Neurology_Adams

Neurology_Adams. The cerebral infection begins in the nasal turbinates and paranasal sinuses and spreads from there along infected vessels to the retroorbital tissues and cavernous sinus (where it results in proptosis, ophthalmoplegia, and edema of the lids and retina) and then to the adjacent brain, causing hemorrhagic infarction. Numerous hyphae are present within the thrombi and vessel wall, often invading the surrounding parenchyma. The cerebral form of mucormycosis is usually fatal in short order. Rapid correction of hyperglycemia and acidosis and treatment with liposomal amphotericin or posaconazole have resulted in recovery in some patients. Debridement, even to the extent of enucleation may be necessary to control the local infection. The differential diagnosis is other forms of septic cavernous sinus thrombosis in a diabetic. Coccidioidomycosis, Histoplasmosis, Blastomycosis, and Actinomycosis


Neurology_Adams

Neurology_Adams. Coccidioidomycosis, Histoplasmosis, Blastomycosis, and Actinomycosis Coccidioidomycosis is a common infection in the southwestern United States. It usually causes only a benign, influenza-like illness with pulmonary infiltrates that mimic those of nonbacterial pneumonia, but in a few individuals (0.05 to 0.2 percent), the disease takes a disseminated form, of which meningitis may be a part. The pathologic reactions in the meninges and CSF and the clinical features are very much like those of tuberculous meningitis. Coccidioides immitis is recovered with difficulty from the CSF but readily from the lungs, lymph nodes, and ulcerating skin lesions. Diagnosis is made from CSF serology.


Neurology_Adams

Neurology_Adams. Treatment consists of the intravenous administration of amphotericin B coupled with implantation of an Ommaya reservoir into the lateral ventricle, permitting injection of the drug for a period of years. Instillation of the drug by repeated lumbar punctures is an alternative, albeit cumbersome, procedure. Even with the most assiduous programs of treatment, only about half the patients with meningeal infections survive.


Neurology_Adams

Neurology_Adams. A similar type of meningitis may occasionally complicate histoplasmosis, blastomycosis, and the anaerobic bacterium actinomycosis. These chronic meningitides possess no specific features except that actinomycosis, like some cases of tuberculosis and nocardiosis, may cause a persistent polymorphonuclear pleocytosis (see “Chronic Persistent and Recurrent Meningitis” in Chap. 32). The CSF yields an organism in a minority of patients, so that diagnosis depends on culture from extraneural sites, biopsy of brain abscesses if present, as well as knowledge of the epidemiology of these fungi. Patients with chronic meningitis in whom no cause can be discovered should also have their CSF tested for antibodies to Sporothrix schenckii, an uncommon fungus that is difficult to culture. Several even rarer fungi that must be considered in the diagnosis of chronic meningitis are discussed in the article by Swartz and Dodge.


Neurology_Adams

Neurology_Adams. Treatment The current preferred treatment is fluconazole and amphotericin B and supplemental antifungal agents are used in the others. Intrathecal amphotericin via a reservoir is administered in patients who relapse. INFECTIONS CAUSED BY RICKETTSIAS, PROTOZOA, AND WORMS


Neurology_Adams

Neurology_Adams. Rickettsias are obligate intracellular parasites that appear microscopically as pleomorphic coccobacilli. The major ones are maintained in nature by a cycle involving an animal reservoir, an insect vector (lice, fleas, mites, and ticks), and humans. Epidemic typhus is an exception, involving only lice and human beings, and Q fever is probably contracted by inhalation. At the time of World War I, the rickettsial diseases, typhus in particular, were remarkably prevalent and of the utmost gravity. In Eastern Europe, between 1915 and 1922, there were an estimated 30 million cases of typhus with 3 million deaths. Now, the rickettsial diseases are of minor importance, the result of insect control by dichlorodiphenyltrichloroethane (DDT) and other chemicals and the therapeutic effectiveness of broad-spectrum antibiotics. In the United States these diseases are quite rare, but they assume significance because, in some types, up to one-third of patients have neurologic manifestations. About


Neurology_Adams

Neurology_Adams. broad-spectrum antibiotics. In the United States these diseases are quite rare, but they assume significance because, in some types, up to one-third of patients have neurologic manifestations. About 2000 cases of Rocky Mountain spotted fever (the most common rickettsial disease) occur each year in the United States, with a mortality of 5 percent or less. Neurologic manifestations occur in a small portion, and neurologists may not encounter a single instance in a lifetime of practice. For this reason, the rickettsial diseases are simply tabulated here.


Neurology_Adams

Neurology_Adams. The following are the major rickettsial diseases: 1. Epidemic typhus, small pockets of which are present in many developing parts of the world. It is transmitted from lice to humans and from person to person. 2. Murine (endemic) typhus, which is present in the same areas as Rocky Mountain spotted fever (see in the following text). It is transmitted by fleas from rats to humans. 3. Scrub typhus or tsutsugamushi fever, which is confined to eastern and southeastern Asia. It is transmitted by mites from infected rodents or humans. 4. Rocky Mountain spotted fever, first described in Montana, is most common in Long Island, Tennessee, Virginia, North Carolina, and Maryland and in the Southwest. It is transmitted by special varieties of ticks.


Neurology_Adams

Neurology_Adams. 5. Q fever, which has a worldwide distribution (except for the Scandinavian countries, New Zealand, and the tropics). It is transmitted in nature by ticks but also by inhalation of dust and handling of materials infected by the causative organism, Coxiella burnetii.


Neurology_Adams

Neurology_Adams. With the exception of Q fever, the clinical manifestations and pathologic effects of the rickettsial diseases are much the same, varying only in severity. Typhus may be taken as the prototype. The incubation period varies from 3 to 18 days. The onset is usually abrupt, with fever rising to extreme levels over several days; headache, often severe; and prostration. A macular rash, which resembles that of measles and involves the trunk and limbs, appears on the fourth or fifth febrile day. An important diagnostic sign in scrub typhus is the necrotic ulcer and eschar at the site of attachment of the infected mite. Delirium—followed by progressive stupor and coma, sustained fever, and occasionally focal neurologic signs and optic neuritis— characterizes the untreated cases. Stiffness of the neck is noted only rarely, and the CSF may be entirely normal or show only a modest lymphocytic pleocytosis.


Neurology_Adams

Neurology_Adams. In fatal cases, the rickettsial lesions are scattered diffusely throughout the brain, affecting gray and white matter alike. The changes consist of swelling and proliferation of endothelial cells of small vessels and a microglial reaction, with the formation of so-called typhus nodules.


Neurology_Adams

Neurology_Adams. Q fever, unlike the other rickettsioses, is not associated with an exanthem. In the few cases with which we are familiar, the main symptoms were those of a low-grade meningitis. Rare instances of encephalitis, cerebellitis, and myelitis are also reported, possibly as postinfectious complications. There is usually a tracheobronchitis or atypical pneumonia (one in which no organism can be cultured from the sputum) and a severe prodromal headache. In these respects, the pulmonary and neurologic illnesses resemble that of the other main cause of “atypical pneumonia,” M. pneumoniae. The Q fever agent (Coxiella) should be suspected if there are concomitant respiratory and meningoencephalitic illnesses and there has been exposure to parturient animals, to livestock (including abattoir workers, who are also exposed to Brucella and anthrax), or to wild deer or rabbits. The diagnosis can be made by the finding of a severalfold increase in specific immunofixation antibodies. Patients who survive


Neurology_Adams

Neurology_Adams. are also exposed to Brucella and anthrax), or to wild deer or rabbits. The diagnosis can be made by the finding of a severalfold increase in specific immunofixation antibodies. Patients who survive the illness usually recover completely; a few are left with residual neurologic signs.


Neurology_Adams

Neurology_Adams. This consists of the administration of doxycycline or chloramphenicol, which are highly effective in all rickettsial diseases. If these drugs are given early, coincident with the appearance of the rash, symptoms abate dramatically and little further therapy is required. Cases recognized late in the course of the disease require considerable supportive care, including the administration of corticosteroids, maintenance of blood volume to overcome the effects of the septic-toxic reaction, and hypoproteinemia.


Neurology_Adams

Neurology_Adams. This disease is caused by Toxoplasma gondii, a tiny (2to 5-μm), obligate, intracellular parasite that is readily recognized in Wrightor Giemsa-stained preparations. It has assumed greater importance in recent decades because of the frequency with which it involves the brain in patients with HIV. In fact, the manifestations of toxoplasmosis are dependent on the response of the host immune system to the infection. Infection in humans is either congenital or acquired postnatally. Congenital infection is the result of parasitemia in the mother who happens to be pregnant at the time of her initial (asymptomatic) Toxoplasma infection. (Treated mothers can be assured, therefore, that there is little carryover risk of producing a second infected infant.) Several modes of transmission of the late-acquired form have been described—eating raw beef, handling uncooked mutton (in Western Europe), and, most often, contact with cat feces, the cat being the natural host of Toxoplasma. Most infections


Neurology_Adams

Neurology_Adams. form have been described—eating raw beef, handling uncooked mutton (in Western Europe), and, most often, contact with cat feces, the cat being the natural host of Toxoplasma. Most infections in HIV patients occur in the absence of an obvious source.


Neurology_Adams

Neurology_Adams. The congenital infection has attracted attention because of its severe destructive effects on the neonatal brain, as discussed in Chap. 37. Signs of active infection—fever, rash, seizures, hepatosplenomegaly—may be present at birth. More often, chorioretinitis, hydrocephalus or microcephaly, cerebral calcifications, and psychomotor retardation are the major manifestations. These may become evident soon after birth or, more often, the infection is asymptomatic and becomes manifest only several months or years later with choriretinitis. Most infants succumb; others survive with varying degrees of the aforementioned abnormalities.


Neurology_Adams

Neurology_Adams. Serologic surveys indicate that the exposure to toxoplasmosis in adults is widespread (approximately 40 percent of American city dwellers have specific antibodies); cases of clinically evident active infection, however, are rare. It is of interest that in 1975, prior to the AIDS epidemic, the medical literature contained only 45 well-documented cases of acquired adult toxoplasmosis (Townsend et al); moreover, in half of them there was an underlying systemic disease (malignant neoplasms, renal transplants, rheumatologic disease) that had been treated intensively with immunosuppressive agents. Now, innumerable cases of acquired toxoplasmosis are being seen because it is the most common cause of focal cerebral lesions in patients with HIV (see Chap. 33). Frequently, the symptoms and signs of infection with Toxoplasma are assigned to the primary immunosuppressive disease with which toxoplasmosis is associated or to other diseases that cause brain masses.


Neurology_Adams

Neurology_Adams. The prevalent problem, and the one of main interest in this chapter, is of cerebral toxoplasmosis in a patient with HIV (Fig. 31-6). The clinical features are usually a single seizure, focal neurological syndrome, or headache or other symptoms of elevated intracranial pressure. The rim enhancing cerebral lesion or multiple lesions of toxoplasmosis also may be found incidentally on cerebral imaging studies. The lesions may be difficult to differentiate from the less common occurrence of CNS lymphoma that arises in immunosuppressed patients. In general, cerebral toxoplasmosis occurs in patients with HIV and CD4 counts below 100/μl whereas other opportunistic infections and lymphoma may occur with higher counts. In many instances, the cerebral toxoplasmosis syndrome defines the inversion from HIV infection to AIDS.


Neurology_Adams

Neurology_Adams. The clinical picture of systemic toxoplasmosis in patients varies. Most often it is a subclinical process or manifested by a painless lymphadenopathy, a mononucleosis-like syndrome, or acute chorioretinitis. There is a rare fulminant, widely disseminated infection with a rickettsia-like rash, encephalitis, myocarditis, and polymyositis. Sometimes, there are signs of a meningoencephalitis, that is, seizures, mental confusion, meningeal irritation, coma, and a lymphocytic pleocytosis and increased CSF protein. The brain in such cases shows one or more foci of inflammatory necrosis, essentially an abscess, (see Fig. 31-6), with free and encysted T. gondii organisms scattered throughout the white and gray matter. Rarely, large areas of necrosis manifest themselves as one or more mass lesions.


Neurology_Adams

Neurology_Adams. In an immunocompetent patient, a rising or greatly elevated IgG antibody titer or a positive IgM indirect fluorescent antibody or another serologic test are useful. Patients with HIV and those who are otherwise immunocompromised, however, may not display an antibody response or an elevation of titers. A presumptive diagnosis can be made on a clinical basis in a patient with HIV and empiric treatment is started before confirmatory testing. If there is no improvement clinically and on imaging after a course of antibiotics, evaluation for cerebral lymphoma and other brain masses is undertaken.


Neurology_Adams

Neurology_Adams. Treatment Patients with a presumptive diagnosis of cerebral toxoplasmosis, are treated with oral sulfadiazine (4 g initially, then 4 to 6 g daily) and pyrimethamine (200 mg initially, then 50 to 100 mg daily) or, when cost or availability of these drugs are issues, the combination of sulfamethoxazole and trimethoprim is used. Leucovorin, 15 to 20 mg daily, should be given to counteract the antifolate action of pyrimethamine. Treatment must be continued for at least 6 weeks. In patients with HIV, treatment at lower doses is continued until the CD4 count exceeds 200 to 250/μL for 6 months or more; otherwise treatment must be lifelong to prevent relapses. Institution of treatment of HIV may precipitate a fulminant inflammatory response (immune reconstitution inflammatory syndrome, IRIS) around the parasite abscess.


Neurology_Adams

Neurology_Adams. This disease is caused by free-living flagellate amoebae, usually of the genus Naegleria and less frequently of the genera Acanthamoeba and Balamuthia. Naegleria is acquired by swimming in ponds or lakes where there is warm fresh water. These are rare but lethal illnesses, with several dozen instances in the last decade in the United States, where most cases have occurred in the Southeastern states.


Neurology_Adams

Neurology_Adams. The onset of the illness caused by Naegleria is usually abrupt, with severe headache, fever, nausea and vomiting, and stiff neck. The course is inexorably progressive—with seizures, increasing stupor and coma, and focal neurologic signs—and the outcome is practically always fatal, usually within a week of onset. The reaction in the CSF is like that in acute bacterial meningitis: increased pressure, a large number of polymorphonuclear leukocytes (not eosinophils, as in the parasitic infestations discussed further on), and increased protein and decreased glucose content. There may be a number of red blood cells in the CSF, reflecting the hemorrhagic and necrotic nature of some amebic brain lesions. The diagnosis is supported by a history of swimming in fresh warm water, particularly of swimming underwater for sustained periods, and on finding viable trophozoites in a wet preparation of unspun spinal fluid. Gram stain and ordinary cultures do not reveal the organism.


Neurology_Adams

Neurology_Adams. Autopsy discloses purulent meningitis and numerous small granulomatous microabscesses in the underlying cortex and white matter. Subacute and chronic granulomatous meningoencephalitis from ameba is a rare disease in humans. Isolated instances have been reported in debilitated and immunosuppressed patients (Gonzalez et al). The organism may be difficult to culture from the CSF; most diagnoses are made from biopsy. A fatal case of ours, in a leukopenic patient who had been receiving granulocyte-stimulating factor, ran a subacute course over 1 month with headache, mild fever, stupor, and unmeasurably low CSF glucose toward the end of life (Katz et al). Initially, there were scattered, round, enhancing lesions on the MRI that disappeared with corticosteroids, much like lymphoma; later, there were more irregular confluent white matter lesions. A brain biopsy revealed amoebae that could have been easily mistaken for macrophages or cellular debris; the organism proved to be Balamuthia.


Neurology_Adams

Neurology_Adams. Treatment with the usual antiprotozoal agents is largely ineffective. Because of the in vitro sensitivity of Naegleria to amphotericin B, this drug has been used by the same schedule as for cryptococcal meningitis. Other suggested regimens have been various combinations of trimethoprim-sulfamethoxazole, rifampin, and antifungal agents Miltefosine, a new drug, is being studied independently and in combination with other drugs for treatment of naegleria and acanthamoeba.


Neurology_Adams

Neurology_Adams. A number of other protozoal diseases are of great importance in tropical regions. The main one of concern here is cerebral malaria, which complicates approximately 2 percent of cases of falciparum malaria. It has been estimated that there are approximately 200 million cases per year worldwide and about half million deaths from malaria. This is a rapidly fatal disease characterized by headache, seizures, and coma, with diffuse cerebral edema and only very rarely by focal features such as hemiplegia, aphasia, hemianopia, or cerebellar ataxia. Bruxism and hiccoughs have been commented on as common features in case reports. Cerebral capillaries and venules are packed with parasitized erythrocytes and the brain is dotted with small foci of necrosis surrounded by glia (Dürck nodes). A retinopathy consisting of macular whitening, orange or white discoloration of retinal vessels, and intraretinal blot-type hemorrhages, has been suggested as a dependable sign of severe malaria as summarized by


Neurology_Adams

Neurology_Adams. consisting of macular whitening, orange or white discoloration of retinal vessels, and intraretinal blot-type hemorrhages, has been suggested as a dependable sign of severe malaria as summarized by Beare and colleagues.


Neurology_Adams

Neurology_Adams. These findings have been the basis of several hypotheses (one of which attributes the cerebral symptoms to mechanical obstruction of the vessels), but none is entirely satisfactory. Also, it seems unlikely that a disorder of immune mechanisms is directly involved in the pathogenesis (see the reviews by Newton et al and by Turner for a discussion of current hypotheses). In a study by Seydel and colleagues, the presence on MRI of cerebral swelling was associated with fatal outcome. They found a variety of signal changes in the cerebra, none consistent among patients, but including varying degrees of cerebral edema and diffusion restriction.


Neurology_Adams

Neurology_Adams. Usually, the neurologic symptoms appear in the second or third week of the infection, but they may be the initial manifestation. Children in hyperendemic regions are the ones most susceptible to cerebral malaria. Among adults in nonenedmic areas, only pregnant women and nonimmune individuals who discontinue prophylactic medication are liable to CNS involvement (Toro and Roman). Useful laboratory findings are anemia and parasitized red blood cells. The CSF may be under increased pressure and sometimes contains a few white blood cells, and the glucose content is normal. With Plasmodium vivax infections, there may be drowsiness, confusion, and seizures without invasion of the brain by the parasite.


Neurology_Adams

Neurology_Adams. Treatment Quinine and artesunate, and related drugs are curative if the cerebral symptoms are not pronounced, but once coma and convulsions supervene, 20 to 30 percent of patients do not survive. Mefloquine, artemether with lumefantrine, and atovaquone are increasingly being used. It had been stated that the administration of large doses of dexamethasone, given as soon as cerebral symptoms appear, may be lifesaving, but most studies demonstrate that corticosteroids are ineffective. Blood or exchange transfusions may confer a modest benefit on survival in severe cases.


Neurology_Adams

Neurology_Adams. This is a common disease in equatorial Africa and in Central and South America. There are two types; the African type (“sleeping sickness”) is caused by Trypanosoma brucei, rhodesiense, and gambiense and is transmitted by several species of the tsetse fly. The second type is Chagas disease, predominantly seen in South America. Most cases in the United States have been in travelers returning from African safari. There had been an alarming increase in trypanosomiasis in sub-Saharan Africa during past decades but now, fewer than several thousand cases have been reported because of active control interventions. The infection begins with a chancre at the site of inoculation and localized lymphadenopathy. Posterior cervical adenopathy is a characteristic feature of subsequent CNS infection (Winterbottom sign); another sign of neurologic interest is pronounced pain at sites of minor injury (called Kerandel hyperesthesia). Later, episodes of parasitemia occur, and at some time during this


Neurology_Adams

Neurology_Adams. sign); another sign of neurologic interest is pronounced pain at sites of minor injury (called Kerandel hyperesthesia). Later, episodes of parasitemia occur, and at some time during this stage of dissemination, usually in the second year of the infection, the trypanosomes can give rise to a diffuse meningoencephalitis. The latter expresses itself clinically as a chronic progressive neurologic syndrome consisting of a reversal or disruption of circadian sleep rhythm (thus, “sleeping sickness”), vacant facial expression, and in some, ptosis and ophthalmoplegia, dysarthria, and then muteness, seizures, progressive apathy, stupor, and coma.


Neurology_Adams

Neurology_Adams. The South American variety of trypanosomiasis (Chagas disease) is caused by Trypanosoma cruzi and is transmitted from infected animals to humans by the bite of reduviid bugs. There have been rare cases from blood transfusion and organ transplantation. The sequence of local lymphadenopathy, hematogenous dissemination, and chronic meningoencephalitis is like that of African trypanosomiasis. There are, of course, numerous other aspects to Chagas disease, including esophageal and colonic motility disorders and cardiac disease. In immunosuppressed hosts, particularly with HIV, the presentation may include meningoencephalitis and brain abscess. Patients undergoing immunosuppression for organ transplantation may have reactivation of the infection. Serologic tests are available to confirm the diagnosis.


Neurology_Adams

Neurology_Adams. Treatment Treatment in the past was with pentavalent arsenicals, mainly melarsoprol, which were more effective in the African than in the South American form of the disease, but is toxic. (It is of historical interest that a search for trypanosomal agents led Ehrlich to the “magic bullet” of pentavalent phenolic arsenic-Salvarsan-that was the first truly effective treatment for syphilis). An encephalopathy occurred in 10 percent of cases during the institution of arsenical treatment; half of these are fatal. As pointed out by Braakman and colleagues, the arsenical encephalopathy is characterized by multiple white matter lesions, sometimes with hemorrhage, and is often quite severe and in those cases, lethal in between 50 and 75 percent. Newer drugs or combinations, particularly eflornithine with nifurtimox are being used for the gambiense disease. Currently, pentamidine and suramin are used for early stages of the African form but is less effective if there are nervous system


Neurology_Adams

Neurology_Adams. with nifurtimox are being used for the gambiense disease. Currently, pentamidine and suramin are used for early stages of the African form but is less effective if there are nervous system manifestations. The treatment of Chagas disease is with nifurtimox, a nitrofurantoin, and benznidazole, a nitroimidazole derivative. A review of the subject of trypanosomiasis has been given by Kennedy and of Chagas disease specifically, by Bern.


Neurology_Adams

Neurology_Adams. Of these, trichinosis is of greatest importance to neurologists. Infections with other roundworms, such as Angiostrongylus, cause an eosinophilic meningitis, as discussed further on. Trichinellosis, Trichinosis (See Also Chap. 45) This disease is caused by the intestinal nematode


Neurology_Adams

Neurology_Adams. Trichinellosis, Trichinosis (See Also Chap. 45) This disease is caused by the intestinal nematode Trichinella spiralis. Infection in humans results from the ingestion of uncooked or undercooked pork (occasionally bear meat) containing the encysted larvae of T. spiralis. The larvae are liberated from their cysts by the gastric juices and develop into adult male and female worms in the duodenum and jejunum. After fertilization, the female burrows into the intestinal mucosa, where she deposits several successive batches of larvae. These make their way—via the lymphatics, regional lymph nodes, thoracic duct, and bloodstream—into all parts of the body. The new larvae penetrate all tissues but survive only in striated muscle, where they become encysted and eventually calcify. Animals are infected in the same way as humans, and the cycle can be repeated only if a new host ingests the encysted larvae. Gould has written an authoritative review of this subject.


Neurology_Adams

Neurology_Adams. The early symptoms of the disease, beginning a day or two after the ingestion of pork, are those of a mild gastroenteritis. Later symptoms coincide with invasion of muscle by larvae. The latter begins about the end of the first week and may last for 4 to 6 weeks. Low-grade fever, pain and tenderness of muscles, edema of the conjunctivae and particularly of the eyelids, and fatigue are the usual manifestations. The myopathic aspects of Trichinella infestation are considered fully in Chap. 45. Particularly heavy infection may be associated with a CNS disorder from larval migration through the nervous system without encystation. Headache, stiff neck, and a mild confusional state are the usual symptoms. Delirium, coma, hemiplegia, and aphasia have also been observed on occasion. The spinal fluid is usually normal but may contain a moderate number of lymphocytes and, rarely, parasites.


Neurology_Adams

Neurology_Adams. An eosinophilic leukocytosis usually appears when the muscles are invaded. Serologic (precipitin) tests become positive early in the third week. The heart is often involved, manifested by tachycardia and electrocardiographic changes; sterile brain embolism may follow the myocarditis. These findings may aid in the diagnosis, which can be confirmed by finding the larvae in a muscle biopsy, using the technique of low-power scan of wet tissue pressed between two glass slides. Trichinosis is seldom fatal. Most patients recover completely, although myalgia may persist for several months. Once recurrent seizures and focal neurologic deficits appear, they may persist indefinitely. The latter are based on the rare occurrence of trichina encephalitis (the filiform larvae may be seen in cerebral capillaries and in cerebral parenchyma) and emboli from mural thrombi arising in infected heart muscle.


Neurology_Adams

Neurology_Adams. Treatment (See also Chap. 45.) In the treatment of severe trichinosis, albendazole, an antihelminthic agent, and corticosteroids are of value. This drug prevents larval reproduction and is therefore useful in patients known to have ingested trichinous meat. It also interferes with the metabolism of muscle-dwelling larvae. Fever, myalgia, and eosinophilia respond well to the antiinflammatory and immunosuppressant effects of prednisone (40 to 60 mg daily), and a salutary effect has been noted on the cardiac and neurologic complications as well. Other nematodes, mainly toxocara (the cause of visceral larva migrans), strongyloides, and angiostrongyloides may rarely migrate to the brain, but each is characterized by a systemic illness, which is far more common than the neurologic one. Parasitic meningitis is discussed later.


Neurology_Adams

Neurology_Adams. This is the larval or intermediate stage of infection with the pork tapeworm Taenia solium. In Central and South America and in parts of Africa and India, cysticercosis is a leading cause of epilepsy and other neurologic disturbances. Because of a considerable emigration from these endemic areas, patients with cysticercosis are now being seen with some regularity in countries where the disease had previously been unknown. Usually the diagnosis is suggested by CT or MRI of the brain but can also be made by the presence of multiple calcified lesions in the thigh, leg, and shoulder muscles and in the cerebrum.


Neurology_Adams

Neurology_Adams. The cerebral manifestations of cysticercosis are diverse, related to the encystment and subsequent calcification of the larvae in the cerebral parenchyma, subarachnoid space, and ventricles (Fig. 31-7). The lesions are most often multiple but may be solitary; in the United States and nonendemic countries, single cysts are more common. Before the cyst degenerates and eventually calcifies, CT scanning and MRI may actually visualize the scolex. Most often the neurologic disease presents with seizures, although many patients are entirely asymptomatic, the cysts being discovered radiologically. It is only when the cyst degenerates, many months or years after the initial infestation that an inflammatory and granulomatous reaction is elicited and focal symptoms arise.


Neurology_Adams

Neurology_Adams. In some patients, a large subarachnoid or intraventricular cyst may obstruct the flow of CSF, in which case the surgical removal of the cyst or a shunt procedure becomes necessary. Proano and colleagues, however, have reported on a series of such cases with cysts larger than 5 cm in diameter, which they have treated medically. In a more malignant form of the disease, the cysticerci are located in the basilar subarachnoid space, where they induce an intense inflammatory reaction leading to hydrocephalus, vasculitis, and stroke as well as cranial nerve palsies. This so-called racemose form of the illness is little altered by the use of praziquantel or any other form of therapy (Estanol et al) but responds less well than the cystic form.


Neurology_Adams

Neurology_Adams. Treatment For a comprehensive treatment of the subject of neurocysticercosis the reader is referred to the review by Nash and colleagues. The following is a summary of current treatment principles. The therapy of this disorder has been greatly improved in recent years by the use of CT and MRI and the administration of albendazole or praziquantel, an antihelminthic agent that is also active against all species of schistosomes. Albendazole is given as 5 mg/kg tid for 15 to 30 days. Initially, treatment may seem to exacerbate neurologic symptoms, with an increase in cells and protein in the CSF, but then the patient improves and may become asymptomatic, with a striking decrease in the size and number of cysts on CT scanning. Corticosteroids are usually used at the onset of antihelminthic treatment and particularly if a large single lesion is causing symptoms by its mass effect.


Neurology_Adams

Neurology_Adams. Infection with Echinococcus occasionally affects the brain. The usual sources of infection are water and vegetables contaminated by canine feces. After they are ingested, the ova hatch and the freed embryos migrate, primarily to lung and liver, but sometimes to brain (approximately 2 percent of cases), where a large solitary (hydatid) cyst may be formed. The typical lesion is a large fluid-filled cyst with the parasite visible by imaging procedures, but a solid nodular brain lesion, a “chitinoma,” is also known to occur. We have also observed a compressive spinal cord lesion. Treatment with the albendazole or mebendazole is recommended when surgery is not feasible.


Neurology_Adams

Neurology_Adams. Cerebral coenuriasis (coenurus cerebralis) is an uncommon infestation by larvae of the tapeworm Taenia multiceps. It occurs mainly in sheep-raising areas where there are many dogs, the latter being the definitive hosts. The larvae form grape-like cysts, most often in the posterior fossa, which obstruct the spinal fluid pathways and cause signs of increased intracranial pressure. Surgical removal is possible. Another cestode, Spirometra mansoni, may migrate within the brain, leaving a visible track as it moves. Subcutaneous nodules are the most common lesions. This parasite is found predominantly in the Far East.


Neurology_Adams

Neurology_Adams. The nervous system may also be invaded directly by certain worms (Ascaris, filaria) and flukes (Schistosoma, Paragonimus). These diseases are virtually nonexistent in the United States except among those who have recently returned from endemic areas. Schistosomiasis, however, is of such great importance and often invades the nervous system in such characteristic ways that it is considered below in detail.


Neurology_Adams

Neurology_Adams. The ova of trematodes seldom involve the nervous system, but when they do, the infecting organism is usually Schistosoma japonicum and, less often, Schistosoma haematobium or Schistosoma mansoni. It is said that S. japonicum has a tendency to localize in the cerebral hemispheres and S. mansoni in the spinal cord, but there have been many exceptions. The cerebral lesions form in relation to direct parasitic deposition of eggs in blood vessels and take the form of mixed necrotizing and ischemic parenchymal foci that are infiltrated by eosinophils and giant cells (Fig. 31-8) (Scrimgeour and Gajdusek). The lesions do not calcify.


Neurology_Adams

Neurology_Adams. Schistosomiasis is widespread in tropical regions; 80 percent of cases are in sub-Saharan Africa. North American neurologists have little contact with it except in travelers who have bathed in lakes or rivers where the snail hosts of the parasite are plentiful. The initial manifestation may be a local skin irritation at the site of entry of the parasite (swimmer’s itch), or a large serpiginous urticarial rash on the trunk, Katayama fever, particularly likely to occur in prior exposure, but the patient frequently does not offer this information unless sought. A small proportion of patients develop neurologic symptoms several months after exposure. Headaches, convulsions (either focal or generalized), and other cerebral signs appear; with lesions of larger size, papilledema may develop, simulating a brain tumor. It has been hypothesized that travelers are more prone to develop symptomatic nervous system disease because of an intense inflammatory reaction surrounding the deposited eggs.


Neurology_Adams

Neurology_Adams. Some types of Schistosoma infections (also called Bilharzia), mainly mansoni, tend to localize in the spinal cord, causing an acute or subacute myelitis that is concentrated in the conus medullaris. The clinical picture is of a subacutely developing transverse cord lesion. There is often preceding leg or radicular pain and bladder control is affected prominently. We have observed a few cases in students returning from Africa; their lesions were in the conus. Unless treated immediately, there may be permanent paralysis of the legs and bladder from inflammatory and microvascular destruction of the lower cord.


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Neurology_Adams. Eosinophilia is common in symptomatic individuals and there is a serologic test but it often becomes negative soon after the initial infection. Examination of the CSF in the myelitic form discloses a pleocytosis, sometimes with an increase in eosinophils (more than half of patients), increased protein content, and increased pressure. Diagnosis is made by the finding of eggs in stool or urine. Serology is probably more sensitive. The other major trematode, Paragonimus, has been known to invade the brain in up to one-quarter of cases, where it creates a solitary granulomatous nodule comparable to that seen in schistosomiasis. Treatment This consists of praziquantel orally in a dosage of 20 mg/kg tid. In one series, 8 of 9 patients with epilepsy caused by cerebral schistosomiasis became seizure free after treatment with praziquantel. Surgical excision of spinal granulomatous tumors is sometimes indicated, but the results are unpredictable. Corticosteroids are often given concurrently.


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Neurology_Adams. An eosinophilic meningoencephalitis, often with cranial nerve and painful polyradicular findings, has been reported with Angiostrongylus cantonensis, Gnathostoma, Paragonimus, and Toxocara canis and cati infections. In Angiostrongylus infections, snails, freshwater prawns, and unwashed lettuce carry the nematode. The resulting illness may last for weeks to months, with pain, paresthesias, sensorimotor abnormalities, and a confusional state as the main manifestations. Cook has reviewed these and other protozoan and helminthic infections of the CNS. An interesting outbreak in a group of medical students who returned to the United States from Jamaica was described by Slom and colleagues; they highlighted paresthesias and dysesthesias but noted eosinophilia in the blood or CSF in only half of their patients. Meningeal Hodgkin disease, other lymphomas, and cholesterol emboli also occasionally incite eosinophilic meningitis.


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Neurology_Adams. More detailed descriptions of parasitic diseases of the nervous system can be found in the monographs of Bia and of Gutierrez. Adams RD, Kubik CS, Bonner FJ: The clinical and pathological aspects of influenzal meningitis. Arch Pediatr 65:354, 1948. Adams M, Rhyner PA, Day J, et al: Whipple’s disease confined to the central nervous system. Ann Neurol 21:104, 1987. Al Deeb SM, Yaqub BA, Sharif HS, Phadke JG: Neurobrucellosis: Clinical characteristics, diagnosis, and outcome. Neurology 39:498, 1989. Anderson M: Neurology of Whipple’s disease. J Neurol Neurosurg Psychiatry 68:1, 2000. Armstrong RW, Fung PC: Brainstem encephalitis (rhombencephalitis) due to Listeria monocytogenes: Case report and review. Clin Infect Dis 16:689, 1993. Baker P, Price T, Allen CD: Brainstem and cerebellar dysfunction with legionnaires’ disease. J Neurol Neurosurg Psychiatry 44:1054, 1981.


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Neurology_Adams. Baker P, Price T, Allen CD: Brainstem and cerebellar dysfunction with legionnaires’ disease. J Neurol Neurosurg Psychiatry 44:1054, 1981. Baloh RW, Honrubia V: Clinical Neurophysiology of the Vestibular System. Oxford, Oxford University Press, 2001, pp 232–234. Bannwarth A: Chronische lymphocytare Meningitis, entzundliche Polyneuritis und “Rheumatismus.” Arch Psychiatr Nervenkr 113:284, 1941. Barnes PF, Bloch AB, Davidson PT, Snider DE Jr: Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 324:1644, 1991. Beare NAV, Taylor TE, Harding SP, et al: Malarial retinopathy: A newly established diagnostic sign in malaria. Am J Trop Med Hyg 75:790, 2006. Berardi VE, Weeks KE, Steere AC: Serodiagnosis of early Lyme disease: Evaluation of IgM and IgG antibody responses by antibody capture enzyme immunoassay. J Infect Dis 158:754, 1988.


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Neurology_Adams. Berardi VE, Weeks KE, Steere AC: Serodiagnosis of early Lyme disease: Evaluation of IgM and IgG antibody responses by antibody capture enzyme immunoassay. J Infect Dis 158:754, 1988. Berenguer J, Moreno S, Laguna F, et al: Tuberculous meningitis in patients infected with the human immunodeficiency virus. N Engl J Med 326:668, 1992. Bern C: Chagas’ disease. New Engl J Med 373:456, 2015. Bia F (ed): Parasitic diseases of the nervous system. Semin Neurol 13(2):1, 1993. Blanc F, Jaulhac B, Fleury M, et al. Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients. Neurology 69:953, 2007. Braakman HM, van de Molengraft FJJ, Hubert WW, et al: Lethal African trypanosomiasis in a traveler: MRI and neuropathology. Neurology 66:1094, 2006. Burgdorfer W, Barbour AG, Hayes SF, et al: Lyme disease CA tick-borne spirochetosis. Science 216:1317, 1982.


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Neurology_Adams. Burgdorfer W, Barbour AG, Hayes SF, et al: Lyme disease CA tick-borne spirochetosis. Science 216:1317, 1982. Chuck SL, Sande MA: Infection with Cryptococcus neoformans in the acquired immunodeficiency syndrome. N Engl J Med 321:794, 1989. Cohen MM: The central nervous system in congenital heart disease. Neurology 10:452, 1960. Cook GC: Protozoan and helminthic infections. In: Lambert HP (ed): Infections of the Central Nervous System. Philadelphia, Decker, 1991, pp 264–282. Day JN, Chau TTH, Wolbers M, et al: Combination antifungal therapy for cryptococcal meningitis. N Engl J Med 368:1291, 2013. deGans J, van de Beck D, et al: Dexamethasone in adults with bacterial meningitis. N Engl J Med 347:1549, 2002. Dodge PR, Davis H, Feigin RD, et al: Prospective evaluation of hearing impairment as a sequela of acute bacterial meningitis. N Engl J Med 311:869, 1984.


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Neurology_Adams. Dodge PR, Davis H, Feigin RD, et al: Prospective evaluation of hearing impairment as a sequela of acute bacterial meningitis. N Engl J Med 311:869, 1984. Durand ML, Calderwood SB, Weber DJ, et al: Acute bacterial meningitis: A review of 493 episodes. N Engl J Med 328:21, 1993. Ellner JJ, Bennett JE: Chronic meningitis. Medicine (Baltimore) 55:341, 1976. Estanol B, Corona T, Abad P: A prognostic classification of cerebral cysticercosis: Therapeutic implications. J Neurol Neurosurg Psychiatry 49:1131, 1986. Ferry PC, Culbertson JL, Cooper JA, et al: Sequelae of Haemophilus influenzae meningitis: Preliminary report of a long-term follow-up study. In: Sell SH, Wright PF (eds): Haemophilus Influenzae—Epidemiology, Immunology and Prevention of Disease. New York, Elsevier, 1982, sec 3, pp 111–116. Fisher RS, Clark AW, Wolinsky JS, et al: Postinfectious leukoencephalitis complicating Mycoplasma pneumoniae infection. Arch Neurol 40:109, 1983.


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Neurology_Adams. Fisher RS, Clark AW, Wolinsky JS, et al: Postinfectious leukoencephalitis complicating Mycoplasma pneumoniae infection. Arch Neurol 40:109, 1983. Garcia-Monico JC, Benach JL: Lyme neuroborreliosis. Ann Neurol 37:691, 1995. Gonzalez MM, Gould E, Dickinson G, et al: Acquired immunodeficiency syndrome associated with Acanthamoeba infection and other opportunistic organisms. Arch Pathol Lab Med 110:749, 1986. Gould SE: Trichinosis in Man and Animals. Springfield, IL, Charles C Thomas, 1970. Gray ML, Killinger AH: Listeria monocytogenes and Listeria infections. Bacteriol Rev 30:309, 1966. Gutierrez Y: Diagnostic Pathology of Parasitic Infections with Clinical Correlations, 2nd ed. New York, Oxford University Press, 2000. Hasbun R, Abrahams J, Jekel J, Quagliarello VJ: Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med 345:1727, 2001.


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Neurology_Adams. Hasbun R, Abrahams J, Jekel J, Quagliarello VJ: Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med 345:1727, 2001. Kasanmoentalib ES, Brouwer MC, vander Ende A, von de Beek D: Hydrocephalus in adults with community-acquired bacterial meningitis. Neurology 75:918, 2010. Kastenbauer S, Pfister HW: Pneumococcal meningitis in adults. Spectrum of complications and prognostic factors in a series of 87 cases. Brain 126:1015, 2003. Katz DA, Berger JR: Neurosyphilis in acquired immunodeficiency syndrome. Arch Neurol 46:895, 1989. Katz JD, Ropper AH, Adelman L, et al: A case of Balamuthia mandrillaris meningoencephalitis. Arch Neurol 57:1210, 2000. Kennedy PGE: The continuing problem of human African Trypanosomiasis (sleeping sickness). Ann Neurol 64:116, 2008. Kubik CS, Adams RD: Subdural empyema. Brain 66:18, 1943. Lanska DJ: Anthrax meningoencephalitis. Neurology 59:327, 2002.


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Neurology_Adams. Kubik CS, Adams RD: Subdural empyema. Brain 66:18, 1943. Lanska DJ: Anthrax meningoencephalitis. Neurology 59:327, 2002. Lebel MH, Freij BJ, Syrogiannopoulos GA, et al: Dexamethasone therapy for bacterial meningitis. Results of two double-blind trials. N Engl J Med 319:964, 1988. Lechtenberg R, Sterra MF, Pringle GF, et al: Listeria monocytogenes: Brain abscess or meningoencephalitis? Neurology 29:86, 1979. Lees AW, Tyrrell WF: Severe cerebral disturbance in legionnaires’ disease. Lancet 2:1331, 1978. Leys D, Destee A, Petit H, Warot P: Management of subdural intracranial empyemas should not always require surgery. J Neurol Neurosurg Psychiatry 49:635, 1986. Lincoln EM: Tuberculous meningitis in children. Serous meningitis. Annu Rev Tuberculosis 56:95, 1947. Louis ED, Lynch T, Kaufmann P, et al: Diagnostic guidelines in central nervous system Whipple’s disease. Ann Neurol 40:561, 1996.


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Neurology_Adams. Louis ED, Lynch T, Kaufmann P, et al: Diagnostic guidelines in central nervous system Whipple’s disease. Ann Neurol 40:561, 1996. Lyon G, Dodge PR, Adams RD: The acute encephalopathies of obscure origin in children. Brain 84:680, 1961. Matthews BR, Jones LK, Saad DA, et al: Cerebellar ataxia and central nervous system Whipple disease. Arch Neurol 62:618, 2005. McGill F, Heyderman RS, Panagiotou S, et al: Acute bacterial meningitis in adults. Lancet 388:3036, 2016. Merritt HH, Adams RD, Solomon H: Neurosyphilis. New York, Oxford University Press, 1946. Mizuguchi M, Yamanouchi H, Ichiyama T, et al: Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand 115:45, 2007. Naber SP: Molecular pathology—diagnosis of infectious disease. N Engl J Med 331:1212, 1994. Nadelman RB, Wormser GP: Lyme borreliosis. Lancet 352:557, 1998.


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Neurology_Adams. Naber SP: Molecular pathology—diagnosis of infectious disease. N Engl J Med 331:1212, 1994. Nadelman RB, Wormser GP: Lyme borreliosis. Lancet 352:557, 1998. Narita M, Matsuzono Y, Togashi T, et al: DNA diagnosis of central venous system infection by Mycoplasma pneumoniae. Pediatrics 90:250, 1992. Nash TE, Singh G, White AC, et al: Treatment of neurocysticercosis: current status and future research needs. Neurology 67:1120, 2006. Newton CRJ, Hien TT, White N: Cerebral malaria. J Neurol Neurosurg Psychiatry 69:433, 2000. Newton EM: Hematogenous brain abscess in cyanotic congenital heart disease. Q J Med 25:201, 1956. Nguyen TH, Tran TH, Thwaites G, et al: Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med 357:2431, 2007. Nigrovic LE, Kuppermann N, Macias CG, et al: Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis. JAMA 297:52, 2007.


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Neurology_Adams. Nigrovic LE, Kuppermann N, Macias CG, et al: Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis. JAMA 297:52, 2007. Peacock JE: Persistent neutrophilic meningitis. Infect Dis Clin North Am 4:747, 1990. Pitchenik AE, Fertel D, Bloch AB: Mycobacterial disease: Epidemiology, diagnosis, treatment, and prevention. Clin Chest Med 9:425, 1988. Pachner AR, Steiner I: Lyme neuroborreliosis: Infection, immunity, and inflammation. Lancet Neurol 6:544, 2007. Pomeroy SL, Holmes SJ, Dodge PR, Feigin RD: Seizures and other neurologic sequelae of bacterial meningitis in children. N Engl J Med 323:1651, 1990. Proano JV, Madrazo I, Avelar F, et al: Medical treatment for neurocysticercosis characterized by giant subarachnoid cysts. N Engl J Med 345:879, 2001. Rennick G: Cerebral herniation during bacterial meningitis in children. BMJ 306:953, 1993. Rich AR: The Pathogenesis of Tuberculosis, 2nd ed. Oxford,


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Neurology_Adams. Rennick G: Cerebral herniation during bacterial meningitis in children. BMJ 306:953, 1993. Rich AR: The Pathogenesis of Tuberculosis, 2nd ed. Oxford, England, Blackwell, 1951. Ropper AH, Kanis KB: Flaccid quadriplegia from tonsillar herniation in pneumococcal meningitis. J Clin Neurosci 7:330, 2000. Rosenstein NE, Perkins BA, Stephens DS, et al: Meningococcal disease. N Engl J Med 344:1378, 2001. Rothstein TL, Kenny GE: Cranial neuropathy, myeloradiculopathy, and myositis: Complications of Mycoplasma pneumoniae infection. Arch Neurol 36:476, 1979. Saag MS, Powderly WG, Cloud GA, et al: Comparison of amphotericin B with fluconazole in the treatment of acute HIV- associated cryptococcal meningitis. N Engl J Med 326:83, 1992. Sali M, Buonsenso D, Goletti D, et al: Accuracy of QuantiFERON-TB Gold Test for Tuberculosis Diagnosis in Children. PLoS One 10:e0138952, 2015.


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Neurology_Adams. Sali M, Buonsenso D, Goletti D, et al: Accuracy of QuantiFERON-TB Gold Test for Tuberculosis Diagnosis in Children. PLoS One 10:e0138952, 2015. Scarborough M, Gorodon SB, Whitty CJ, et al: Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa. N Engl J Med 357:2441, 2007. Schuchat A, Robinson K, Wenger JD, et al: Bacterial meningitis in the United States. N Engl J Med 337:970, 1997. Schwartz MA, Selhorst JB, Ochs AL, et al: Oculomasticatory myorhythmia: A unique movement disorder occurring in Whipple disease. Ann Neurol 20:677, 1986. Scrimgeour EM, Gajdusek DC: Involvement of the central nervous system in Schistosoma mansoni and S. haematobium infection. Brain 108:1023, 1985. Seydel KB, Kampondeni SD, Valim C, et al: Brain swelling and death in children with cerebral malaria. N Engl J Med 372: 1126, 2014. Shetty KR, Cilvo CL, Starr BD, Harter DH: Legionnaires’ disease with profound cerebellar involvement. Arch Neurol 37:379, 1980.


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Neurology_Adams. Shetty KR, Cilvo CL, Starr BD, Harter DH: Legionnaires’ disease with profound cerebellar involvement. Arch Neurol 37:379, 1980. Slom TJ, Cortese MM, Gerber SJ, et al: An outbreak of eosinophilic meningitis caused by Angiostrongylus cantonensis in travelers returning from the Caribbean. N Engl J Med 346:688, 2002. Snedeker JD, Kaplan SL, Dodge PR, et al: Subdural effusion and its relationship with neurologic sequelae of bacterial meningitis in infancy: A prospective study. Pediatrics 86:163, 1990. Snider DE, Roper WL: The new tuberculosis. N Engl J Med 326:703, 1992. Steere AC, Strle F, Wormser GP, et al: Lyme borreliosis. Nat Rev Dis Primers 2:1, 2016. Swartz MN: “Chronic meningitis”—many causes to consider. N Engl J Med 317:957, 1987. Swartz MN, Dodge PR: Bacterial meningitis: A review of selected aspects. N Engl J Med 272:725, 779, 842, 898, 1965.


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Neurology_Adams. Swartz MN, Dodge PR: Bacterial meningitis: A review of selected aspects. N Engl J Med 272:725, 779, 842, 898, 1965. Symonds, C: Hydrocephalic and focal cerebral symptoms in relation to thrombophlebitis of the dural sinuses and cerebral veins. Brain 60:531, 1937. Thi VA, Nordmann P, Landrieu P: Encéphalopathie associée aux infections bactériennes sévères de l’enfant: (“encéphalite presuppurative” ou “syndrome toxi-infectieux”). Rev Neurol 158:709, 2002. Thigpen MC, Whitney CG, Messonnier et al: Bacterial meningitis in the United States, 1998-2007. N Engl J Med 364:2016, 2011. Thwaites GE, Bang ND, Dung NH, et al: Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 351:1741, 2004. Toro G, Roman G: Cerebral malaria. Arch Neurol 35:271, 1978. Townsend JJ, Wolinsky JS, Baringer JR, Johnson PC: Acquired toxoplasmosis. Arch Neurol 32:335, 1975.


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Neurology_Adams. Toro G, Roman G: Cerebral malaria. Arch Neurol 35:271, 1978. Townsend JJ, Wolinsky JS, Baringer JR, Johnson PC: Acquired toxoplasmosis. Arch Neurol 32:335, 1975. Tunkel AR, Scheld WM: Corticosteroids for everyone with meningitis? N Engl J Med 347:1613, 2002. Turner G: Cerebral malaria. Brain Pathol 7:569, 1997. Uldry PA, Kuntzer T, Bogousslavsky J, et al: Early symptoms and outcome of Listeria monocytogenes rhombencephalitis: 14 adult cases. J Neurol 240:235, 1993. van de Beek D, de Gans J, Tunkel AR, Wijdicks EFM: Community-acquired bacterial meningitis in adults. N Engl J Med 354:44, 2006. van de Beek D, Drake JM, Tunkel AR: Nosocmial bacterial meningitis. N Engl J Med 362:146, 2010. Vartdal F, Vandvik B, Michaelsen TE, et al: Neurosyphilis: Intrathecal synthesis of oligoclonal antibodies to Treponema pallidum. Ann Neurol 11:35, 1982.


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Neurology_Adams. Vartdal F, Vandvik B, Michaelsen TE, et al: Neurosyphilis: Intrathecal synthesis of oligoclonal antibodies to Treponema pallidum. Ann Neurol 11:35, 1982. Vodopivec I, Rinehart EM, Griffin GK, et al: A Cluster of CNS Infections Due to B. cereus in the Setting of Acute Myeloid Leukemia: Neuropathology in 5 Patients. J Neuropathol Exp Neurol 74:1000, 2015. Walsh TJ, Hier DB, Caplan LR: Fungal infections of the central nervous system: Comparative analysis of risk factors and clinical signs in 57 patients. Neurology 35:1654, 1985. Wasz-Hockert O, Donner M: Results of the treatment of 191 children with tuberculous meningitis. Acta Paediatr 51(Suppl 141):7, 1962. Westenfelder GO, Akey DT, Corwin SJ, Vick NA: Acute transverse myelitis due to Mycoplasma pneumoniae infection. Arch Neurol 38:317, 1981. Figure 31-1. MRI, FLAIR sequence showing microabscesses of melioidosis in some of the typical locations of the deep cerebellum (left panel) and cerebral white matter (right panel).


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Neurology_Adams. Figure 31-1. MRI, FLAIR sequence showing microabscesses of melioidosis in some of the typical locations of the deep cerebellum (left panel) and cerebral white matter (right panel). Figure 31-2. MRI showing a right frontal brain abscesses associated with bacterial endocarditis (S. aureus) in a 55-year-old man. There is characteristic rim enhancement with gadolinium (left panel) and restricted diffusion within the abscess (right panel). Figure 31-3. MRI in tuberculous meningitis showing gadolinium enhancement of the basal meninges, reflecting multiple abscesses, accompanied by hydrocephalus and cranial nerve palsies. Figure 31-4. A tuberculoma of the pons on a gadolinium-enhanced MRI (left panel). There is a thick, uniform enhancing rim. The mass behaved clinically like a malignant brain tumor. The right panel shows the same lesion after antituberculous treatment. Figure 31-5. Diagram of the evolution of neurosyphilis.


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Neurology_Adams. Figure 31-5. Diagram of the evolution of neurosyphilis. Figure 31-6. MRI showing a rim-enhancing Toxoplasma abscess in the deep left cerebral hemisphere in a patient with HIV. There is mass effect and surrounding edema, features which are variable. Figure 31-7. Cysticercosis on CT without contrast. Multiple vesicular lesions, some with visible scolices and without mass effect (left panel) that became calcified 2 years later (right panel). Figure 31-8. MRI of schistosomiasis (S. mansoni) with gadolinium enhancement of patchy lesions in the left temporal lobe in a traveler returning from Ghana. Chapter 31 Bacterial, Fungal, Spirochetal, and Parasitic Infections of the Nervous System Viral Infections of the Nervous System


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Neurology_Adams. A number of viruses share the unique tendency to primarily affect the human nervous system. In some conditions, the systemic effects of the viral infection are negligible; it is the neurologic disorder that brings them to medical attention, that is, the viruses are neurotropic. Included in this group are the human immunodeficiency viruses (HIV-1 and HIV-2), the group of human herpes viruses including herpes simplex viruses (HSV-1 and HSV-2), herpes zoster or varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), poliovirus, rabies, and several seasonal arthropod-borne viruses (Flaviviruses). Some of these exhibit an affinity for certain types of neurons: for example, poliomyelitis viruses and motor neurons, VZV and peripheral sensory neurons, and rabies virus and brainstem neurons. Yet others attack nonneuronal supporting glial cells; John Cunningham (JC) virus causing progressive multifocal leukoencephalopathy is the prime example. For many of the rest, the


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Neurology_Adams. brainstem neurons. Yet others attack nonneuronal supporting glial cells; John Cunningham (JC) virus causing progressive multifocal leukoencephalopathy is the prime example. For many of the rest, the affinity is less selective in that all elements of the nervous system are involved. Herpes simplex, for example, may devastate the medial parts of the temporal lobes, destroying neurons, glia cells, myelinated nerve fibers, and blood vessels; and HIV may induce multiple foci of tissue necrosis throughout the cerebrum. These relationships and many others, which are the subject of this chapter, are of wide interest in medicine.


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


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


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


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Neurology_Adams. Viruses, once they invade the nervous system, have numerous clinical and pathologic effects. One reason for this diversity is that different cell populations within the CNS vary in their susceptibility to infection with different viruses. To be susceptible to a viral infection, the host cell must have on its cytoplasmic membrane specific receptor sites to which the virus attaches. Thus, some infections are confined to meningeal cells, enteroviruses being the most common, in which case the clinical manifestations are those of aseptic meningitis. Other viruses involve particular classes of neurons of the brain or spinal cord, giving rise to the more serious disorders such as encephalitis and poliomyelitis. The virus or its nucleocapsid must be capable of penetrating the cell, mainly by the process of endocytosis, and of releasing its protective nucleoprotein coating. For viral reproduction to occur, the cell must have the metabolic capacity to transcribe and translate virus-coated


Neurology_Adams

Neurology_Adams. the process of endocytosis, and of releasing its protective nucleoprotein coating. For viral reproduction to occur, the cell must have the metabolic capacity to transcribe and translate virus-coated proteins, to replicate viral nucleic acid, and, under the direction of the virus’s genome, to assemble virions. Certain viruses depend on cell-surface receptors to ingress into the cell; these relationships have potential therapeutic interest as, for example, the serotonin receptor for entry of the JC virus into oligodendrocytes.


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


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Neurology_Adams. Differentiating cells of the fetal brain have particular vulnerabilities, and viral incorporation may give rise to malformations and to hydrocephalus; an example is mumps virus with ependymal destruction and aqueductal stenosis. In experimental animals cerebral neoplasms can be induced when certain viral genomes are incorporated into the DNA of the host cell. There is suggestive evidence of such a mechanism relating to EBV in B-cell lymphoma of the brain. The prions have yet other means of affecting cells that do not conform to the traditional concepts of infection and are discussed in a later section of this chapter.


Neurology_Adams

Neurology_Adams. A large number of viruses are able to affect the nervous system. Among the enteroviruses alone, nearly 70 distinct serologic types are associated with CNS disease, and additional types from this family of viruses and others are still being discovered. Rather than considering them individually, there are only a limited number of ways in which they express themselves clinically: (1) acute aseptic (“lymphocytic”) meningitis; (2) a less-common recurrent meningitis; (3) acute encephalitis and meningoencephalitis; (4) ganglionitis (herpes zoster); (5) chronic invasion of nervous tissue by retroviruses, that is, HIV and tropical spastic paraparesis (HTLV-I); (6) acute anterior poliomyelitis; (7) reactivation of chronic viral infections including the viruses causing PML and subacute sclerosing panencephalitis (SSPE).


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


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


Neurology_Adams

Neurology_Adams. Systemic symptoms and signs aside from fever are infrequent and depend mainly on the more mundane effects of the invading virus; these include sore throat, nausea and vomiting, vague weakness, pain in the back and neck, conjunctivitis, cough, diarrhea, vomiting, rash, petechia, hepatitis, adenopathy, or splenomegaly. The childhood exanthems associated with meningitis and encephalitis (varicella, rubella, mumps) produce well-known eruptions and other characteristic signs. An erythematous papulomacular, nonpruritic rash, confined to the head and neck or generalized, may also be a prominent feature, particularly in children, of certain echoviruses and Coxsackie viruses. Adults may also demonstrate a nonspecific rash but this finding is not specific. An enanthem (herpangina), taking the form of a vesiculoulcerative eruption of the buccal mucosa, may also occur with these viral infections.


Neurology_Adams

Neurology_Adams. In milder cases, in the first hours or day of the illness, there may be no abnormalities of the spinal fluid, and the patient may erroneously be thought to have migraine or a headache induced by a systemic infectious illness. Microorganisms cannot be demonstrated by conventional smear or culture but may be detected by polymerase chain reaction, the last of these techniques being employed largely in cryptic cases. As a rule, the glucose content of the CSF is normal; but infrequently, mild depression of the CSF glucose (rarely below 25 mg/dL) occurs with the meningitis caused by mumps, HSV-2, lymphocytic choriomeningitis, or VZV.


Neurology_Adams

Neurology_Adams. Aseptic meningitis is a common occurrence, with an annual incidence of approximately 20 cases per 100,000 population (Beghi et al; Ponka and Pettersson). Most are caused by viral infections. Of these, the most common are from enterovirus—mainly echovirus and Coxsackie virus. These make up 80 percent of cases in which a specific viral cause can be established. HSV-2 is perhaps next in frequency in adults, followed by varicella, HIV, mumps in children, lymphocytic choriomeningitis (LCM), HSV-1, and adenovirus infections. The remainder are due to a variety of agents, including EBV (infectious mononucleosis), cytomegalovirus (CMV,) leptospira, and the bacterium Mycoplasma pneumoniae (see Chap. 31), influenza virus, and in some parts of the world, tick-borne encephalitides and Borrelia, including Lyme (Kupila et al). During local outbreaks anywhere, the dominant agent is usually one of the arboviruses in the family of Flaviviruses.


Neurology_Adams

Neurology_Adams. It is also recognized that infection with HIV may present as acute, self-limited aseptic meningitis with an infectious mononucleosis-like clinical picture. While HIV has been obtained from the CSF in the acute phase of the illness, seroconversion occurs only later, during convalescence from the meningitis (see The HIV-Acquired Immunodeficiency Syndrome (AIDS)). HSV-2 and HSV-1 have been isolated from the CSF of patients with recurrent bouts of benign aseptic meningitis (Mollaret meningitis), but this finding has not been consistent (Steel et al). As discussed in Chap. 44, it is now considered that a virus, particularly HSV-1, also underlies many cases of what has been traditionally considered idiopathic Bell’s palsy.


Neurology_Adams

Neurology_Adams. Two other aspects of the virology of aseptic meningitis should be noted: first, in most published series of cases from virus isolation laboratories, a specific cause cannot be established with conventional testing in one-third or more of cases of presumed viral origin; second, most agents capable of producing aseptic meningitis also sometimes cause encephalitis. Of course, as most cases of aseptic meningitis are self-limited and relatively benign, extensive testing for the etiology is unnecessary. Differential Diagnosis of the Cause of Viral Meningitis


Neurology_Adams

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


Neurology_Adams

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


Neurology_Adams

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


Neurology_Adams

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


Neurology_Adams

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


Neurology_Adams

Neurology_Adams. HSV-2 and HIV may be associated with a cauda equina neuritis and meningitis. In the case of HSV, there is often a preceding genital infection with the virus (see Chap. 42). The presence of sore throat, generalized lymphadenopathy, transient rash, and mild icterus is suggestive of infectious mononucleosis caused by EBV or, at times, CMV infection. Icterus is a prominent manifestation of viral hepatitis and some serotypes of leptospirosis and, at times, of Q fever. Among the bacterial and spirochetal cause of an aseptic meningitis syndrome, leptospirosis, M. pneumoniae, and Lyme borreliosis are notable as discussed in the previous chapter. Certain forms of encephalitis occur particularly in individuals who are immunosuppressed from HIV, chemotherapy for neoplasm, organ transplantation, or hematologic and lymphoid malignancy. The manifestation is usually encephalitis but aseptic meningitis is known to occur. The main causative organisms in this group are HHV-6, CMV, and VZV.


Neurology_Adams

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


Neurology_Adams

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


Neurology_Adams

Neurology_Adams. Panels of serologic tests for the main viruses that cause aseptic meningitis are available; most use complement fixation or enzyme-linked immunosorbent assay (ELISA) techniques; an infection is demonstrated by a fourfold increase in titer from acute to convalescent serum drawn at least 10 days apart, but these, of course, do no more than confirm the diagnosis after the illness has mostly passed. In some instances, elevation of specific IgM antibody directed at an infectious agent is useful. Serologic reactions of CSF for syphilis should be interpreted with caution, because inflammation of many types, including infectious mononucleosis, can produce a false-positive reaction. In the last few years, the polymerase chain reaction (PCR) has been applied to the diagnosis of viral infections of the nervous system, among them being CMV and HSV. The test is most sensitive during the active stage of viral replication, in contrast to serologic tests, which are more accurate later in the course


Neurology_Adams

Neurology_Adams. the nervous system, among them being CMV and HSV. The test is most sensitive during the active stage of viral replication, in contrast to serologic tests, which are more accurate later in the course of the infection. There are numerous false-negative and fewer false-positive PCR tests for CMV, but they are nonetheless useful in some circumstances, such as the early diagnosis of fulminant CMV infection in HIV patients (see later in this chapter). Even more recently, sequencing of DNA from spinal fluid allows comparison to reference sources for a wide variety infectious organisms and the identification of obscure infections in a matter of days or less (see Wilson and Tyler); the findings can then be confirmed by PCR. For the most part, neither serologic nor PCR testing is required in clinical practice.


Neurology_Adams

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


Neurology_Adams

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


Neurology_Adams

Neurology_Adams. have been much the same. These series excluded chemical or irritative meningitis, which should be considered if there had been spinal surgery or infusion of even apparently innocuous substances into the spinal space.


Neurology_Adams

Neurology_Adams. The special problem of chronic neutrophilic meningitis has been mentioned in the preceding chapter in relation to Nocardia, Aspergillus, Actinomyces, or certain Mycobacterium species; other causes include coccidioidomycosis, histoplasmosis, and blastomycosis, (see Peacock, cited in Chap. 31). Also of interest is an unusual group of meningitides with disproportionate numbers (to peripheral blood) of eosinophils. This includes parasitic disorders, Hodgkin lymphoma infiltrating the meninges, widespread cholesterol emboli, and sometimes, with allergic meningitis associated with nonsteroidal anti-inflammatory drugs such as ibuprofen.


Neurology_Adams

Neurology_Adams. A reasonable approach in patients with chronic meningitis is to repeat the lumbar puncture several times to obtain all cultures including for fungi and cytology of CSF, using markers to detect uniform populations of B and T lymphocytes and tumor cells, biochemical tests that are sensitive to neoplastic meningitis (such as b2-microglobulin, lactate dehydrogenase [LDH]), and PCR amplification of herpesviruses, serologic tests mainly for HIV, syphilis, coccidioidomycosis, Brucella, and Lyme disease. MRI of the brain and spinal cord with gadolinium should also be performed to detect parameningeal collections. If hydrocephalus develops, it should be managed along the lines described in Chap. 29.


Neurology_Adams

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


Neurology_Adams

Neurology_Adams. The CSF formula in a number of other chronic or acutely recurring meningitides corresponds to that of aseptic meningitis. These include (1) the Vogt-Koyanagi-Harada syndrome, which is characterized by various combinations of iridocyclitis, depigmentation of a thick swath of hair (poliosis circumscripta) and of the skin, vitiligo, loss of eyelashes, dysacusis, and deafness (the pathologic basis of the syndrome is not known). (2) Mollaret recurrent meningitis, many instances of which have been associated with HSV-1 (Steel) and others (perhaps most) with HSV-2 infection (Cohen et al). The syndrome is characterized by episodes of acute meningitis with severe headache and sometimes low-grade fever, lasting for about 2 weeks, and recurring over a period of several months or years. In a few patients of ours, in whom no virus could be identified in the CSF, antiviral therapy met with some success, although corticosteroids seemed to reduce the severity of acute episodes. A proportion of these


Neurology_Adams

Neurology_Adams. of ours, in whom no virus could be identified in the CSF, antiviral therapy met with some success, although corticosteroids seemed to reduce the severity of acute episodes. A proportion of these cases follow bouts of genital herpes and individual cases have been reported with EBV, herpes-6 in children, and other viruses. A special syndrome that has been associated with HSV-2 is that of aseptic meningitis and bladder failure and vaginal or vulvar pain after a bout of genital herpes (Elsberg syndrome as reviewed by Ellie and colleagues). (3) In some patients, the recurrent attacks are associated with encephalopathy and headache; this is probably identical to the illness called “pseudomigraine with temporary neurological symptoms” by Gomez-Aranda et al and described earlier by Bartleson et al. The entity, also known as HaNDL syndrome (“headache neurologic deficit and lymphocytic pleocytosis”) is allied more closely with the headache syndromes as discussed and cited in Chap. 9. (4)


Neurology_Adams

Neurology_Adams. et al. The entity, also known as HaNDL syndrome (“headache neurologic deficit and lymphocytic pleocytosis”) is allied more closely with the headache syndromes as discussed and cited in Chap. 9. (4) Allergic or hypersensitivity meningitis, in the past occurring in the course of serum sickness and now more commonly of autoimmune diseases such as lupus erythematosus, and in relation to certain medications such as nonsteroidal anti-inflammatory drugs and intravenously administered immunoglobulin. (5) Behçet disease, which is an important acute, recurrent inflammatory CNS disease, particularly in individuals of Middle Eastern origin. It is essentially a diffuse inflammatory disease of small blood vessels that has several other characteristic features such as oral and genital ulcers and is more appropriately considered with the vasculitides in Chap. 33.


Neurology_Adams

Other Causes of Aseptic, Chronic, and

Neurology_Adams. Other Causes of Aseptic, Chronic, and


Neurology_Adams

Neurology_Adams. In addition to the aforementioned bacterial infections that can cause aseptic meningitis, several other categories of disease may cause a sterile, predominantly lymphocytic or mononuclear reaction in the leptomeninges: (1) foci of bacterial infection lying adjacent to the meninges, such as spinal or cranial epidural abscess (parameningeal infection); (2) partially treated bacterial meningitis; (3) meningeal infections in which the organism is difficult or impossible to isolate—fungal and tuberculous meningitis are at times in this category and parasitic infections are in this group; (4) neoplastic invasion of the leptomeninges (lymphomatous and carcinomatous meningitis); (5) granulomatous, vasculitic, or other inflammatory diseases such as sarcoidosis, Behçet disease, and granulomatous angiitis; (6) acute or chronic recurrent inflammatory meningitides as a result of chemical irritation, including an aseptic chemical meningitis incited by rupture of a craniopharyngioma or other cystic


Neurology_Adams

Neurology_Adams. (6) acute or chronic recurrent inflammatory meningitides as a result of chemical irritation, including an aseptic chemical meningitis incited by rupture of a craniopharyngioma or other cystic structure containing proteinaceous fluid—these are described earlier on under the section “Chronic Persistent and Recurrent Meningitis”; (7) rarely, children with a mundane infectious disorders develop meningeal signs and slight pleocytosis, the result of a sterile inflammation that does not involve invasion of the meninges by organisms—the same may occur in bacterial endocarditis; (8) an idiosyncratic, presumably immunologic meningitis as mentioned earlier, may result from the use of nonsteroidal anti-inflammatory drugs, intravenous immune globulin (due probably to a carrier chemical in the solution), and, rarely, from other drugs, including certain antibiotics. Individuals with systemic lupus erythematosus have an increased risk of aseptic meningitic reactions to anti-inflammatory medications.


Neurology_Adams

Neurology_Adams. In respect to the first two categories, parameningeal and partially treated bacterial infections, smoldering paranasal sinusitis or mastoiditis may produce a CSF picture of aseptic meningitis because of epidural or subdural extension into the intracranial compartments; it is infrequent that the entire syndrome of meningitis is present. Uncomplicated sinusitis alone does not cause a meningeal reaction. Antibiotic therapy given for a systemic or pulmonary infection may suppress a bacterial meningitis to the point where mononuclear cells predominate, glucose is near normal, and organisms cannot be cultured from the CSF although they may still be evident by Gram stain. Careful attention to the history of recent antimicrobial therapy permits recognition of these cases.


Neurology_Adams

Neurology_Adams. Syphilis, cryptococcosis, and tuberculosis are the important members of the third group that cause aseptic meningitis and in which the organism may be difficult to culture, as detailed in Chap. 31. Tuberculous meningitis, in its initial stages, may masquerade as innocent aseptic meningitis and the diagnosis may be delayed. Similarly, the diagnosis of cryptococcosis, other fungal infection, or nocardiosis is occasionally missed because the organisms may be present in such low numbers as to be overlooked in smears, especially in HIV patients. Brucellosis (Mediterranean fever, Malta fever) is a rare disease that may present as an acute meningitis or meningoencephalitis, with the CSF findings of aseptic meningitis. The diagnosis depends on the detection of high serum antibody titers and Brucella-specific immunoglobulins, using the ELISA or serum agglutination testing. There are also new genetic detection techniques, alluded to earlier, that may expose the cause of an otherwise obscure


Neurology_Adams

Neurology_Adams. immunoglobulins, using the ELISA or serum agglutination testing. There are also new genetic detection techniques, alluded to earlier, that may expose the cause of an otherwise obscure meningitis (see Wilson et al).


Neurology_Adams

Neurology_Adams. In the neoplastic group, leukemias and lymphomas are the most common sources of meningeal infiltrations. In children, leukemic “meningitis” with cells (lymphoblasts or myeloblasts) in the CSF numbering in the thousands may occur. In leptomeningeal metastases (carcinomatous meningitis), neoplastic cells extend throughout the leptomeninges and involve cranial and spinal nerve roots, producing a picture of meningoradiculitis with normal or low CSF glucose values. There is also a primary CNS lymphomatous meningitis. Lymphocytic meningitis that is accompanied by cranial-nerve palsies may prove to be tuberculous if the patient is febrile and the CSF glucose is low (or even without these signs in an endemic area); it is likely to be neoplastic if the patient is afebrile and the CSF glucose is normal or mildly decreased. Concentrated cytologic preparations and tumor cell markers may permit identification of the tumor cells. Chapter 30 discusses neoplastic meningitis in detail.


Neurology_Adams

Neurology_Adams. Occlusion of many small cerebral blood vessels by cholesterol emboli may also excite a reaction in meningeal vessels and a pleocytosis that includes eosinophils. In summary, the temporal history of the illness, associated clinical findings, and laboratory tests usually provide clues to the diagnosis of nonviral and chronic forms of aseptic meningitis. It is useful to keep in mind the possibility of neoplasia, HIV, tuberculosis, cryptococcosis, sarcoidosis, syphilis, borreliosis, allergic reactions, parameningeal collection, and inadequately treated bacterial meningitis—each of which presents an urgent diagnostic problem.


Neurology_Adams

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


Neurology_Adams

Neurology_Adams. Rarely have they caused demonstrable postmortem cerebral lesions, and surviving patients have no residual neurologic signs. Conversely, several agents, notably the arboviruses, may cause encephalitic lesions with only mild meningeal symptoms.


Neurology_Adams

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


Neurology_Adams

Neurology_Adams. Differentiation of viral from postinfectious encephalitis (See Also Chap. 35). The acute encephalitis syndrome described above may take two forms: the more common direct invasion of brain and meninges (true viral encephalitis) and a postinfectious encephalomyelitis that is presumably based on an autoimmune reaction to the systemic viral infection but in which virus is not present in neural tissue. The distinction between postinfectious encephalomyelitis and infectious encephalitis may be difficult, especially in younger patients who have a proclivity to develop the postinfectious variety with fever. The latter, termed acute disseminated encephalomyelitis (ADEM), occurs after a latency of several days, as the infectious illness is subsiding. It is expressed by a low-grade fever and cerebral symptoms such as confusion, seizures, coma, or ataxia. The spinal fluid shows slight inflammation and elevation of protein—sometimes a more intense reaction, and there are usually characteristic


Neurology_Adams

Neurology_Adams. symptoms such as confusion, seizures, coma, or ataxia. The spinal fluid shows slight inflammation and elevation of protein—sometimes a more intense reaction, and there are usually characteristic confluent, scattered, bilateral lesions in the white matter in imaging studies, findings that differ from those of viral encephalitis. When there is no coexistent epidemic of encephalitis to suggest the diagnosis, or the preceding systemic illness is absent or obscure, a differentiation between the two may not be possible on clinical grounds alone. The fever is generally higher in the infectious type but even this difference does not always hold in young children with ADEM. The encephalitis that follows certain childhood exanthems (postexanthematous) and vaccinations at any age (postvaccinal) are essentially forms of ADEM.


Neurology_Adams

Neurology_Adams. Because ADEM is predominantly an inflammatory and demyelinative process, we mention it here but discuss its clinical features and imaging more fully in Chap. 35, with the other demyelinating diseases such as multiple sclerosis, with which it shares some features. We also place in special categories further on the now rare Reye syndrome of postinfectious acute encephalopathy with hepatic failure that follows influenza, and other viral infections and postinfectious cerebellitis. Whereas numerous viral, bacterial, fungal, and parasitic agents are cited as causes of the encephalitis syndrome, only the viral ones are considered here, for they are the most common and it is to these that one usually refers when the term encephalitis is used. The nonviral forms (mycoplasmal, rickettsial, Lyme, etc.) are considered in Chap. 31, under “Encephalitis Caused by Bacterial Infections,” and should be reviewed with this section.


Neurology_Adams

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


Neurology_Adams

Neurology_Adams. The types of viral encephalitis that occur with sufficient frequency to be of clinical importance are relatively few. HSV is by far the most common sporadic cause of encephalitis and has no seasonal or geographic predilections. Its age distribution is slightly skewed and biphasic, affecting persons mainly between ages 5 and 30 years and those older than age 50 years. Many other viruses, exemplified by the arboviral encephalitides, have a characteristic geographic and seasonal incidence. The most important of these is the Japanese encephalitis serogroup (Flaviviruses), of which the now common West Nile virus is a member. In recent outbreaks in the United States, the West Nile virus has been more frequent than any of the other arboviruses and has had a wide geographic distribution (Solomon). In the United States, eastern equine encephalitis, as the name implies, is observed mainly in the eastern states and on both the Atlantic and Gulf coasts. Western equine encephalitis is fairly


Neurology_Adams

Neurology_Adams. In the United States, eastern equine encephalitis, as the name implies, is observed mainly in the eastern states and on both the Atlantic and Gulf coasts. Western equine encephalitis is fairly uniformly distributed west of the Mississippi. St. Louis encephalitis, another arthropod-borne late-summer encephalitis, occurs nationwide but especially along the Mississippi River in the South; outbreaks occur in August through October, slightly later than is customary for the other arboviruses. Venezuelan equine encephalitis is common in South and Central America; in the United States it is practically confined to Florida and the southwestern states. California virus encephalitis predominates in the northern Midwest and northeastern states. After West Nile, the La Crosse variety had in the past been the most frequent identifiable arbovirus encephalitis in the United States.


Neurology_Adams

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