoster paresis) of a portion of a limb or trunk, is probably linked to a restricted form of VZV myelitis.

There are two rather characteristic cranial herpetic syndromes—ophthalmic herpes and geniculate herpes. In ophthalmic herpes, which accounts for 10 to 15 percent of all cases of zoster, the pain and rash are in the distribution of the first division of the trigeminal nerve, and the pathologic changes are centered in the gasserian ganglion. The main hazard in this form of the disease is herpetic involvement of the cornea and conjunctiva, resulting in corneal anesthesia and residual scarring. Palsies of extraocular muscles, ptosis, and mydriasis are frequently associated, indicating that the third, fourth, and sixth cranial nerves are affected in addition to the gasserian ganglion. The less common but also characteristic cranial nerve syndrome consists of a facial palsy in combination with a herpetic eruption of the external auditory meatus, sometimes with tinnitus, vertigo, and deafness. Ramsay Hunt (whose name has been attached to the syndrome) attributed this illness to herpes of the geniculate ganglion. Denny-Brown, Adams, and Fitzgerald found the geniculate ganglion to be only slightly affected in a man who died 64 days after the onset of a so-called Ramsay Hunt syndrome (during which time the patient had recovered from the facial palsy); there was, however, inflammation of the facial nerve.

Herpes zoster of the palate, pharynx, neck, and retroauricular region (herpes occipitocollaris) depends on herpetic infection of the upper cervical roots and the ganglia of the vagus and glossopharyngeal nerves. Herpes zoster in this distribution may also be associated with the Ramsay Hunt syndrome. The relative frequency of distribution of zoster in these truncal dermatomes and a proclivity for facial eruption, suggests to us that herpetic neurologic syndromes are more likely to occur if the distance of the ganglia from the skin is short.

Encephalitis and cerebral angiitis (see below) are rare but well-described complications of cervicocranial zoster, as discussed below, and a restricted but destructive myelitis is a similarly rare but often quite serious complication of thoracic zoster. Devinsky and colleagues reported their findings in 13 patients with zoster myelitis (all of them immunocompromised) and reviewed the literature on this subject. The signs of spinal cord involvement appeared 5 to 21 days after the rash and then progressed for a similar period of time. Asymmetrical paraparesis and sensory loss, sphincteric disturbances, and, less often, a Brown-Séquard syndrome were the usual clinical manifestations. The CSF findings were more abnormal than in uncomplicated zoster (pleocytosis and raised protein) but otherwise similar. The pathologic changes, which take the form of a necrotizing inflammatory myelopathy and vasculitis, involve not just the dorsal horn but also the contiguous white matter, predominantly on the same side and at the same segment(s) as the affected dorsal roots, ganglia, and posterior horns. Early therapeutic intervention with acyclovir appeared to be beneficial. Our experience with the problem includes an elderly man who was not immunosuppressed; he remained with an almost complete transverse myelopathy.

Many of the writings on zoster encephalitis give the impression of a severe illness that occurs temporally remote from the attack of shingles in an immunosuppressed patient. Indeed, such instances have been reported in patients with AIDS and may be concurrent with the small vessel vasculitis described below. However, our experience is more in keeping with that of Jemsek and colleagues and of Peterslund, who described a less severe form of encephalitis in patients with normal immune systems. Our several patients with this process, all elderly women, developed self-limited encephalitis during the latter stages of an attack of shingles. They were confused and drowsy, with low-grade fever but little meningismus, and a few had seizures. Recovery was complete and the MRI was normal, in distinction to the vasculitic syndromes. In some reported cases, VZV has been isolated from the CSF and specific antibody to VZV membrane antigen (VAMA) has been found in the CSF and serum, although it is hardly needed for purposes of diagnosis. (The differential diagnosis in these elderly patients also includes a drowsy confusional state induced by narcotics given for the control of pain.) Varicella cerebellitis, a post- or parainfectious condition, was discussed earlier in the chapter.

Zoster Angiitis

A cerebral angiitis that occasionally complicates VZV infection is histologically similar to granulomatous angiitis and to Wegener granulomatosis. Typically, 2 to 10 weeks after the onset specifically of ophthalmic zoster, the patient develops an acute hemiparesis, hemianesthesia, aphasia, or other focal neurologic or retinal deficits associated with a mononuclear pleocytosis in the spinal fluid and elevated IgG indices in the CSF. Nagel and colleagues have found that specific antibodies in the CSF to the virus were more sensitive for the diagnosis of this condition than was detection of viral DNA. CT or MRI scans demonstrate small, deep infarcts in the hemisphere ipsilateral to the outbreak of shingles on the face. Angiograms show narrowing or occlusion of the internal carotid artery adjacent to the ganglia; but in some cases, vasculitis is more diffuse, even involving the contralateral hemisphere.

Whether the angiitis results from direct spread of the viral infection via neighboring nerves as postulated by Linnemann and Alvira, or represents an allergic reaction during convalescence from zoster, has not been settled. VZV-like particles have been found in the vessel walls, suggesting a direct infection and viral DNA has been extracted in a few cases from affected vessels. Because the exact pathogenetic mechanism is uncertain, treatment with both intravenous acyclovir and corticosteroids may be justified. There are occasional instances of a cerebral vasculitis following dermatomal zoster on the trunk.

An entirely different type of delayed vasculitis that affects small vessels, with which we have had limited experience, is being reported in patients with AIDS and other forms of immunosuppression. In this condition, weeks or months after one or more attacks of zoster, a subacute encephalitis ensues, including fever and focal signs. Some cases apparently arise without a rash, but viral DNA and antibodies to VZV are found in the CSF. The MRI shows multiple cortical and white matter lesions, the latter being smaller and less confluent than in progressive multifocal leukoencephalopathy. There is usually a mild pleocytosis. Almost all cases have ended fatally. The vasculitic and other neurologic complications of zoster have been reviewed by Gilden and colleagues (2002). Nagel and coworkers from Gilden's laboratory have also found cases in which the temporal arteries contain VZV particles and they have suggested that the vascular changes caused by the virus may simulate temporal arteritis.

Finally, as mentioned earlier, a facial palsy or pain in the distribution of a trigeminal or segmental nerve (usually lumbar or intercostal) as a result of herpetic ganglionitis, may occur rarely without involvement of the skin (zoster sine herpete); lumbar disc herniation may be suspected. In a few such cases, an antibody response to VZV has been found (Mayo and Booss), and Dueland and associates have described an immunocompromised patient who developed a pathologically and virologically proved zoster infection in the absence of skin lesions. Similarly, Gilden and colleagues (2002) recovered VZV DNA from two otherwise healthy immunocompetent men who had experienced chronic radicular pain without a zoster rash. But practically no instances of Bell's palsy, tic douloureux, and intercostal neuralgia are associated with serologic evidence of activation of VZV (Bell's palsy has instead been associated with HSV, as indicated in Chap. 47).

Treatment

An important inception for shingles has been a live, attenuated vaccine that can be administered to adults over age 60. It has been shown to reduce the emergence of shingles and to decrease the incidence of postherpetic complications by two-thirds (Oxman et al).

During the acute stage of shingles, analgesics and drying and soothing lotions, such as calamine, help to blunt the pain. Nerve root blocks may provide temporary relief but are not often used. After the lesions have dried, the repeated application of capsaicin ointment (derived from hot peppers) may relieve the pain in some cases by inducing a cutaneous anesthesia. When applied too soon after the acute stage, however, capsaicin is highly irritating and should be used cautiously.

Acyclovir shortens the duration of acute pain and speeds the healing of vesicles, provided that treatment is begun within approximately 48 h (some authorities say 72 h) of the appearance of the rash (McKendrick et al, 1986). Several studies have suggested that the duration of postherpetic neuralgia is reduced by treatment during the acute phase with famciclovir or valacyclovir, but the incidence of this complication is not markedly affected. Famciclovir (500 mg tid for 7 d) or the better absorbed valacyclovir (2 g orally qid) are possibly better alternatives than the previously favored acyclovir (see below on the subject of postherpetic neuralgia). Other studies have shown favorable results in preventing postherpetic pain by starting a tricyclic antidepressant during the acute phase.

All patients with ophthalmic zoster should receive acyclovir or valacyclovir orally; in addition, acyclovir applied topically to the eye, in either a 0.1 percent solution every hour or a 0.5 percent ointment 4 or 5 times a day, is recommended by some ophthalmologists. Patients who are immunocompromised or have disseminated zoster (lesions in more than 3 dermatomes) should generally receive intravenous acyclovir for 10 days. There is now available (from state health agencies) a VZV immune globulin (VZIG) that may protect against dissemination in immunosuppressed patients but is not indicated for established disease. Although it may reduce the incidence of postherpetic neuralgia (Hugler et al), this is not its main purpose and it does not appear to prevent or ameliorate CNS complications.

Postherpetic Neuralgia (See also Chaps. 8 and 10)

This severely painful syndrome follows shingles in 5 to 10 percent of patients but occurs almost three times more often among individuals older than age 60 years. The possible effect of acute treatment on the severity of postherpetic neuralgia is mentioned above but potential prevention with the vaccine is even more appealing.

The management of postherpetic pain and dysesthesia can be a trying matter for both the patient and the physician. It is likely that incomplete interruption of nerve impulses results in a hyperpathic state in which every stimulus excites pain. In a number of controlled studies, amitriptyline proved to be an effective therapeutic measure. Initially, it is given in doses of approximately 50 mg at bedtime; if needed, the dosage can be increased gradually to 125 mg daily. The addition of carbamazepine, gabapentin, pregabalin, or valproate may further moderate the pain, particularly if it is of lancinating type.

Capsaicin ointment can be applied to painful skin, as noted above. A salve of two aspirin tablets, crushed and mixed with cold cream or chloroform (15 mL) and spread on the painful skin, was reported to be successful in relieving the pain for several hours (King). The effect of nerve root blocks is inconsistent, but this procedure may afford temporary relief. In one randomized trial, the preemptive use of epidural steroids at the onset of the rash had minimal effects (van Wijck et al). It should be emphasized that postherpetic neuralgia eventually subsides even in the most severe and persistent cases but the short-term use of narcotics is appropriate when the pain is severe. Until the pain subsides, the physician must exercise skill and patience and avoid the temptation of subjecting the patient to one of the many surgical measures that have been advocated for this disorder (see Chap. 9 for further discussion of pain management). Some patients with the most persistent complaints, beyond a year, have symptoms of a depressive state and will be helped by antidepressive medications.

Retroviruses are a large group of RNA viruses, so called because they contain the enzyme reverse transcriptase, which permits the reverse flow of genetic information from RNA to DNA. Two families of retroviruses are known to infect humans: (1) the lentiviruses, the most important of which is the HIV, the cause of AIDS, and (2) the oncornaviruses, which include the human T-cell lymphotropic viruses (HTLV-I), the agents that induce chronic T-cell leukemias and lymphomas (HTLV-II) and tropical spastic paraparesis (HTLV-I). A comprehensive account of the neurobiology, pathology, and clinical features of these infections can be found in the appropriate sections of Harrison's Principles of Internal Medicine and authoritative information regarding treatment is given in the text by Rubin and Young.

The Acquired Immunodeficiency Syndrome

In 1981, physicians became aware of the frequent occurrence of otherwise rare opportunistic infections and neoplasms—notably Pneumocystis carinii pneumonia and Kaposi sarcoma—in otherwise healthy young homosexual men. The study of these patients led to the recognition of a new viral disease, AIDS.

HIV infection is characterized by an acquired and usually profound depression of cell-mediated immunity as manifest by cutaneous anergy, lymphopenia, reversal of the T-helper–to–T-suppressor cell ratio—more accurately, CD4+/CD8+ lymphocytes, as a result of reduction in CD4+ cells—and depressed in vitro lymphoproliferative response to various antigens and mitogens. It is this failure of immune function that explains the development of a wide range of opportunistic infections and unusual neoplasms. Virtually all organ systems are vulnerable, including all parts of the CNS, the peripheral nerves and roots, and muscle. Moreover, the nervous system is susceptible to a number of unusual syndromes that are the direct result of the AIDS virus infection.

Epidemiology

In a span of 25 years, HIV infection and AIDS have attained pandemic proportions. At the time of this writing it was estimated by the World Health Organization (WHO) that approximately 34 million persons are infected worldwide and that approximately 1 million adults in the United States are seropositive for the virus with 50,000 new cases yearly. The CDC furthermore estimates that 18 percent of infections have not been diagnosed. Though the incidence is decreasing, particularly startling are the statistics from sub-Saharan Africa and Southeast Asia, where the WHO estimated that approximately 25,000,000 adults—or almost 9 percent of the adult population—were infected. In some areas of East Africa, 30 percent of adults are infected with the virus.

In the United States, AIDS affects mainly homosexual and bisexual males (two-thirds of all cases) and male and female drug users (almost one-third of cases). Somewhat less than 2 percent of patients who are at risk are hemophiliacs and others who receive infected blood or blood products, and the disease has occurred in infants born of mothers with AIDS. Moreover, the virus may be transmitted by asymptomatic and still immunologically competent mothers to their offspring. Spread of the disease by heterosexual contact accounts for approximately 5 percent of cases, but this number is gradually increasing, partly through the activities of intravenous drug users. By contrast, an estimated 80 percent of African AIDS patients acquire their disease through heterosexual contact.

The related but less common entity of HIV-2 infection causes a generally less severe illness than HIV-1 but may include almost any of the features described below, including dementia. The virus is currently most prolific in Brazil, Cape Verde, and West African countries. The diagnosis is made complicated by the usual findings of a positive ELISA test but a negative or indeterminate Western blot results when conventional methods are used. A specific Western blot is available for HIV-2.

Clinical Features

Infection with HIV produces a spectrum of disorders, ranging from clinically inevident seroconversion to widespread lymphadenopathy and other systemic manifestations such as diarrhea, malaise, and weight loss, which comprises the direct effects of the virus on all organ systems as well as the complicating effects of a multiplicity of secondary parasitic, fungal, viral, and bacterial infections and a number of neoplasms, all of which require cell-mediated immunity for containment. Until the recent advent of multiple antiviral drug therapy, once the manifestations of AIDS had become established, half of patients died by 1 year and most by 3 years. Neurologic abnormalities had been found in about one-third of untreated patients with AIDS, but at autopsy the nervous system is affected in nearly all of them. Table 33-2 lists the main infections and neoplastic lesions of the nervous system that complicate AIDS.

It has already been mentioned that HIV infection may present as an acute asymptomatic meningitis with a mild lymphocytic pleocytosis and modest elevation of CSF protein. The acute illness may also take the form of a meningoencephalitis or even a myelopathy or neuropathy (see further on). Most patients recover from the initial acute neurologic illnesses; the relationship to AIDS may pass unrecognized, as these illnesses are quite nonspecific clinically and may precede or coincide with seroconversion. Once seroconversion has occurred, the patient becomes vulnerable to all the late complications of HIV infection. In adults, the interval between infection and the development of AIDS ranges from several months to 15 years or even longer; the mean latency is 8 to 10 years and 1 year or less in infants.

HIV-2 may display special features of a subacute confusional-dementing illness with deep white matter and basal ganglionic damage.

HIV-Associated Neurocognitive Disorders (AIDS Dementia Complex)

In the later stages of HIV infection, the most common neurologic complication is a subacute or chronic HIV encephalitis presenting as a form of dementia; formerly it was called AIDS encephalopathy or encephalitis, but it is now generally referred to as AIDS dementia complex (ADC; Navia, Jordan, and Price). It has been estimated that only 3 percent of AIDS cases present in this manner, but the frequency is far higher, close to two-thirds, after the constitutional symptoms and opportunistic infections of AIDS have become established. In children with AIDS, dementia is more common than all opportunistic infections, more than 60 percent of children eventually being affected.

The disorder in adults takes the form of a slowly or subacutely progressive dementia (loss of retentive memory, inattentiveness, language disorder, and apathy) accompanied variably by abnormalities of motor function. Patients complain of being unable to follow conversations, taking longer to complete daily tasks, and becoming forgetful. Incoordination of the limbs, ataxia of gait, and impairment of smooth pursuit and saccadic eye movements may be early accompaniments of the dementia. Heightened tendon reflexes, Babinski signs, grasp and suck reflexes, weakness of the legs progressing to paraplegia, bladder and bowel incontinence reflecting spinal cord or cerebral involvement, and abulia or mutism are prominent in the later stages of the disease. In the untreated case, the dementia evolves, over a period of weeks or months; survival after the onset of dementia is generally 3 to 6 months but may be considerably longer if treatment is instituted. Treatment with antiretroviral drugs can result in cognitive improvement. There is an interest in rare cases of poor penetration of antiretroviral drugs into the central nervous system, allowing for viral replication and reemergence despite elimination of HIV from the peripheral blood.

Tests of psychomotor speed seem to be most sensitive in the early stages of dementia (e.g., trail making, pegboard, and symbol-digit testing). Epstein and colleagues have described a similar disorder in children, who develop a progressive encephalopathy as the primary manifestation of AIDS. The disease in children is characterized by an impairment of cognitive functions and spastic weakness and secondarily by impairment of brain growth.

The CSF (including those lacking other manifestations of AIDS) may be normal or show only a slight elevation of protein content and, less frequently, a mild lymphocytosis. HIV can be isolated from the CSF. In the CT scan there is widening of the sulci and enlargement of the ventricles; MRI may show patchy but confluent or diffuse white matter changes with ill-defined margins (Fig. 33-2). These findings are useful in diagnosis, although CMV infection of the brain in AIDS produces a similar MRI appearance, as described further on.

The pathologic basis of the dementia appears to be a diffuse and multifocal rarefaction of the cerebral white matter accompanied by scanty perivascular infiltrates of lymphocytes and clusters of a few foamy macrophages, microglial nodules, and multinucleated giant cells (Navia, Chos, Petito et al). Evidence of CMV infection may be added, but accumulating virologic evidence indicates that the AIDS dementia complex is a result of direct infection with HIV. Which of these changes corresponds most closely to the presence and severity of dementia has not been settled. The pathologic changes in AIDS dementia are actually not as uniform as portrayed here. In one group of patients, there is a diffuse pallor of the cerebral white matter, most obvious with myelin stains, accompanied by reactive astrocytes and macrophages; the myelin pallor seems to reflect a breakdown of the blood–brain barrier.

In another form of this process, referred to as "diffuse poliodystrophy," there is widespread astrocytosis and microglial activation in the cerebral cortex, with little recognizable neuronal loss. In yet other patients, small or large perivascular foci of demyelination, like those of postinfectious encephalomyelitis, are observed; the nature of this diffuse white matter lesion is not understood. These forms of pathologic change may occur singly or together and all correlate poorly with the severity of the dementia. Progressive multifocal leukoencephalopathy also occurs in patients with AIDS and is simulated by the primary white matter encephalopathy.

HIV Myelopathy, Peripheral Neuropathy, and Myopathy

A myelopathy, taking the form of a vacuolar degeneration that bears a marked pathologic resemblance to subacute combined degeneration because of vitamin B12 deficiency, is sometimes associated with the AIDS dementia complex; or the myelopathy may occur in isolation, as the leading manifestation of the disease (Petito et al). This disorder of the spinal cord is discussed further in Chap 47.

AIDS may also be complicated by several forms of peripheral neuropathy, as discussed in Chap 46. A distal, symmetrical, axonal polyneuropathy, predominantly sensory and dysesthetic in type has been the most common neuropathic pattern. The HIV virus has been isolated from the peripheral nerves and ganglia. In fact, this stands as the first proven viral polyneuritis in humans (zoster being more a ganglionopathy). In other patients, a painful mononeuropathy multiplex occurs, seemingly related to a focal vasculitis, or there may be a subacute inflammatory cauda equina syndrome (a polyradiculitis) that is usually caused by an accompanying CMV infection (Eidelberg et al). Cornblath and colleagues have documented the occurrence of an inflammatory demyelinating peripheral neuropathy, of both the acute (Guillain-Barré) and chronic types, in otherwise asymptomatic patients with HIV infection. Most of these patients had a mild pleocytosis in addition to an elevated CSF protein content. Most patients with inflammatory demyelinating neuropathy have recovered—either spontaneously or in response to plasma exchange—suggesting an immunopathogenesis similar to that of the Guillain-Barré syndrome. Cornblath and associates suggest that all patients with inflammatory demyelinating polyneuropathies should now be tested for the presence of HIV infection. Facial palsy is being reported with increasing frequency as a feature of AIDS; its relationship to the generalized polyneuritis of AIDS is uncertain.

In a rare peripheral neuropathy of AIDS termed diffuse infiltrative lymphocytosis syndrome (DILS), a variety of clinical syndromes have been described including all patterns of the usual AIDS polyneuropathies. Some instances of polyneuropathy in AIDS patients are probably caused by the nutritional depletion that characterizes advanced stages of the disease and to the effects of therapeutic agents. These AIDS-related neuropathies are discussed in Chap. 46 and are summarized by Wulff and Simpson.

A primary myopathy, taking the form of an inflammatory polymyositis, has been described in HIV patients at any stage of the disease (Simpson and Bender). In some of these cases, the myopathy has improved with corticosteroid therapy. The original anti-AIDS drug, zidovudine (AZT), has caused a myopathy, probably because of its effect on mitochondria, but some investigators have attributed almost all such cases to be attributable to the AIDS virus itself (see "HIV and HTLV-I Myositis" in Chap. 49). It is apparent that this remains an area of some controversy.

Opportunistic Infections and Neoplasms of the CNS in AIDS

In addition to the direct neurologic effects of HIV infection, a variety of opportunistic disorders, both focal and generalized, occur in such patients as outlined in Table 33-2. Interestingly, there appears to be a predilection for certain ones—toxoplasmosis, CMV infection, primary B-cell lymphoma, cryptococcosis, and progressive multifocal leukoencephalopathy, in approximately this order of frequency (Johnson). The focal encephalitis and vasculitis of VZV infection, considered earlier in this chapter, and unusual types of tuberculosis and syphilis are other common opportunistic infections of AIDS. Usually P. carinii infection and Kaposi sarcoma do not spread to the nervous system. In almost of these categories, the infectious process is accelerated or intensified by the presence of the HIV infection.

Toxoplasmosis

Of the focal infectious complications, cerebral toxoplasmosis is the most frequent (and treatable; see Chap 32). In the autopsy series of AIDS reported by Navia, Petito, Gold, and colleagues, areas of inflammatory necrosis caused by Toxoplasma were found in approximately 13 percent (see Fig. 32-6). Lumbar puncture, contrast-enhanced CT scanning, and MRI are useful in diagnosis. The spinal fluid usually shows an elevation of protein in the range of 50 to 200 mg/dL, and one-third of patients have a lymphocytic pleocytosis. Because the disease usually represents reactivation of a prior Toxoplasma infection, it is important to identify Toxoplasma-seropositive patients early in the course of AIDS and to treat them with oral pyrimethamine (100 mg initially and then 25 mg daily) and a sulfonamide (4 to 6 g daily in four divided doses). Curiously, the toxoplasmosis, so common in the brains of AIDS patients, is not a frequent cause of one of its more typical manifestation, myositis. The main clinical problem in reference to toxoplasmosis in AIDS is its differentiation from cerebral lymphoma as discussed below and in Chap. 31.

In a series from Johns Hopkins (see Johnson, 1998), approximately 11 percent of AIDS patients developed a primary CNS lymphoma, which may, in some cases, be difficult to distinguish from toxoplasmosis clinically and radiologically. If the cytologic study of the CSF is negative and there has been no response to antibiotics (see below), stereotaxic brain biopsy may be necessary for diagnosis. The prognosis in such patients is considerably less favorable than in non-AIDS patients; the response to radiation therapy, methotrexate, and corticosteroids is short-lived, and survival is usually measured in months.

In the face of enhancing focal brain lesions in AIDS, the current approach is to initially assume the presence of toxoplasmosis, which is treatable. Antibody tests for toxoplasmosis should be obtained; the absence of IgG antibodies mandates that treatment be changed in order to address the problem of brain lymphoma. Also, if antitoxoplasmal therapy with pyrimethamine and sulfadiazine fails to reduce the size of the lesions within several weeks, another cause should be sought, again mainly lymphoma. In those patients who cannot tolerate the frequent side effects of pyrimethamine or sulfonamides (rash or thrombocytopenia), clindamycin may be of value. Recently, it has been suggested that positron emission tomography (PET) and other metabolic imaging techniques can identify lymphoma as the cause of a mass lesion in the HIV patient. The less frequent possibilities of tuberculous or bacterial brain abscess should be kept in mind if none of these avenues allow a confident diagnosis.

Cytomegalovirus

Among the nonfocal neurologic complications of AIDS, the most common are CMV and cryptococcal infections. At autopsy, about one-third of AIDS patients are found to be infected with CMV. However, the contribution of this infection to the total clinical picture is often uncertain. Despite this ambiguity, certain features have emerged as typical of CMV encephalitis in the AIDS patient. According to Holland and colleagues, late in the course of AIDS and usually concurrent with CMV retinitis, the encephalopathy evolves over 3 to 4 weeks. Its clinical features include an acute confusional state or delirium combined in a small proportion of cases with cranial nerve signs including ophthalmoparesis, nystagmus, ptosis, facial nerve palsy, or deafness. In one of our patients, there were progressive oculomotor palsies that began with light-fixed pupils.

Pathologic specimens and MRI show the process to be concentrated in the ventricular borders, especially evident as T2 signal hyperintensity in these regions. The lesions may extend more diffusely through the adjacent white matter and be accompanied by meningeal enhancement by gadolinium in a few cases. Extensive destructive lesions have also been reported; this has been true in two of our own cases. Such lesions may be associated with hemorrhagic changes in the CSF in addition to showing an inflammatory response. CMV may also produce a painful lumbosacral polyradiculitis in AIDS (Chap. 44).

The diagnosis of CMV infection during life is often difficult. Cultures of the CSF are usually negative and IgG antibody titers are nonspecifically elevated. Newer PCR methods prove useful here. Where the diagnosis is strongly suspected, treatment with the antiviral agents ganciclovir and foscarnet has been recommended, but, as pointed out by Kalayjian and colleagues, the CMV disease may develop and progress while patients are taking these medications as maintenance therapy.

Cryptococcal Infection

Meningitis with this fungus and less often, solitary cryptococcoma are the most frequent fungal complications of HIV infection. Flagrant symptoms of meningitis or meningoencephalitis may be lacking and the CSF may show little abnormality with respect to cells, protein, and glucose. For these reasons, evidence of cryptococcal infection of the spinal fluid should be actively sought with antigen testing, and fungal cultures. India ink preparations are still valuable and rapid but are not currently performed consistently and well enough in many hospitals to be entirely dependable. Treatment is along the lines outlined in Chap. 32.

Varicella Zoster

Cerebral infections with this virus are less common complications of AIDS, but when they do occur, they tend to be severe. They take the form of multifocal lesions of the cerebral white matter, somewhat like those of progressive multifocal leukoencephalopathy, a cerebral vasculitis with hemiplegia (usually in association with ophthalmic zoster), or, rarely, a myelitis. Encephalitis caused by HSV-1 and HSV-2 has also been identified in the brains of AIDS patients, but the clinical correlates are unclear. Shingles involving several contiguous dermatomes is known to occur in AIDS with CD4 counts below 500, as in other immunosuppressed conditions.

Tuberculosis

Two particular types of mycobacterial infection tend to complicate AIDS—Mycobacterium tuberculosis and Mycobacterium avium-intracellulare. Tuberculosis predominates among drug abusers and HIV patients in developing countries, and a higher-than-usual proportion of these immunosuppressed individuals develop tuberculous meningitis. Diagnosis and treatment are along the same lines as in non-AIDS patients.

Neurosyphilis

Syphilitic meningitis and meningovascular syphilis appear to have an increased incidence in AIDS patients. Cell counts in the CSF are unreliable as signs of activity; diagnosis depends entirely upon serologic tests. It is possible that AIDS causes false-positive tests for syphilis. It appears that the presence of HIV infection accelerates the transition of syphilis to later stages, including infection of the nervous system. Indeed, a category of quaternary syphilis has emerged that consists of an aggressive and rapidly progressive necrotizing process that causes strokes and dementia as a result of involvement of brain parenchyma and vessels. The incidence of relapse of syphilis and resistance to conventional doses of antisyphilitic medication are probably increased with HIV coinfection. It is unclear, however, if the tertiary forms of syphilis, general paresis and tabes dorsalis, are increased in incidence because of AIDS; they may require the chronicity of meningovascular syphilis to evolve. Readers are referred to the review by Marra.

Other rare organisms, such as Bartonella henselae, the cause of cat scratch fever, are found rarely in AIDS patients and have been implicated in an encephalitis. Progressive multifocal leukoencephalopathy, a viral disease now closely linked with the immunosuppressed state of AIDS and seen in high numbers, is discussed further on in this chapter.

Treatment

The treatment of HIV infection/AIDS, as is true for any chronic, life-threatening disease, is difficult. Treatment with several antiretroviral drugs is required not just for control of the neurologic manifestations of retroviral infection but also to control secondary infections. Recommendations regarding drug therapy for HIV infection change rapidly (Rubin and Young) and the reader is referred to any of the modern sources for the details of treatment, including Harrison's Principles of Internal Medicine. It is believed that these approaches will prolong survival but it might be expected also to increase the prevalence of neurologic complications of AIDS, each of which needs to be treated as it is recognized. A special result of HIV antiretroviral treatment may induce an intense inflammatory response to a coexistent infection. This complication, immune reconstitution inflammatory syndrome, or IRIS, is perhaps most pertinent to progressive multifocal leukoencephalopathy discussed later.

Tropical Spastic Paraparesis, HTLV-I Infection

This is an endemic neurologic disorder in many tropical and subtropical countries. Its cause was overlooked until 1985, when Gessain and coworkers found IgG antibodies to HTLV-I in the sera of 68 percent of tropical spastic paraparesis (TSP) patients in Martinique. The same antibodies were then identified in the CSF of Jamaican and Colombian patients with TSP, and in patients with a similar neurologic disorder in the temperate zones of southern Japan. The latter disorder was originally called HTLV-I–associated myelopathy (HAM), but it is now considered to be identical to HTLV-I–positive TSP (Roman and Osame). It is a curious feature of this disorder that only a small proportion of HTLV-I–infected persons (estimated at 2 percent) develop a myelopathy. Sporadic instances have now been reported from many parts of the Western world. The virus is transmitted in one of several ways—from mother to child, across the placenta or in breast milk; by intravenous drug use or blood transfusions; or by sexual contact. The age of onset is in mid adult life, and it is more common in females than in males, in a ratio of 3:1.

The clinical and pathologic features of the disease are described in Chap. 44 and in several recommended reviews (Rodgers-Johnson et al); the differentiation from the progressive spinal form of multiple sclerosis and with subacute combined degeneration, with which it is most likely to be confused, is discussed further on under "Differential Diagnosis." There are also clinical and pathologic differences from the myelopathy caused directly by HIV infection. No form of treatment has proved effective in reversing this disorder, although there are anecdotal reports that the intravenous administration of immune globulin may halt its progress.

The retrovirus HTLV-II is less common than HTLV-I but the two are virologically very similar. There is a high rate of infection with HTLV-II among drug users who are coinfected with HIV. A few cases of myelopathy have been reported in HTLV-II–infected patients, similar in all respects to HTLV-I–associated myelopathy (Lehky et al).

See Chap. 38.

Viral infections of the fetus, notably rubella, CMV, HIV, herpes zoster, Epstein-Barr, and HSV infection of the newborn are important causes of CNS abnormalities. This subject is covered in detail in "Intrauterine and Neonatal Infections" in Chap. 38.

In the past, this syndrome was almost invariably the result of infection by one of the three types of poliovirus. However, illnesses that clinically resemble poliovirus infections can be caused by other enteroviruses such as the Coxsackie groups A and B and Japanese encephalitis, as well as by West Nile virus. Epidemics of hemorrhagic conjunctivitis (caused by enterovirus 70 and formerly common in Asia and Africa) can also be associated with a lower motor neuron paralysis resembling poliomyelitis (Wadia et al). In countries with successful poliomyelitis vaccination programs, these other viruses are now the most common causes of the anterior poliomyelitis syndrome. In some cases, the illnesses induced by these viruses are benign and the associated paralysis is insignificant. West Nile virus is an exception that has been associated with a severe and persistent asymmetrical flaccid poliomyelitis.

The important (paralytic) disease in this category nonetheless remains poliomyelitis. Although no longer a scourge in areas where vaccination is routine, its lethal and crippling effects are still fresh in the memory of physicians who practiced in the 1950s. In the summer of 1955, when New England experienced its last epidemic, 3,950 cases of acute poliomyelitis were reported in Massachusetts alone, and 2,771 were paralytic. The details of this epidemic described by Pope and colleagues are worth reviewing by any student of the disease. Polio has essentially from the Americas, the only cases currently being imported ones. Live polio vaccine, which had been the source of approximately 150 cases in previous decades, is no longer used in the United States.

Of course, because it is highly communicable, acute poliomyelitis still occurs in regions of the world where large-scale and recurrent vaccination is not practiced. In a recent year, there were fewer than 2,000 cases in the world but there are periodic small outbreaks. For these reasons and also because it stands as a prototype of a neurotropic viral infection, the main features of the disease should be known to neurologists.

The paralytic residua of previous epidemics can still be seen. In these cases, a delayed progression of muscle weakness may appear many years after the acute paralytic illness—a condition termed postpolio syndrome (see discussion of amyotrophic lateral sclerosis [ALS] in Chap. 39).

Etiology

The poliomyelitis agent is a small RNA virus that is a member of the enterovirus group of the picornavirus family. Three antigenically distinct types have been defined and infection with one does not protect against the others. Poliomyelitis is a highly communicable disease. The main reservoir of infection is the human intestinal tract (humans are the only known natural hosts), and the main route of infection is fecal-oral, i.e., hand to mouth, as with other enteric pathogens. The virus multiplies in the pharynx and intestinal tract. During the incubation period, which is from 1 to 3 weeks, the virus can be recovered from both of these sites. In only a small fraction of infected patients is the nervous system invaded. Between 95 and 99 percent of infected patients are asymptomatic or experience only a nonspecific febrile illness. It is the latter type of patient—the carrier with inapparent infection—who is most important in the spread of the virus from one person to another.

Clinical Manifestations

In the inapparent infections, and those in which there are only mild systemic symptoms with pharyngitis or gastroenteritis had been called abortive poliomyelitis. The mild symptoms correspond to the period of viremia and dissemination of the virus; they give rise in most cases to an effective immune response—a feature that accounts for the failure to cause meningitis or poliomyelitis. In the relatively small proportion of patients in whom the nervous system is invaded, the illness still has a wide range of severity from mild aseptic meningitis (nonparalytic or preparalytic poliomyelitis) to the most severe forms of paralytic poliomyelitis.

Nonparalytic Poliomyelitis

The prodromal symptoms consist of listlessness, generalized, nonthrobbing headache, fever of 38 to 40°C (100.4 to 104°F), stiffness and aching in the muscles, sore throat in the absence of upper respiratory infection, anorexia, nausea, and vomiting. These symptoms may subside to a varying extent, to be followed after 3 to 4 days by recrudescence of headache and fever and by symptoms of nervous system involvement; more often the second phase of the illness blends with the first. Tenderness and pain in the muscles, tightness of the hamstrings (spasm), and pain in the neck and back become increasingly prominent. Other early manifestations of nervous system involvement include irritability, restlessness, and emotional instability; these are frequently a prelude to paralysis. Added to these symptoms are stiffness of the neck on forward flexion and the characteristic CSF findings of aseptic meningitis. This may constitute the entire illness; alternatively, paralysis may follow the preparalytic symptoms.

Paralytic Poliomyelitis

Weakness becomes manifest while the fever is at its height, or, just as frequently, as the temperature falls and the general clinical picture seems to be improving. Muscle weakness may develop rapidly, attaining its maximum severity in 48 h or even less; or it may develop more slowly or in stuttering fashion over a week, rarely even longer. As a general rule, there is no progression of weakness after the temperature has been normal for 48 h. The distribution of spinal paralysis is quite variable; rarely there may be an acute symmetrical paralysis of the muscles of the trunk and limbs as occurs in the Guillain-Barré syndrome. Excessive physical activity and local injections during the period of asymptomatic infection were thought to favor the development of paralysis of the exercised or injected limbs.

Coarse fasciculations are seen as the muscles weaken; they are transient as a rule, but occasionally they persist. Tendon reflexes are diminished and lost as the weakness evolves and paralyzed muscles become flaccid. Patients frequently complain of paresthesias in the affected limbs but objective sensory loss is seldom demonstrable. Retention of urine is a common occurrence during the early phase in adult patients, rarely persisting. Atrophy of muscle can be detected within 3 weeks of onset of paralysis, is maximal at 12 to 15 weeks, and is permanent.

Bulbar paralysis is more common in young adults, but usually such patients have spinal involvement as well. The most frequently involved cranial muscles are those of deglutition, reflecting involvement of the nucleus ambiguus. The other great hazards of medullary disease are disturbances of respiration and vasomotor control—hiccough, shallowness and progressive slowing of respiration, cyanosis, restlessness and anxiety from air hunger, hypertension, and, ultimately, hypotension and shock. When these disturbances are added to paralysis of diaphragmatic and intercostal musculature, the patient's survival is threatened and the institution of respiratory assistance and intensive care becomes urgent.

Pathologic Changes and Clinicopathologic Correlations

In fatal infections, lesions are found in the precentral (motor) gyrus of the brain (usually of insufficient severity to cause symptoms), brainstem, and spinal cord. The brunt of the disease in these cases is borne by the hypothalamus, thalamus, motor nuclei of the brainstem and surrounding reticular formation, vestibular nuclei and roof nuclei of the cerebellum, and mainly the neurons of the anterior and intermediate gray matter of the spinal cord. In these areas, nerve cells are destroyed and phagocytosed by microgliacytes (neuronophagia). A local leukocytic reaction is present for only a few days, but mononuclear cells persist as perivascular accumulations for many months. Inclusion bodies are not seen. The earliest histopathologic changes in the anterior horns of the cord are central chromatolysis of the nerve cells, along with an inflammatory reaction. These changes correlate with a multiplication of virus in the CNS and, in the infected monkey, precede the onset of paralysis by one or several days.

In Bodian's experimental material, the infected motor neurons continued to function until a stage of severe chromatolysis was reached. Moreover, if damage to the cell had attained only the stage of central chromatolysis, complete morphologic recovery could be expected—a process that took a month or longer. After this time, the degrees of paralysis and atrophy were closely correlated with the number of motor nerve cells that had been destroyed; where limbs remain atrophic and paralyzed, less than 10 percent of neurons survived in corresponding cord segments. Lesions in the motor nuclei of the brainstem are associated with paralysis in corresponding muscles. Disturbances of swallowing, respiration, and vasomotor control are related to neuronal lesions in the medullary reticular formation, centered in the region of the nucleus ambiguus, as mentioned earlier.

Atrophic, areflexic paralysis of muscles of the trunk and limbs relates, of course, to destruction of neurons in the anterior and intermediate horns of the corresponding segments of the spinal cord gray matter. The affected regions can be quite focal or scattered, giving rise, for instance, to permanent paralysis of only one limb. Stiffness and pain in the neck and back, attributed to "meningeal irritation," are probably related to the mild inflammatory exudate in the meninges and to the generally mild lesions in the dorsal root ganglia and dorsal horns. These lesions also account for the muscle pain and paresthesia in parts that later become paralyzed. Abnormalities of autonomic function are attributable to lesions of autonomic pathways in the reticular substance of the brainstem and in the lateral horn cells in the spinal cord.

It is of interest that poliovirus has been readily isolated from CNS tissue of fatal cases but can rarely be recovered from the CSF during clinical disease. This is in contrast to the closely related Coxsackie and echo picornaviruses, which have been isolated frequently from the CSF during the neurologic illness.

Treatment

Patients in whom acute poliomyelitis is suspected require careful observation of swallowing function, vital capacity, heart rate, and blood pressure in anticipation of respiratory and circulatory complications. With paralysis of limb muscles, footboards, hand and arm splints, and knee and trochanter rolls prevent foot-drop and other deformities. Frequent passive movement prevents contractures, ankylosis, and pressure sores.

Respiratory failure as a result of paralysis of the intercostal and diaphragmatic muscles or of depression of the respiratory centers in the brainstem calls for the use of a positive-pressure respirator and in most patients, for a tracheostomy as well. It was during the epidemics of the mid-twentieth century that the use of Drinker's "iron lung" attained widespread use. The management of the pulmonary and circulatory complications does not differ from their management in diseases such as myasthenia gravis and Guillain-Barré syndrome and is best carried out in special respiratory or neurologic intensive care units.

The authors know of no systematic study of the potency of antiviral agents in this disease.

Prevention

Prevention, of course, has proved to be one of the outstanding accomplishments of modern medicine. The cultivation of poliovirus in cultures of human embryonic tissues and monkey kidney cells—the achievement of Enders and associates—made possible the development of effective vaccines. The first of these was the injectable Salk vaccine, containing formalin-inactivated virulent strains of the three viral serotypes. This was followed by the Sabin vaccine, which consists of attenuated live virus, administered orally in two doses 8 weeks apart; boosters are required at 1 year of age and again before starting school. Since 1965, the reported annual incidence rate of poliomyelitis in the United States has been less than 0.01 per 100,000 (compared to a rate of 24 cases per 100,000 during the years 1951 to 1955). Very rarely in the past, poliomyelitis followed vaccination with the attenuated live virus (0.02 to 0.04 cases per 1 million doses). The virus is not used in the United States and polio is essentially eradicated in the Americas. The only obstacle to eradication of the disease elsewhere is inadequate utilization of the vaccine. Conceivably, with an increasing lack of immunity in underdeveloped nations (so-called herd immunity), outbreaks of poliomyelitis could occur once again.

Prognosis

Mortality from acute paralytic poliomyelitis is between 5 and 10 percent—higher in the elderly and very young. If the patient survives the acute stage, paralysis of respiration and deglutition usually recovers completely; in only a small fraction of such patients is chronic respiratory care necessary. Many patients also recover completely from early muscular weakness, and even the most severely paralyzed often improve to some extent. The return of muscle strength occurs mainly in the first 3 to 4 months and is probably the result of morphologic restitution of partially damaged nerve cells. Branching of axons of intact motor cells with collateral reinnervation of muscle fibers of denervated motor units may also play a part. Slow recovery of slight degree may then continue for a year or more. The postpolio syndrome is discussed in "Differential Diagnosis of ALS" in Chap. 39 and in Chap. 48.

Nonpoliovirus Poliomyelitis

As indicated earlier, a number of RNA viruses that normally cause mundane upper respiratory or enteric infections are now the main causes of a sporadic poliomyelitic syndrome. Fifty-two such cases were recorded by the Centers for Disease Control over a 4-year period. Most of them were caused by one of the echoviruses and a smaller number to Coxsackie enteroviruses, particularly strains 70 and 71. The former illness leaves little residual paralysis, but the Coxsackie viruses, which have been studied in several outbreaks in the United States, Bulgaria, and Hungary, have had more variable effects. Enterovirus 70 causes acute hemorrhagic conjunctivitis in limited epidemics and is followed by a poliomyelitis in 1 of every 10,000 cases. European outbreaks of enterovirus 71, known in the United States as a cause of hand-foot-and-mouth disease and of aseptic meningitis, have resulted in poliovirus-type paralysis, including a few fatal bulbar cases (Chumakov et al). In a recent outbreak of enterovirus 71 in Taiwan, Huang and associates described brainstem encephalitis with myoclonus and cranial nerve involvement in a high proportion of the patients. The tendency of West Nile virus to cause a poliomyelitis has already been mentioned.

Our own experience with this form of poliomyelitis has consisted of several patients who were referred over the years for paralyzing illnesses initially thought to be Guillain-Barré syndrome (Gorson and Ropper). In each case, the illness began with fever and aseptic meningitis (50 to 150 lymphocytes/mm3 in the CSF), followed by backache and widespread, relatively symmetrical paralysis, including the oropharyngeal muscles in two cases and asymmetrical weakness limited to the arms in two patients. There were no sensory changes. One patient had a mild concurrent encephalitic illness and died months later. The evolving electromyographic changes indicated that the paralysis was caused by a loss of anterior horn cells rather than by a motor neuropathy or a purely motor radiculopathy, but this distinction was not always certain. MRI was remarkable in showing distinct changes in the gray matter of the cord, mainly ventrally (Fig. 33-3). No virus could be isolated from the CSF and serologic tests in our patients failed to implicate any of the usual encephalitic RNA viruses, including poliovirus. The patients had been immunized against the poliomyelitis viruses.

The concept that viral infections may lead to chronic disease, especially of the nervous system, had been entertained since the 1920s, but only many decades later was it firmly established. Indirect and direct evidence supported this view: (1) the demonstration of a slowly progressive noninflammatory degeneration of nigral neurons long after an attack of encephalitis lethargica; (2) the finding of inclusion bodies in cases of subacute and chronic sclerosing encephalitis; (3) the discovery of chronic neurologic disease in sheep caused by a conventional RNA virus (visna)—it was in relation to this disease in sheep that Sigurdsson first used the term slow virus infection to describe long incubation periods during which the animals appeared well; and (4) the demonstration by electron microscopy of viral particles in the lesions of progressive multifocal leukoencephalopathy and, later, isolation of virus from the lesions. The suggestion that the late onset of progressive weakness after poliomyelitis ("postpolio syndrome") might represent a slow infection has never been verified. Claims have also been made numerous times over the years for a viral causation of multiple sclerosis, amyotrophic lateral sclerosis, and other degenerative diseases, but the evidence in all instances has been questionable.

The established human slow infections of the nervous system caused by conventional viruses include subacute sclerosing panencephalitis (measles virus), progressive rubella panencephalitis, and progressive multifocal leukoencephalopathy (JC virus). These diseases, except for PML, are decidedly rare. They are caused by conventional viruses and are not to be confused with a group of subacute and chronic neurologic diseases that are instead the result of prions, entirely distinct unconventional transmissible agents. These are accorded a separate section later in this chapter.

Subacute Sclerosing Panencephalitis

This disease was first described by Dawson in 1934 under the name "inclusion body encephalitis" and extensively studied by Van Bogaert, who renamed it subacute sclerosing panencephalitis. It is now recognized to be the result of chronic measles virus infection. Never a common disease, the condition occurred until recently at a rate of about 1 case per 1 million children per year and now, with the introduction and widespread use of measles vaccine, it has practically disappeared.

Children and adolescents were affected for the most part, the disease rarely appearing beyond the age of 10 years. Typically there is a history of primary measles infection at a very early age, often before 2 years, followed by a 6- to 8-year asymptomatic period. The illness evolved in several stages. Initially there was a decline in proficiency at school, temper outbursts and other changes in personality, difficulty with language, and loss of interest in usual activities. These soon give way to a severe and progressive intellectual deterioration in association with focal or generalized seizures, widespread myoclonus, ataxia, and sometimes visual disturbances caused by progressive chorioretinitis. As the disease advances, rigidity, hyperactive reflexes, Babinski signs, progressive unresponsiveness, and signs of autonomic dysfunction appear. In the final stage, the child lies insensate, virtually "decorticated."

The course is usually steadily progressive, death occurring within 1 to 3 years. A series of 39 such adult cases from India with mean age of 21 years was reported by Prashanth and coworkers, the oldest patient a 43-year old. The main features were similar in most ways to childhood cases, except that several had visual disturbances and two had extrapyramidal features, raising the possibility of prion disease. Myoclonus was present early in the illness in 26 and developed later in all cases; the movements were described as "slow," a characteristic alluded to in other series. In two cases that occurred in pregnant women, blurred vision and weakness of limbs was followed by akinetic mutism, without a trace of myoclonus or cerebellar ataxia. Nevertheless, the progressive ataxic-myoclonic chronic dementia in a child is so typical that bedside diagnosis was usually possible.

The EEG shows a characteristic abnormality consisting of periodic (every 5 to 8 s) bursts of 2 to 3/s high-voltage waves, followed by a relatively flat pattern. The CSF contains few or no cells, but the protein content is increased, particularly the gamma globulin fraction, and agarose gel electrophoresis discloses oligoclonal bands of IgG. These proteins have been shown to represent measles-virus-specific antibody (Mehta et al). MRI changes begin in the subcortical white matter and spread to the periventricular region (Anlar et al).

Histologically, the lesions involve the cerebral cortex and white matter of both hemispheres and the brainstem. The cerebellum is usually spared. Destruction of nerve cells, neuronophagia, and perivenous cuffing by lymphocytes and mononuclear cells indicate the viral nature of the infection. In the white matter there is degeneration of medullated fibers (both myelin and axons), accompanied by perivascular cuffing with mononuclear cells and fibrous gliosis (hence the term sclerosing encephalitis). Eosinophilic inclusions, the histopathologic hallmark of the disease, are found in the cytoplasm and nuclei of neurons and glia cells. Virions, thought to be measles nucleocapsids, have been observed in the inclusion-bearing cells examined electron microscopically.

How a ubiquitous and transient viral infection in a seemingly normal young child allows the development, many years later, of a rare encephalitis is a matter of speculation. Sever believes that there is a delay in the development of immune responses during the initial infection and a later inadequate immune response that is incapable of clearing the suppressed infection.

The differential diagnosis of SSPE includes the childhood and adolescent dementing diseases such as lipid storage diseases (see Chap. 37), prion disease (Creutzfeldt-Jakob), and Schilder-type demyelinative disease (see Chap. 36). In presumptive clinical cases of SSPE, the findings of periodic complexes in the EEG, elevated gamma globulin and oligoclonal bands in the CSF, and elevated measles antibody titers in the serum and CSF are sufficient to make the diagnosis.

No effective treatment is available. The administration of amantadine and inosine pranobex (formerly inosiplex) was found by some investigators to lead to improvement and prolonged survival, but these effects have not been corroborated.

Subacute Measles Encephalitis with Immunosuppression

Whereas SSPE occurs in children who were previously normal, another rare type of measles encephalitis has been described that affects both children and adults with defective cell-mediated immune responses (Wolinsky et al). In this type, measles or exposure to measles precedes the encephalitis by 1 to 6 months. Seizures (often epilepsia partialis continua), focal neurologic signs, stupor, and coma are the main features of the neurologic illness and lead to death within a few days to a few weeks. The CSF may be normal, and levels of measles antibodies do not increase. Aicardi and colleagues have isolated measles virus from the brain of such a patient. The lesions are similar to those of SSPE (eosinophilic inclusions in neurons and glia, with varying degrees of necrosis) except that inflammatory changes are lacking. In a sense, this subacute measles encephalitis is an opportunistic infection of the brain in an immunodeficient patient. The relatively short interval between exposure and onset of neurologic disease, the rapid course, and lack of antibodies distinguish this form of subacute measles encephalitis from both SSPE and postmeasles (postinfectious) encephalomyelitis (see Chap. 36).

Progressive Rubella Panencephalitis

The deficits associated with congenital rubella infection of the brain are nonprogressive at least after the second or third year of life. There are, however, descriptions of children with the congenital rubella syndrome in whom a progressive neurologic deterioration occurred after a stable period of 8 to 19 years (Townsend et al; Weil et al). In 1978, Wolinsky described 10 instances, a few of them apparently related to acquired rather than to congenital rubella. Since then, this late-appearing progressive syndrome seems to have disappeared, no definite new cases having been reported in the past 30 years but it nonetheless remains of biological interest.

The clinical syndrome was quite uniform. On a background of the features of congenital rubella, a decade later there occurred a deterioration in behavior and school performance, often associated with seizures, and, soon thereafter, a progressive impairment of mental function (dementia). Clumsiness of gait was an early symptom, followed by a frank ataxia of gait and then of the limbs. Spasticity and other corticospinal tract signs, dysarthria, and dysphagia ensue.

Progressive Multifocal Leukoencephalopathy

This disorder, first observed clinically by Adams and colleagues in 1952, was described morphologically in 1958 by Åstrom and coworkers, and then with a larger body of material by Richardson in 1961. It is characterized by widespread demyelinating lesions, mainly of the cerebral hemispheres but sometimes of the brainstem and cerebellum, and, rarely, of the spinal cord. The lesions vary greatly in size and severity—from microscopic foci of demyelination to massive multifocal zones of destruction of both myelin and axons involving large parts of a cerebral or cerebellar hemisphere. The abnormalities of the glia cells are distinctive. Many of the reactive astrocytes in the lesions are gigantic and contain deformed and bizarre-shaped nuclei and mitotic figures, changes that are seen otherwise only in malignant glial tumors. Also, at the periphery of the lesions, the nuclei of oligodendrocytes are greatly enlarged and contain abnormal inclusions. Many of these cells are destroyed, accounting for the demyelination. Vascular changes are lacking, and inflammatory changes are present but usually insignificant, except in a small number of interesting cases in which immune reconstitution by retroviral drugs for AIDS allows the emergence of intense inflammation.

Clinical Features

An uncommon disease of late adult life, PML usually develops in a patient with a neoplasm or chronic immunodeficiency state. The large majority of cases are now observed in patients with AIDS in whom the incidence of PML approaches 5 percent. Viewed from another perspective, more than 75 percent of cases of PML in the current era are associated with HIV. Indeed, the incidence is so much higher than in any other form of immunosuppression that an interaction between HIV and the causative virus of PML has been suggested. Other important associations are with chronic neoplastic disease (mainly chronic lymphocytic leukemia, Hodgkin disease, lymphosarcoma, and myeloproliferative disease) and less often, with nonneoplastic granulomatosis, such as tuberculosis or sarcoidosis. A number of cases occur in patients receiving immunosuppressive drugs for renal transplantation, multiple sclerosis (see Chap. 36), or for other reasons.

Personality changes and intellectual impairment may introduce the neurologic syndrome, which then evolves over a period of several days to weeks. Any one or some combination of hemiparesis progressing to quadriparesis, visual field defects, cortical blindness, aphasia, ataxia, dysarthria, dementia, confusional states, and coma are manifestations. Some of the cases under our observation had a predominantly cerebellar syndrome. Seizures are infrequent, occurring in only about 10 percent of cases. In most cases, death occurs in 3 to 6 months from the onset of neurologic symptoms and even more rapidly in patients with AIDS unless aggressive antiretroviral treatment is undertaken. The CSF is usually normal. CT and MRI localize the nonenhancing demyelinating lesions with clarity (Fig. 33-4) but the variability in size, location, and multiplicity make the diagnosis more dependent on viral DNA isolation from CSF and on the context of immunosuppression.

Pathogenesis

Waksman's original suggestion (quoted by Richardson) that PML could be caused by viral infection of the CNS in patients with impaired immunologic responses proved to be correct. ZuRhein and Chou, in an electron microscopic study of cerebral lesions from a patient with PML later demonstrated crystalline arrays of particles resembling papovaviruses in the inclusion-bearing oligodendrocytes. Since then a human polyomavirus, designated "JC virus" or JCV (initials of the patient from whom the virus was originally isolated), has definitively been shown to be the causative agent. JCV is ubiquitous, as judged by the presence of antibodies to the virus in approximately 70 percent of the normal adult population. It is thought to be dormant in the kidney or bone marrow until an immunosuppressed state permits its active replication. The virus has been isolated from the urine, blood lymphocytes, bone marrow, and kidney, but there is no clinical evidence of damage to extraneural structures.

Treatment

The disease is generally believed to be untreatable in the non-AIDS patient. Anecdotal reports of the efficacy of various medications such as cytosine arabinoside, cidofovir, mirtazapine, interferon, and topotecan, either have not been tested in, or have failed to be sustained in larger trials. In AIDS patients, aggressive treatment using antiretroviral drug combinations, including protease inhibitors, greatly slows the progression of PML and has led to remission in almost half of cases for a year, as in the large series reported by Antinori and colleagues. Several retrospective series found that a CD4 count below 100 cells/μL is a poor prognostic sign for recovery from PML. A review of these issues, particularly relating to AIDS and PML, is in the report by Mangi and Miller.

A special comment should be made regarding the transient but sometimes severe clinical worsening of PML that may occur during the initial treatment of HIV infection with antiretroviral drugs. This syndrome has been attributed to the emergence of acute inflammation surrounding the demyelinating lesions as a result of reconstitution of the immune system (immune reconstitution syndrome or IRIS that has been mentioned in the section on the treatment of HIV). In support of this mechanism, there is a parallel blossoming of the lesions with gadolinium enhancement on MRI. Treatment with corticosteroids has been suggested and is said to allow survival and temporary remission of PML, although we have seen at least one dramatic exception. Judicious use of corticosteroids is implemented to mute this reaction.

Encephalitis Lethargica (von Economo Disease, Sleeping Sickness)

Although examples of a somnolent-ophthalmoplegic encephalitis dot the early medical literature (e.g., nona, fébre lethargica, Schlafkrankheit), it was in the wake of the influenza pandemic of World War I that this disease appeared prominently and continued to reappear for about 10 years. The viral agent was never identified, but the clinical and pathologic features were typical of viral infection. Nonetheless recent testing of archived brain material has failed to reveal influenzal RNA, so that encephalitis lethargica may be considered a putative viral disease. An alternative view of an immune pathogenesis is presented below.

The importance of encephalitis lethargica relates to its unique clinical syndromes and sequelae and to its place as the first recognized "slow virus infection" (ironically, without identification of the agent) of the nervous system in humans. The unique symptoms were ophthalmoplegia and pronounced somnolence, from which the disease took its name. Some patients were overly active, and a third group manifested a disorder of movement in the form of bradykinesia, catalepsy, mutism, chorea, or myoclonus. Lymphocytic pleocytosis was found in the spinal fluid of half the patients, together with variable elevation of the CSF protein content. More than 20 percent of the victims died within a few weeks, and many survivors were left with varying degrees of impairment of mental function. However, the most extraordinary feature was the appearance of a parkinsonian syndrome, after an interval of weeks or months (occasionally years), in a high proportion of survivors. Myoclonus, dystonia, oculogyric crises (Chap. 14) and other muscle spasms, bulimia, obesity, reversal of the sleep pattern, and, in children, a change in personality with compulsive behavior ("organic driveness") were other distressing sequelae. This is not the only form of encephalitis known to cause a delayed extrapyramidal syndrome of this type (a similar though not identical syndrome with a much shorter latency may follow Japanese B encephalitis and other arboviral encephalitis).

The pathology was typical of a viral infection, localized principally to the midbrain, subthalamus, and hypothalamus. In the patients who died years later with Parkinson syndrome, the main findings were depigmentation of the substantia nigra and locus ceruleus because of nerve cell destruction. Neurofibrillary changes in the surviving nerve cells of the substantia nigra and the oculomotor and adjacent nuclei were also described, indistinguishable from those of progressive supranuclear palsy. Lewy bodies were not seen, in contrast to idiopathic Parkinson disease, where they are consistently present. Only a few new cases of postencephalitic type have been seen in the United States and western Europe since 1930. Sporadic cases, such as the four reported by Howard and Lees, may be examples of this disease, but there is no way of proving their identity.

More often currently, a postinfectious extrapyramidal syndrome is putatively the result of circulating autoantibodies. While not necessarily viral in origin, this is an appropriate place to summarize the recent findings of Dale and colleagues, who have studied the problem carefully and presented 20 cases that were remarkably similar to the ones described by von Economo. Half of their patients had a preceding pharyngitis that was followed by somnolence or pathologic insomnia, parkinsonism, dyskinesias, and psychiatric symptoms. Many had oligoclonal bands in the cerebrospinal fluid and some had changes on MRI in the basal ganglia. Their singular finding was that 95 percent had serum autoantibodies against basal ganglia neural antigens (two-thirds also had antibodies to anti–streptolysin O). Pathologic examination in one case showed perivascular inflammation. Thus, the long-held notion that this form of encephalitis was, and is, a viral illness might be challenged. Dale and colleagues comment that von Economo and his contemporaries in fact doubted that there was a connection to influenza.

Other Forms of Subacute Encephalitis

A number of uncommon conditions not covered above are characterized by regional inflammation in the cerebrum. Among these, Rasmussen encephalitis, which causes intractable focal seizures and progressive hemiparesis (see Chap. 16), has been tentatively connected to infections by CMV and HSV-I in various studies that used PCR techniques but the presence of autoantibodies to glutamate receptors suggest this is an immune process. However, a specific immune reaction consisting of antibodies to glutamate receptors has been implicated more consistently and immunosuppressive treatments may be effective. It is not clear whether this process can be classed with the infectious encephalitides; it is discussed in detail with other epileptic diseases in Chap. 16. Similarly, the restricted inflammatory conditions called limbic encephalitis and "brainstem encephalitis"—most often a distant effect of lung cancer—have some characteristics of a subacute viral encephalitis, but no agent has been consistently isolated and they are also best considered immunologic reactions. They are included in the discussion of paraneoplastic illnesses in Chap 31.

This category of infections includes a quartet of human diseases—Creutzfeldt-Jakob disease (and a variant that infects cows and may be rarely transmitted to humans), the Gerstmann-Sträussler-Scheinker syndrome, kuru, and fatal familial insomnia.

Although this group of diseases has been included for discussion in the chapter on viruses that affect the nervous system, it has been evident for some time that the cause of these diseases is neither a virus nor a viroid (nucleic acid alone, without a capsid structure). The transmissible, or "infectious" nature of prions was discovered by Gadjusek and Gibbs in the Fore tribes of New Guinea, who practiced ritual cannibalism and ate the brains of the deceased. The resulting disease, kuru, is described further on but the important point is that the aforementioned workers were able to transmit the disease to chimpanzees after a long latent period of years. Prusiner is credited with doggedly pursuing this problem, for which he was awarded the Nobel Prize. He (1993, 1994, 2001) has presented evidence that the transmissible pathogen is a proteinaceous infectious particle that is devoid of nucleic acid, resists the action of enzymes that destroy RNA and DNA, fails to produce an immune response, and electron microscopically does not have the structure of a virus. To distinguish this pathogen from viruses and viroids, Prusiner introduced the term prion.

The very same prion protein (PrP) is normally encoded by a gene on the short arm of chromosome 20 in humans. The discovery of mutations in the PrP genes of patients with familial Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker syndrome (described below) attests to the fact that prion diseases may be both genetic and infectious. This is another way in which prions are unique among all pathogens. It is now possible to detect inherited types of prion diseases during life, using DNA extracted from leukocytes. How prions arise in sporadic forms of spongiform encephalopathy is not fully understood. The conversion of the normal cellular protein to the infectious form involves a conformational change in the protein structure as described in Prusiner's review in 2001. Remarkably, as discussed below, the current theory holds that an abnormally folded prion protein can act as a template for the conversion of normal PrP to PrPsc (the latter denoting the scrapie prion; see further on). A description of the human prion diseases is given here, the most important by far being Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob Disease (Subacute Spongiform Encephalopathy)

These terms refer to a distinctive cerebral disease in which a rapidly or subacutely progressive and profound dementia is associated with diffuse myoclonic jerks and a variety of other neurologic abnormalities, mainly visual or cerebellar. The major neuropathologic changes are found in the cerebral and cerebellar cortices, and the outstanding features are widespread neuronal loss and gliosis accompanied by a striking vacuolation or spongy state of the affected regions—hence the designation subacute spongiform encephalopathy (SSE). Less severe changes in a patchy distribution are found in cases with a briefer clinical course.

The widely used term Creutzfeldt-Jakob disease (CJD) may be an inappropriate eponym as it is most unlikely that the patient described by Creutzfeldt and at least three of the five patients described by Jakob did not have the same disease that we now recognize as subacute spongiform encephalopathy. However, decades of use make it virtually impossible to displace.

One of the more interesting aspects of the development of the prion concept has been the hypothesis that many conditions, most in the category of degenerative neurologic disease and characterized by the accumulation of specific proteins such as amyloid, tau, synuclein, and ubiquitin may have a similar mechanism in sequential, contiguous conformational change in protein aggregation.

Epidemiology and Pathogenesis

The disease appears in all parts of the world and in all seasons, with an annual incidence of 1 to 2 cases per million of population. The incidence is higher in Israelis of Libyan origin, in immigrants to France from North Africa, and perhaps in Slovakia. The incidence of spongiform encephalopathy is somewhat higher in urban than in rural areas, but a consistent temporal or spatial clustering of cases has not been observed, at least in the United States. A small proportion of all series is familial—varying from 5 percent reported by Cathala and associates to 15 percent of 1,435 cases analyzed by Masters and coworkers (1979). The occurrence of familial cases that are not in the same household probably indicates a genetic susceptibility to infection, although the possibility of common early exposure to the transmissible agent cannot be excluded. A small number of conjugal cases have also been reported. The only clearly demonstrated mechanism of spread of the usual type of CJD is iatrogenic, having occurred in a few cases after transplantation of corneas or dural grafts from infected individuals, after implantation of infected electroencephalographic depth electrodes, and after the injection of human growth hormone or gonadotropins that had been prepared from pooled cadaveric sources. At least one neurosurgeon is known to have acquired the disease. Of some interest is the finding by Zanusso and colleagues of the infectious prion protein in the nasal mucosa of all nine patients studied with the sporadic disease. This suggests a route for entry into the nervous system of the aberrant prion and also a potential diagnostic test. As noted further on, the tonsils of patients affected with variant CJD may also show immunostaining for prions.

Attention has been drawn to an outbreak of prion disease among cows in the British Isles ("mad cow disease," bovine spongiform encephalopathy, BSE). Cows elsewhere have sporadically been found to be infected. The mini-epidemic began in 1986, with putative transmission of the disease to some 24 humans. These patients were younger (average age of onset 27 years) than those with typical CJD (average age of onset 65 years) and manifested psychiatric and sensory symptoms as the first sign of illness; they did not exhibit the usual EEG findings even as the illness advanced to its later stages (Will et al). This has been called "new variant Creutzfeldt-Jakob disease (vCJD)." One reason for including a lengthy explanation of this illness is the potential for cases to appear in future years. It was shown that the prion strain in affected patients is identical to the one from affected cattle and different from the prion agent that causes sporadic CJD. The mode of transmission, presumed to be the ingestion of infected meat, is reminiscent of the propagation of kuru in New Guinea by ceremonial ingestion of brain tissue from infected individuals that opened the era of understanding of prion disease.

Prion (spongiform) encephalopathy or all types has now been firmly associated with the conversion of a normal cellular protein, PrPc to an abnormal isoform, PrPsc. The transformation involves a change in the physical conformation of the protein in which its helical proportion diminishes and the proportion of the β pleated sheet increases (see reviews by Prusiner). The current understanding is that the "infectivity" of prions and their propagation in brain tissue result from the susceptibility of the native PrP to alter its shape as a result of physical exposure to the abnormal protein, a so-called conformational disease. Conformationally altered prions have a tendency to aggregate, and this may be the mode of cellular destruction that leads to neuronal disease. In contrast, familial cases of prion disease are thought to be the result of one of several gene aberrations residing in the region that code for PrPc.

As the isoforms of the prions that causes the sporadic disease have been characterized, clinical patterns have emerged as more or less typical of certain protein configurations and their underlying genotypes. Several competing classification systems have been devised that are based on both the presence of methionine (M) or valine (V) at codon 129 of the prion protein and on which of two physicochemical properties it displays (termed types 1 or 2; see Parchi et al). The most common variant in most studies has been MM and the least common, VV, and type 1 is more frequent than type 2 (hence MM1 is the most common type overall, present in approximately two-thirds of sporadic cases). However, classification is complicated by the fact that some brain samples show more than one type of protein. Although several studies conflict on these points, a typical EEG pattern was most common in type 1 cases with at least one methionine, whereas MV2 cases were most likely to have MRI changes (see further on). Some studies have suggested that the MV2 subtype, comprising a small proportion of cases, was likely to present with ataxia, psychiatric changes, a lack of positive sharp waves on EEG, and a prolonged duration of disease, but none of the distinctions has been even close to absolute. There has also been controversy regarding the relationship of the genotype to the sensitivity of diagnostic tests discussed below. Details of these putative associations can be found in an extensive international study of 2,541 pathologically confirmed cases of CJD reported by Collins and colleagues.

Clinical Features

Prion encephalopathy is in most cases a spontaneously occurring disease of late middle age, although it occurs in young adults. The sexes are affected equally. In the large series of pathologically verified cases reported by Brown and coworkers, prodromal symptoms—consisting of fatigue, depression, weight loss, and disorders of sleep and appetite lasting for several weeks—were observed in about one-third of the patients.

The early stages of the neurologic disease are characterized by a great variety of clinical manifestations, but the most frequent are changes in behavior, emotional response, and intellectual function, often followed by ataxia and abnormalities of vision, such as distortions of the shape and alignment of objects or impairment of visual acuity. Typically, the early phase of the disease is dominated by symptoms of confusion, with hallucinations, delusions, and agitation. In other instances, cerebellar ataxia (Brownell-Oppenheimer variant) or visual disturbances (Heidenhain variant) precede the mental changes and may be the most prominent features for several months. Headache, vertigo, and sensory symptoms are complaints in some patients but become quickly obscured by dementia and muteness.

As a rule, the disease progresses rapidly, so that obvious deterioration is seen from week to week and even day to day. Sooner or later, in almost all cases, myoclonic contractions of various muscle groups appear, perhaps unilaterally at first but later becoming generalized. Or, infrequently, the myoclonus may not appear for weeks or months after the initial mental changes. In a few patients, a startle response, that is elicitable for a brief period of time, is the only manifestation of myoclonus. In general, the myoclonic jerks are evocable by sudden sensory stimuli of all sorts, a startle response (to noise, bright light, touch) but they occur spontaneously as well. Twitches of individual fingers are typical but it should be emphasized that well-formed seizures are not a component of the illness. These changes gradually give way to a mute state, stupor, and coma, but the myoclonic contractions may continue to the end. Signs of degeneration of the pyramidal tracts or anterior horn cells, palsies of convergence and upgaze, and extrapyramidal signs occur in a small number of patients as the disease advances.

The clinical diagnosis during life rests mostly on the recognition of one of the clusters of typical clinical features, particularly the special rate of rapid progression of dementia—much more quickly than that of common degenerative diseases—coupled with stimulus-sensitive myoclonus and the characteristic MRI and EEG changes that occur in most patients (see below).

The disease is invariably fatal, usually in a few months and almost always less than a year from the onset. In approximately 10 percent of patients, the illness begins with almost stroke-like suddenness and runs its course rapidly, in a matter of a few weeks. At the other extreme, a small number of patients have reportedly survived for 2 to 10 years, but these reports should be accepted with caution; in some of them, the illness appears to have been superimposed on Alzheimer or Parkinson disease or some other chronic condition that predated the prion illness.

Laboratory Diagnosis

The routine CSF and other laboratory tests are normal—useful findings in that they exclude a number of chronic inflammatory causes of dementia such as neurosyphilis. In most patients, the EEG pattern is distinctive, changing over the course of the disease from one of diffuse and nonspecific slowing to one of stereotyped high-voltage slow- (1- to 2-Hz) and sharp-wave complexes on an increasingly slow and low-voltage background (see Fig. 2-5G). The high-voltage sharp waves, which give the appearance of periodicity (they have been called pseudoperiodic), are synchronous with the myoclonus, but may persist in its absence.

MRI of the brain has now been appreciated to show hyperintensity of the lenticular nuclei on T2-weighted and diffusion-weighted images in the basal ganglia and cortex when the disease is fully established (Fig. 33-5). Long contiguous segments of the cortex, as well as various parts of the basal ganglia, show these alterations in a pattern that is characteristic and mistakable only perhaps for the appearance of diffuse cerebral anoxia. According to Shiga and colleagues, these changes occur in 90 percent of cases (cortex more often than caudate or lenticular nuclei and sometimes both), making them potentially the most sensitive test for the disease but the proportion has been lower in our patients. Complicating the interpretation of the MRI findings in this disease have been reports from Japan of extensive white matter lesions in several autopsy-proven cases (Matsusue et al).

There are helpful confirmatory diagnostic tests but they are not always necessary. Hsich and colleagues described a now widely used test of CSF—the finding by immunoassay of peptide fragments of normal brain proteins, termed "14-3-3." This test is particularly useful in separating CJD from other chronic noninflammatory dementing diseases but it has been sometimes disappointing on our wards, giving both false-positive and false-negative results. Several studies have given conflicting information on the sensitivity of the 14-3-3 test in relation to the various forms of prions and differing clinical presentations, but all seem to converge on the fact that repeated testing, up to three times is more likely to give positive results. A summary publication has indicated an overall sensitivity from pooled reports of 92 percent and specificity of 80 percent (report of the Guidelines Development Committee of the American Academy of Neurology). Also, enolase and neopterin concentrations in CSF are elevated in most cases, but the release of these substances is found with other types of brain lesions, particularly infarction. A number of other tests are emerging from specialized laboratories that are able to detect the specific abnormal PrPsc isoform of the prion protein in the spinal fluid. Prusiner's laboratory has been able to detect eight prion strains but it is not yet clear if this scientific advance can be put to clinical use.

Tonsillar material from patients with new variant Creutzfeldt-Jakob disease ("mad cow disease") stains with antibodies against abnormal prion protein, but this technique does not appear to be applicable to the early diagnosis of the sporadic disease (Hill). Whether the earlier-mentioned finding of infectious prion material in the nasal mucosa in the sporadic form will prove to have practical value in diagnosis is yet to be determined.

The National Prion Disease Pathology Surveillance Center, which was established at Case Western Reserve University, is available to assist clinicians by performing, free of charge, a variety of specific diagnostic tests (accessible through http://www.cjdsurveillance.com).

Pathology

The disease affects principally the cerebral and cerebellar cortices, generally in a diffuse fashion, although in some cases the occipitoparietal regions are almost exclusively involved, as in those described by Heidenhain. In others, such as the cases of Brownell and Oppenheimer alluded to earlier, the cerebellum has been most extensively affected, with early and prominent ataxia. The degeneration and disappearance of nerve cells are associated with extensive astroglial proliferation; ultrastructural studies have shown that the microscopic vacuoles, which give the tissue its typically spongy appearance, are located within the cytoplasmic processes of glia cells and dendrites of nerve cells. The loss in particular of certain inhibitory neurons in the thalamic reticular nuclei seems to correspond to the presence of myoclonus and positive sharp waves in the EEG according to Tschampa and colleagues. Despite the fact that the disease is caused by a transmissible agent, the lesions show no evidence of an inflammatory reaction and no viral particles are seen.

Differential Diagnosis

The diagnosis of most cases presents no difficulty if the rapidity of progression and the myoclonus are recognized. Not infrequently, however, we have been surprised by a "typical" case that proves to be some other disease. Lithium intoxication, Hashimoto encephalopathy (as emphasized by Seipelt and colleagues who found a number of these cases in an epidemiologic survey of SSE; Chap. 40), Whipple disease (see Chap. 32), intravascular lymphoma, and carcinomatous meningitis—all of them characterized by myoclonus and dementia—may mimic CJD in the early weeks of illness. Contrariwise, the early mental changes of SSE may be misinterpreted as an atypical or unusually intense emotional reaction, as one of the major psychoses, as an unusual form of Alzheimer disease with myoclonus, corticobasal degeneration (see Chap. 39), or as Lewy-body disease. Despite the designation of CJD as a progressive dementia, the similarities to even rapidly developing Alzheimer disease are superficial. Also, diagnosis may be difficult in patients who present with dizziness, gait disturbance, diplopia, or visual disturbances until the rapidly evolving clinical picture clarifies the issue. Subacute sclerosing panencephalitis (see earlier in this chapter) in its fully developed form may resemble CJD, but the former is chiefly a disease of children or young adults, and the CSF shows elevation of gamma globulin (IgG), whereas the latter is essentially a disease of middle age and the presenile period and the CSF is normal. Limbic-brainstem-cerebellar encephalitis in patients with an occult tumor and AIDS dementia (discussed earlier) also figure in the differential diagnosis. Cerebral lipidosis in children or young adults can result in a similar combination of myoclonus and dementia, but the clinical course in such cases is extremely chronic and there are retinal changes that do not occur in spongiform encephalopathy. Well-formed convulsions should direct attention to another diagnosis.

Management

No specific treatment is known. Antiviral agents have been ineffective. In view of the transmissibility of the disease from humans to primates and iatrogenically from person to person with infected materials, certain precautions should be taken in the medical care and handling of materials from affected patients. Special isolation rooms are unnecessary, and the families of affected patients and nursing staff can be reassured that casual contact poses no risk. Needle punctures and cuts are not thought to pose a risk, but some uncertainty remains. The transmissible agent is resistant to boiling, treatment with formalin and alcohol, and ultraviolet radiation but can be inactivated by autoclaving at 132°C (269.6°F) at 15 lb/in2 for 1 h or by immersion for 1 h in 5 percent sodium hypochlorite (bleach). Workers exposed to infected materials (butchers, abattoir workers, healthcare workers) should wash thoroughly with ordinary soap. Needles, glassware, needle electrodes, and other instruments should be handled with great care and immersed in appropriate disinfectants and autoclaved or incinerated. The performance of a brain biopsy or autopsy requires that a set of special precautions be followed, as outlined by Brown but this surgical procedure is not necessary as more diagnostic tools have become available. Obviously such patients or any others known to have been demented should not be donors of organs or corneas for transplantation or blood for transfusion.

Gerstmann-SträUssler-Scheinker Syndrome

This is a rare, strongly familial disease inherited as an autosomal dominant trait. It begins insidiously in midlife and runs a chronic course (mean duration 5 years). The main characteristics are progressive cerebellar ataxia, corticospinal tract signs, dysarthria, and nystagmus. Dementia is often associated but is relatively mild.

Dysesthesias and proximal weakness of the legs have been emphasized as an early feature by Arata and colleagues. Their report may be consulted for details of 11 well-studied cases. The MRI is usually normal; with progression, generalized atrophy is found.

There are characteristic spongiform changes in brain tissue, as in CJD. Brain tissue from patients with this disease, when inoculated into chimpanzees, has produced a spongiform encephalopathy (Masters et al, 1981). Molecular genetic studies of affected family members demonstrate a mutation of the prion protein gene. This syndrome should be considered as a small familial subset of SSE, of slowly progressive type.

Fatal Insomnia (Familial and Sporadic)

This is another rare and usually familial disease in the spongiform encephalopathy group. It is characterized by intractable insomnia, sympathetic overactivity, and dementia, leading to death in 7 to 15 months (see also Chap. 16). The pathologic changes, consisting of neuronal loss and gliosis, are found mainly in the medial thalamic nuclei. Studies of a few families have shown a mutation of the prion protein gene and brain material was found to contain a protease-resistant form of the gene that is characterized by a mutation in the prion gene at codon 178 in conjunction with the presence of methionine at codon 129 on chromosome 20, the latter being a feature of sporadic CJD. Transmission of the disease by inoculation of infected brain material has not been accomplished (Medori et al). There is also a rare sporadic form of this disease and the configuration of the prion alteration is different from the familial variety.

Kuru

This disease occurs exclusively among the Fore linguistic group of natives of the New Guinea highlands and is included here because of its historical interest as the first slow infection caused by an unconventional transmissible agent to be documented in human beings. Clinically the disease takes the form of an afebrile, progressive cerebellar ataxia, with abnormalities of extraocular movements, weakness progressing to immobility, incontinence in the late stages, and death within 3 to 6 months of onset. In some ways it is similar to the ataxic (Brownell-Oppenheimer) variant of CJD. The remarkable epidemiologic and pathologic similarities between kuru and scrapie in sheep were pointed out in 1959 by Hadlow, who suggested that it might be possible to transmit kuru to subhuman primates. This was accomplished in 1966 by Gajdusek and coworkers; inoculation of chimpanzees with brain material from affected humans produced a kuru-like syndrome in chimpanzees after a latency of 18 to 36 months. Since then the disease has been transmitted from one chimpanzee to another and to other primates by using both neural and nonneural tissues. The pioneering work in this field led to the awarding of a Nobel Prize to these workers and the same prize was awarded to Prusiner 23 years later, representing a landmark in which the Nobel was awarded twice for work regarding the same disease. Histologically there is a noninflammatory loss of neurons and spongiform change throughout the brain, but predominantly in the cerebellar cortex, with astroglial proliferation and periodic acid-Schiff–positive stellate plaques of amyloid-like material ("kuru plaques"). The transmissible agent has not been visualized, however.

Kuru has gradually disappeared because of the cessation of ritual cannibalism by which the disease had been transmitted. In this ritual, infected brain tissue was ingested and rubbed over the body of the victim's kin (women and young children of either sex), permitting absorption of the infective agent through conjunctivae, mucous membranes, and abrasions in the skin.