Neurology_Adams

Neurology_Adams. 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. 31. 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; in the past a characteristic syndrome of residual parkinsonian


Neurology_Adams

Neurology_Adams. which they occur. Definite cases of “epidemic encephalitis” (encephalitis lethargica) have not been observed in acute form since 1930; in the past a characteristic syndrome of residual parkinsonian syndrome was seen in neurology clinics. However, various movement disorders, including parkinsonism, are being seen as a residuum 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 HIV 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 in the following text, under “Opportunistic Infections and Neoplasms of the CNS with HIV.” Our personal experience, predicated on practicing in New England, has been heavily biased toward HSV encephalitis, seasonal outbreaks of eastern equine or West Nile encephalitis, and HIV-related cases.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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). Several 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. 16.


Neurology_Adams

Neurology_Adams. Management of Raised Intracranial Pressure” in Chap. 16. 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.


Neurology_Adams

Neurology_Adams. Diagnosis The CSF findings are much the same as in aseptic meningitis (lymphocytic pleocytosis, mild protein elevation, normal glucose values). Occasionally, early sampling of CSF may show few or no cells and subsequent tests may be more typical of an inflammatory disorder. Recovery of virus from blood or CSF is usually not possible and PCR testing is routinely only applied during local epidemics and for the detection of herpes viruses. Recently, it has been possible to use next generation sequencing to identify obscure causes of encephalitis. 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 serologic 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


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. Japanese B virus group, West Nile, EEE, and rabies).


Neurology_Adams

Neurology_Adams. 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).


Neurology_Adams

Neurology_Adams. Of the common viral encephalitides, this is perhaps the gravest and is by far the most common. HSV encephalitis occurs sporadically throughout the year and in patients of all ages and in all parts of the world. About 2,000 cases occur yearly in the United States, accounting for approximately 10 percent of all cases of encephalitis (a rate of 2 to 4 per million population per year). Between 30 and 70 percent were in the past fatal, and many patients who survive are left with serious neurologic abnormalities, more so in the era before effective antiviral treatment. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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. These symptoms and findings include olfactory or gustatory hallucinations, 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


Neurology_Adams

Neurology_Adams. 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 poor prognostic sign.


Neurology_Adams

Neurology_Adams. 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 is infrequently 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.”


Neurology_Adams

Neurology_Adams. 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 often 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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. 31). 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 incorrectly 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.


Neurology_Adams

Neurology_Adams. 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. 32-1). 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.


Neurology_Adams

Neurology_Adams. 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 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


Neurology_Adams

Neurology_Adams. 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, and to obtain PCR testing for HSV-2 as well, while antiviral treatment is continued.


Neurology_Adams

Neurology_Adams. Alternative ways to establish the diagnosis of acute HSV encephalitis are by fluorescent antibody study or culture of cerebral tissue obtained from brain biopsy. The approach to biopsy as a diagnostic test is now infrequently employed with the availability of PCR. We have found it necessary to perform biopsy in only exceptional cases.


Neurology_Adams

Neurology_Adams. 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 14 to 21 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 few patients.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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 value of these medications prophylactically for seizures has not been resolved.


Neurology_Adams

Neurology_Adams. 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. A curious finding in approximately 20 percent of patients has been the subsequent appearance of anti-NMDA antibodies, a finding more typical of antibody mediated limbic encephalitis; there may be movement disorders or seizures in children and delirium in adults, usually more than a month removed from the onset of the infection. Ostensible relapses of encephalitis have been attributed to the antibodies but they may also be asymptomatic as noted by Armangue and coauthors.


Neurology_Adams

Neurology_Adams. 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 may be advisable to continue antiepileptic medications for a year or more and then judge the risk of discontinuing them on


Neurology_Adams

Neurology_Adams. became available. If there were seizures during the acute illness, it may be 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.


Neurology_Adams

Neurology_Adams. 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 a mild case of herpes encephalitis but more so, the paraneoplastic and anti–voltage-gated potassium channel limbic encephalitis that is discussed in Chap. 30. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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 in the following text and also Chap. 35).


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. The main neurologic symptoms, following a 2to 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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). 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 hyperand 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)


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. Chap. 35), 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 in dermatomal patterns, 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.


Neurology_Adams

Neurology_Adams. 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. 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 et al and by Weller et al.


Neurology_Adams

Neurology_Adams. 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 Zoster Angiitis).


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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, HIV, and after


Neurology_Adams

Neurology_Adams. 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, HIV, and after radiation therapy. Increasingly, monoclonal antibodies and other immunosuppressive drugs have been associated with the reemergence of zoster, mostly as dermatomal shingles but also, in extreme cases, as a generalized systemic illness or eruption.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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).


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. Ophthalmic herpes 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.


Neurology_Adams

Neurology_Adams. Ramsay Hunt syndrome 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 et al 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.


Neurology_Adams

Neurology_Adams. Herpes occipitocollaris 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.


Neurology_Adams

Neurology_Adams. Zoster myelitis Devinsky and colleagues reported their findings in 13 patients with zoster myelitis (all of them immunocompromised) following segmental zoster 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. Encephalitis and cerebral angiitis 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. A regional subacute amyotrophy following an attack of shingles is referred to above.


Neurology_Adams

Neurology_Adams. Zoster encephalitis 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 HIV 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,


Neurology_Adams

Neurology_Adams. 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 postor parainfectious condition, was discussed earlier in the chapter.


Neurology_Adams

Neurology_Adams. 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-see Gilden et al 1994); 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. 44).


Neurology_Adams

Neurology_Adams. A cerebral angiitis that occasionally complicates VZV infection is histologically similar to granulomatosis with polyangiitis (formerly Wegener). 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 (Hilt et al).


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. An entirely different type of delayed vasculitis that affects small vessels, with which we have had limited experience, is being reported in patients with HIV 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 be the cause of temporal


Neurology_Adams

Neurology_Adams. 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 be the cause of temporal arteritis.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 days) 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.


Neurology_Adams

Neurology_Adams. 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. The treatments of zoster myelitis and encephalitis are uncertain but intravenous valaciclovir, with or without corticosteroids has been used. Postherpetic Neuralgia (See Also Chaps. 7 and 9)


Neurology_Adams

Neurology_Adams. The treatments of zoster myelitis and encephalitis are uncertain but intravenous valaciclovir, with or without corticosteroids has been used. Postherpetic Neuralgia (See Also Chaps. 7 and 9) 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.


Neurology_Adams

Neurology_Adams. 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, valproate or one of the serotonin reuptake inhibitor drugs may further moderate the pain, particularly if it is of lancinating type.


Neurology_Adams

Neurology_Adams. 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. 7 for further discussion of pain management). Some patients with the most persistent complaints,


Neurology_Adams

Neurology_Adams. the patient to one of the many surgical measures that have been advocated for this disorder (see Chap. 7 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.


Neurology_Adams

Neurology_Adams. 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). The HIV-Acquired Immunodeficiency 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 caused by HIV, AIDS.


Neurology_Adams

Neurology_Adams. 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, the 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. Moreover, the nervous system is susceptible to a number of unusual syndromes that are the direct result of the HIV infection. Virtually all organ systems are vulnerable, including all parts of the CNS, the peripheral nerves and roots, and muscle. AIDS is currently defined as either a CD4+ below 200 cells/μL due to HIV or the presence of opportunistic infections related to HIV immunodeficiency, as such, representing the most advanced stages of HIV infection.


Neurology_Adams

Neurology_Adams. In a span of 45 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 37 million persons are infected worldwide and that approximately 1 million adults in the United States are seropositive for the virus with approximately 40,000 new cases yearly, a number which gas been slowly declining. 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 20,000,000 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.


Neurology_Adams

Neurology_Adams. In the United States, HIV affects mainly homosexual and bisexual males (currently termed “men who sex with men [MSM], comprising two-thirds of all new 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 HIV. 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.


Neurology_Adams

Neurology_Adams. 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 test is available for HIV-2. The inception of highly active anti-retroviral treatment has greatly altered the frequency and presentations of all of the disorders associated with HIV infections, foremost among these, the neurological ones.


Neurology_Adams

Neurology_Adams. 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 HIV but at autopsy the nervous system is affected in nearly all of them. Table 32-2 lists the main infections and neoplastic lesions of the nervous system that complicate AIDS.


Neurology_Adams

Neurology_Adams. 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 Myelopathy, Peripheral Neuropathy, and Myopathy). Most patients recover from the initial acute neurologic illnesses; the relationship to HIV 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.


Neurology_Adams

Neurology_Adams. HIV-2 may display special features of a subacute confusional-dementing illness with deep white matter and basal ganglionic damage. 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 AIDS dementia complex but it is now generally referred to as HIV encephalopathy. It has been estimated that only 3 percent of HIV 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.


Neurology_Adams

Neurology_Adams. 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 (see Navia and Price). 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 was in the past generally 3 to 6 months but is considerably longer if treatment is instituted. Treatment


Neurology_Adams

Neurology_Adams. the dementia evolves over a period of weeks or months; survival after the onset of dementia was in the past generally 3 to 6 months but is 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.


Neurology_Adams

Neurology_Adams. 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 HIV. The disease in children is characterized by an impairment of cognitive functions and spastic weakness and secondarily by impairment of brain growth.


Neurology_Adams

Neurology_Adams. The CSF (including those lacking other manifestations of HIV) 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 and generally displays cerebral atrophy (Fig. 32-2). These findings are useful in diagnosis, although CMV infection of the brain in HIV produces a similar MRI appearance, as described in the following text.


Neurology_Adams

Neurology_Adams. 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 HIV encephalopathy 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 HIV 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.


Neurology_Adams

Neurology_Adams. In another form of this process, referred to in the past 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. This important entity is discussed in the following text. HIV Myelopathy, Peripheral Neuropathy,


Neurology_Adams

Neurology_Adams. HIV Myelopathy, Peripheral Neuropathy, A myelopathy, taking the form of a vacuolar degeneration that bears a marked pathologic resemblance to subacute combined degeneration (due to 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. 42.


Neurology_Adams

Neurology_Adams. AIDS may also be complicated by several forms of peripheral neuropathy, as discussed in Chap. 43. 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.


Neurology_Adams

Neurology_Adams. 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. Typically, 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. A ganglioneuronitis is also known to occur. Facial palsy is being reported with increasing frequency as a feature of HIV; its relationship to the generalized polyneuritis of AIDS is uncertain.


Neurology_Adams

Neurology_Adams. 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 HIV 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 HIV-related neuropathies are discussed in Chap. 43 and are summarized by Wulff and Simpson.


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Neurology_Adams. 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. 45). It is apparent that this remains an area of some controversy. Opportunistic Infections and Neoplasms of the CNS With HIV


Neurology_Adams

Neurology_Adams. 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 32-2. As noted earlier, recent treatment with antiretroviral agents have decreased the frequency of these complications. Interestingly, there appears to be a predilection for certain ones—toxoplasmosis, CMV infection, primary B-cell lymphoma, cryptococcosis, and progressive multifocal leukoencephalopathy (discussed further on under Syndromes of Herpes Zoster), 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.


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Neurology_Adams. Toxoplasmosis and CNS lymphoma Of the focal infectious complications, cerebral toxoplasmosis is the most frequent (and treatable; see Chap. 31). In the autopsy series reported by Navia, Petito, Gold, and colleagues, areas of inflammatory necrosis caused by


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Neurology_Adams. Toxoplasma were found in approximately 13 percent (see Fig. 31-6). 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 (200 mg initially and then 50 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, does not frequently cause myositis in these patients, as it does in non-HIV infected individuals.


Neurology_Adams

Neurology_Adams. The main clinical challenge in reference to toxoplasmosis with HIV is its differentiation from cerebral lymphoma as also discussed in Chap. 30. In a series from Johns Hopkins in the pre-antiretroviral era (see Johnson, 1998), approximately 11 percent of AIDS patients developed a primary CNS lymphoma. In a patient with a cerebral nodule, if there has been no response to antibiotics (see below), stereotaxic brain biopsy may be necessary for diagnosis of lymphoma. There is an association of this type of CNS lymphoma with Epstein-Barr virus in AIDS patients. The prognosis of cerebral lymphoma in AIDS 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.


Neurology_Adams

Neurology_Adams. Antibody tests for toxoplasmosis may be obtained; the absence of IgG antibodies makes infection unlikely and raises the consideration 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.


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Neurology_Adams. Progressive multifocal leukoencephalopathy This important brain infection with the JC virus appears regularly in patients with HIV, generally when CD4+ counts are below 50 cells/μL. In the past, the disorder had been closely associated with iatrogenic immunosuppression, mainly for hematologic malignancy and solid organ transplantation and ironically, this is now increasingly the case. As the name implies, there are areas of cerebral demyelination with characteristic changes in the oligodendrocytes. This disease is discussed further on in this chapter.


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Neurology_Adams. Cytomegalovirus Among the nonfocal neurologic complications of AIDS, the most common are CMV and cryptococcal infections. At autopsy, about one-third of HIV 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 HIV 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.


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Neurology_Adams. 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. 43).


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Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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. 31.


Neurology_Adams

Neurology_Adams. 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 HIV with CD4 counts below 500, as in other immunosuppressed conditions. Varicella has been discussed earlier in this chapter.


Neurology_Adams

Neurology_Adams. Tuberculosis Two particular types of mycobacterial infection tend to complicate HIV—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. Tuberculosis of the nervous system is discussed in Chap. 31.


Neurology_Adams

Neurology_Adams. Neurosyphilis Syphilitic meningitis and meningovascular syphilis have an increased incidence in HIV patients. Cell counts in the CSF are unreliable as signs of activity; diagnosis depends entirely upon serologic tests. It is possible that HIV 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 typical tertiary forms of syphilis, general paresis and tabes dorsalis, are increased in incidence because of HIV; they may require the chronicity of meningovascular


Neurology_Adams

Neurology_Adams. It is unclear, however, if the typical tertiary forms of syphilis, general paresis and tabes dorsalis, are increased in incidence because of HIV; they may require the chronicity of meningovascular syphilis to evolve. Readers are referred to Chap. 31 and the review by Marra.


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Neurology_Adams. 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.


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Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. response to a coexistent infection. This complication, immune reconstitution inflammatory syndrome, or IRIS, is perhaps most pertinent to progressive multifocal leukoencephalopathy discussed later.


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Neurology_Adams. Tropical Spastic Paraparesis, HTLV-I Myelopathy


Neurology_Adams

Neurology_Adams. 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;


Neurology_Adams

Neurology_Adams. 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; organ transplantation, 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.


Neurology_Adams

Neurology_Adams. The clinical and pathologic features of the disease are described in Chap. 42 and in several reviews (Rodgers-Johnson et al and more recently, Gessain and Mahieux). The main characteristic is a very slowly progressive spastic gait with early sphincter control difficulty and some degree of later proprioceptive loss and Romberg sign. Differentiation from the progressive spinal form of multiple sclerosis, hereditary spastic paraparesis, and with subacute combined degeneration, with which it may be confused. 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 corticosteroids or the intravenous administration of immune globulin may temporarily halt its progress. More recently, the anti-CCR4 antibody, mogamulizumab, an agent used in the treatment of T-cell lymphoma, has been found to have activity against the virus and may have


Neurology_Adams

Neurology_Adams. temporarily halt its progress. More recently, the anti-CCR4 antibody, mogamulizumab, an agent used in the treatment of T-cell lymphoma, has been found to have activity against the virus and may have been effective in this disease in phase 1-2 trials (Sato et al).


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Neurology_Adams. HTLV-II myelopathy 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). VIRAL INFECTIONS OF THE DEVELOPING NERVOUS SYSTEM (SEE CHAP. 37) 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. 37.


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Neurology_Adams. In the past, this syndrome was almost invariably the result of infection of anterior horn cells by one of the three types of poliovirus (“polio” referring to grey matter). 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) and probably enterovirus 68 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.


Neurology_Adams

Neurology_Adams. 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 vanished 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.


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Neurology_Adams. Of course, because it is highly communicable, acute poliomyelitis still occurs in regions of the world where large-scale and recurrent vaccination is not yet practical. In a recent year, there were fewer than 2,000 cases in the world but there are periodic small outbreaks. For these reasons and 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.


Neurology_Adams

Neurology_Adams. 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, that is, 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 or meningitic 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


Neurology_Adams

Neurology_Adams. experience only a nonspecific febrile or meningitic 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.


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Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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,


Neurology_Adams

Neurology_Adams. 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.


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Neurology_Adams. 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.


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Neurology_Adams. 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.