Until comparatively recently, the nonvenereal spirochetes were of little interest to neurologists of the Western world. Yaws, pinta, and endemic syphilis rarely, if ever, affected the nervous system. Leptospirosis was essentially an acute liver disease, with only one variant causing nonicteric lymphocytic meningitis; tick- and louse-borne relapsing fevers were medical curiosities that did not involve neurologists. However, in the late 1970s, a multisystem disease with prominent neurologic features was recognized in the eastern United States (it had been known in Northern Europe). It was named after the town of Lyme, Connecticut, where a cluster of cases was first recognized in 1975. An early skin manifestation of the disease had previously been described in Western Europe and referred to as erythema chronicum migrans. In 1982, Burgdorfer and colleagues identified the causative spirochetal agent, Borrelia burgdorferi. Later manifestations of the disease—taking the form of acute radicular pain followed by chronic lymphocytic meningitis and frequently accompanied by peripheral and cranial neuropathies—had long been known in Europe as the Bannwarth or Garin-Bujadoux syndrome. The identity of these diseases has been established, as well as their close relationship to relapsing fever—a disease that is also caused by spirochetes of the genus Borrelia and transmitted by ticks. The entire group is now classed as the borrelioses.
In humans, all these spirochetoses induce a subacute or chronic illness that evolves in ill-defined stages, with early spirochetemia, vascular damage in many organs, and a high level of neurotropism. As in syphilis, the nervous system is invaded early in the form of asymptomatic meningitis. Later, neurologic abnormalities appear, but only in a proportion of such cases. The early neurologic complications are mainly derivations of meningitis. In this disease, unlike syphilis, peripheral and cranial nerves are often damaged (see further on and Chap. 46). Immune factors may be important in the later phases of the disease and in the development of the neurologic syndromes.
Lyme disease is less acute than leptospirosis (Weil disease) and less chronic than syphilis. It successively involves the skin, nervous system, heart, and articular structures over a period of a year or longer. The responsible organism, as stated above, is the spirochete B. burgdorferi and the vector in the United States is the common ixodid tick. The precise roles of the infecting spirochete, the antibodies it induces, and other features of the human host response in the production of clinical symptoms and signs are not fully understood, but the development of an animal model by Pachner and colleagues suggests that there is a chronic form of Borrelia infection.
Lyme borreliosis has a worldwide distribution but the typical neurologic manifestations differ slightly in Europe and America, as emphasized in the review by Garcia-Monico and Benach. In the United States, where approximately 15,000 cases are reported annually, the disease is found mainly in the Northeast and the North Central states. Most infections are acquired from May to July. In 60 to 80 percent of cases, a skin lesion (erythema chronicum migrans, or erythema migrans) at the site of a tick bite is the initial manifestation, occurring within 30 days of exposure. It is a solitary, enlarging, ring-like erythematous lesion that may be surrounded by annular satellite lesions. Usually fatigue and influenza-like symptoms (myalgia, arthralgia, and headache) are associated, and these seem to be more prominent in the North American than the European form of the illness—possibly attributable to a more virulent species of spirochete (Nadelman and Wormser). This assumes importance in patients who may have acquired the illness in another part of the world in whom the correct diagnosis may be missed if the specific antibody for the regional organism is not sought.
Weeks to months later, neurologic or cardiac symptoms appear in 15 and 8 percent of the cases, respectively. Still later, if the patient remains untreated, arthritis or, more precisely, synovitis develops in approximately 60 percent of the cases. Death from this disease does not occur; consequently, little is known of the pathology. A long period of disability is to be expected if the disease is not recognized and treated.
Diagnosis is not difficult during the summer season in regions where the disease is endemic and when all the clinical manifestations are present. But in some cases, a skin lesion is not observed or may have been forgotten, or there may have been only a few or no secondary lesions and the patient is first seen in the neurologic phase of the illness. Then clinical diagnosis may be difficult.
The usual pattern of neurologic involvement is one of aseptic meningitis or a fluctuating meningoencephalitis with cranial or peripheral neuritis, lasting for months (Reik). By the time the neurologic disturbances appear, the systemic symptoms and skin lesions may have long since receded. A cardiac disorder, which may accompany or occur independently of the neurologic changes, takes the form of myocarditis, a pericarditis, or an atrioventricular block.
The initial nervous system symptoms are rather nonspecific. They consist of headache, mild stiff neck, nausea and vomiting, malaise, and chronic fatigue, fluctuating over a period of weeks to months. These symptoms relate to the meningitis. There is a CSF lymphocytosis with cell counts from 50 to 3,000/mL and protein levels from 75 to 400 mg/dL, but both values are typically in the lower part of the range. Polymorphonuclear cells may be prominent in the early part of the illness. Usually the glucose content is normal. Somnolence, irritability, faulty memory, depressed mood, and behavioral changes have been interpreted as marks of encephalitis but are difficult to separate from the effects of meningitis. Seizures, choreic movements, cerebellar ataxia, and dementia have been reported but are infrequent. A myelitic syndrome, causing quadriparesis, is also documented.
In about half the cases, cranial neuropathies become manifest within weeks of onset of the illness. The most frequent is a unilateral or bilateral facial palsy but involvement of other cranial nerves, including the abducens and optic nerve has been observed, usually in association with meningitis. One-third to one-half of the patients with meningitis have multiple radicular or peripheral nerve lesions in various combinations. These are described in Chap. 46. In addition to facial palsies, a severe and painful meningoradiculitis of the cauda equina (Bannwarth syndrome) is particularly characteristic and seems to be more common in Europe than in the United States (there are other causes of this syndrome, including herpesvirus and cytomegalovirus). There is also an infrequent occurrence of Guillain-Barré syndrome following Lyme infection, but there is no reason to believe that the illness then differs from other cases of the acute inflammatory demyelinating polyneuropathy that follows numerous other infections.
Because of the paucity of autopsy material, knowledge of the nature of Lyme encephalitis is still imprecise. Such pathologic material as is available has shown a perivascular lymphocytic inflammatory process of the leptomeninges and the presence of subcortical and periventricular demyelinative lesions, like those of multiple sclerosis (Fig. 32-6). Oksi and colleagues have recovered B. burgdorferi DNA from the involved areas, suggesting that the encephalitis is caused by direct invasion by the spirochete.
In the peripheral nerves (see Chap. 46) there are scattered lymphocytic infiltrates, without vasculitis. It seems likely to us that the organism will eventually be found in nervous tissue as the cause of disease, as there is active antibody production reflected in the CSF.
A problematic aspect of Lyme disease relates to the development in some patients of a mild chronic encephalopathy coupled with extreme fatigue. That such a disorder may occur after a well-documented attack of Lyme disease is undoubted. However, in the absence of a history of the characteristic rash, arthritis, or aseptic meningitis, the attribution to Lyme disease of fatigue alone or various other vague mental symptoms, such as difficulty in concentration, is almost always erroneous, even if there is serologic evidence of exposure to the spirochete. It would be an understatement that a large number of patients are persuaded that various symptoms are the result of Lyme infection and seek and receive unnecessary treatment.
In acute and subacute cases that involve the spinal or cranial nerve roots or spinal cord, the CSF routinely shows a pleocytosis (20 to 250 lymphocytes/mm3) with moderately elevated protein; the glucose concentration is usually normal but may be slightly depressed. The majority of cases with facial palsy alone are associated with this CSF formula, but there are exceptions.
Serologic tests are of great value but must be interpreted with caution if there has not been an inciting clinical syndrome of erythema migrans or arthritis or a well-documented tick bite. The most valuable initial screening is performed by the ELISA; if both acute and convalescent sera are tested, approximately 90 percent of patients have a positive IgM response. After the first few weeks, most patients have elevated IgG antibody responses to the spirochete (Berardi et al); a positive test of this nature may simply reflect prior exposure. The ratio of IgG intrathecal anti-Borrelia antibody to that of the serum is greater than 2 in cases of neuroborreliosis; this elevated ratio is a necessary criterion for the diagnosis in Europe. However, Blanc and colleagues studied a sample of 123 consecutive patients with clinical signs of neurologic involvement and found the sensitivity of the index was only 75 percent and the specificity was 97 percent. These authors have proposed more pragmatic diagnostic, but somewhat contrived, criteria for neuroborreliosis, consisting of the presence of 4 of the following 5 items: no past history of neuroborreliosis, active CSF ELISA serology, anti-Borrelia antibody index greater than 2, favorable outcome after specific antibiotic treatment, and no alternative diagnosis. False-positive tests do occur in some of the conditions that react to syphilitic reagin; B. burgdorferi–specific antibodies can also be demonstrated in the CSF (these are also reflected by the presence of oligoclonal bands).
Positive ELISA testing should be pursued further with Western blot or immunoblot analysis or other more specific serologies in clinically uncertain cases. Although these latter tests are difficult to carry out and have not been standardized, the presence of both IgG and IgM antibodies is strongly supportive of a recent infection, whereas the IgG is useful in later cases. These complex laboratory diagnostic issues are discussed and put in perspective by Golightly.
In only approximately 30 percent of cases, the organism can be detected in the spinal fluid using PCR techniques, usually early in the neurologic illness.
In the chronic phase of the disease, CT and MRI in cases of encephalopathy may display multifocal and periventricular cerebral lesions (see Fig. 32-6) but these are by no means indicative alone of Lyme disease, as they also appear in numerous other conditions.
The recommended treatment in the first stage of the disease, mainly referring to the presence of facial or other cranial nerve palsies alone, is oral or doxycycline (100 mg bid). Alternate therapies include amoxicillin 500 mg tid or cefuroxime axetil 500 mg bid. CNS cardiac and arthritic disease can thereby be prevented in almost all cases. (It follows that one is justified in being suspect of cases of "late Lyme" that have undergone adequate early treatment.) Once the meninges and central or peripheral nervous system are implicated, high-dose penicillin, 20 million units daily for 10 to 14 d, or, probably more effective, ceftriaxone, 2 g daily, is usually given intravenously for a similar period.
Tetracycline, 500 mg qid for 30 d, is recommended by Reik for patients who are allergic to these intravenous drugs. Other alternative drugs are cefotaxime 2 g IV q8h and penicillin G 18 to 20 million units per day in divided doses q4h. For late abnormalities, no treatment has proved to be effective. However, most of the symptoms tend to regress regardless of the type of treatment given.
According to Kaiser, more than 90 percent of subacute neuropathies and facial palsies resolve by 1 year after treatment, but a lower proportion of spastic and ataxic myelopathy cases are improved. In other studies, up to a fifth of children with facial palsies have residual weakness.
This systemic spirochetal infection, caused by Leptospira interrogans, is characterized primarily by hepatitis but may include aseptic meningitis during the second part of a biphasic illness. Initially there is high fever, tender muscles, chest and abdominal pain, and cough. An extreme form (Weil disease) comprises hepatic and renal failure. Prominent conjunctival suffusion and photophobia are typical of leptospirosis and should draw attention to the diagnosis. The CSF during the meningitic stage contains approximately 100 lymphocytes/mm3, but cell counts in excess of 10,000 have been reported and the protein concentration may reach high levels. Subarachnoid and intracerebral bleeding, probably from inflamed blood vessels, is known to occur. The diagnosis is made by serologic methods (complement fixation screening followed by specific agglutination tests). Antibiotic treatment seems to be effective only if implemented during the initial febrile phase. The meningitis is usually self-limited.
Fungal Infections of the Nervous System
Described in the following pages are a number of infectious diseases, much less common than bacterial ones, in which a systemic fungal infection secondarily involves the CNS. For the neurologist, the diagnosis rests on two lines of clinical information: evidence of infection in the lungs, skin, or other organs and the appearance of a subacute meningeal or multifocal encephalitic disorder. Although a large number of fungal diseases may involve the nervous system, only a few do so with regularity. Of 57 cases assembled by Walsh and coworkers, there were 27 of candidiasis, 16 of aspergillosis, and 14 of cryptococcosis. Among the opportunistic mycoses (see below), the majority is accounted for by species of Aspergillus and Candida. Mucormycosis and coccidioidomycosis are less frequent, and blastomycosis and actinomycosis (Nocardia) occur in isolated instances. However, of all of these infections, cryptococcal meningitis, which can occur in immunocompetent patients, is being seen more frequently as a result of its association with AIDS. Infections related to impairment of the body's protective mechanisms are referred to as opportunistic and include not only fungal infections but also those caused by certain bacteria (Pseudomonas and other gram-negative organisms, L. monocytogenes), protozoa (Toxoplasma), and viruses (cytomegalovirus, herpes simplex, and varicella zoster). It follows that these types of infections should be considered in the aforementioned clinical situations.
Fungal infections of the CNS may arise without obvious predisposing cause, but they typically complicate some other disease process such as AIDS, organ transplantation, severe burns, leukemia, lymphoma or other malignancy, diabetes, collagen vascular disease, or prolonged corticosteroid therapy. The factors operative in these clinical situations are the interference with the body's normal flora and impaired T-cell and humoral responses. Thus fungal infections tend to occur in patients with leukopenia, inadequate T-lymphocyte function, or insufficient antibodies.
Fungal meningitis develops insidiously, as a rule, over a period of several days or weeks, similar to tuberculous meningitis; the symptoms and signs are also much the same as with tuberculous infection. Involvement of several cranial nerves, arteritis with thrombosis and infarction of brain, multiple cortical and subcortical microabscesses, and hydrocephalus frequently complicate the course of fungal meningitis, just as they do in all chronic meningitides. Sometimes the patient is afebrile or has only intermittent fever.
The spinal fluid changes in fungal meningitis are like those of tuberculous meningitis. Pressure is elevated to a varying extent, pleocytosis is moderate and lymphocytes predominate. Exceptionally, in acute cases, a pleocytosis above 1,000/mm3 and a predominant polymorphonuclear response are observed (especially nocardia and actinomyces). On the other hand, in patients with AIDS or with pronounced leukopenia for other reasons, the pleocytosis may be minimal or even absent. Glucose is subnormal and protein is elevated, sometimes to very high levels.
The specific diagnosis is made from smears of the CSF sediment, from cultures and by demonstrating antigens of the organism by immunodiffusion, latex particle agglutination, or comparable antigen recognition tests. The CSF examination should also include a search for tubercle bacilli and abnormal white cells because of the not infrequent concurrence of fungal infection and tuberculosis, leukemia, or lymphoma.
Some of the special features of the more common fungal infections are indicated below.
Cryptococcosis (Torulosis, European Blastomycosis)
Cryptococcosis (formerly called torulosis) is one of the more frequent fungal infections of the CNS. Cryptococcus is a common soil fungus found in the roosting sites of birds, especially pigeons. Usually the respiratory tract is the portal of entry, less often the skin and mucous membranes. The pathologic changes are those of granulomatous meningitis; in addition, there may be small granulomas and cysts within the cerebral cortex, and sometimes larger granulomas and cystic nodules deep in the brain (cryptococcomas). The cortical cysts contain a gelatinous material and large numbers of organisms; the solid granulomatous nodules are composed of fibroblasts, giant cells, aggregates of organisms, and areas of necrosis.
Cryptococcal meningitis has an indistinct clinical syndrome. Most cases evolve subacutely, like other fungal infections and tuberculosis. In most cases, headaches, fever, and stiff neck are lacking altogether, and the patient presents with symptoms of gradually increasing intracranial pressure because of hydrocephalus (papilledema is present in half such patients) or with a confusional state, dementia, cerebellar ataxia, or spastic paraparesis, usually without other focal neurologic deficit. A few cases have had an explosive onset, rendering the patient quite ill in a day. Large series of affected patients indicate that 20 to 40 percent of patients have no fever when first examined (the figure applies to patients without AIDS). Cranial nerve palsies are infrequent. Rarely, a granulomatous lesion forms in one part of the brain, and the only clue to the etiology of the cerebral mass is a lung lesion and an abnormality of the CSF.
Meningovascular lesions, presenting as small deep strokes in an identical manner to meningovascular syphilis, may be superimposed on the clinical picture. A pure motor hemiplegia, like that caused by a hypertensive lacune, has been the most common type of stroke in our experience.
The course of the disease is quite variable. It may be fatal within a few weeks if untreated. More often, it is steadily progressive over a period of several weeks or months; in a few patients, it may be remarkably indolent, lasting for years, during which there may be periods of clinical improvement and normalization of the CSF. Lymphoma, Hodgkin disease, leukemia, carcinoma, tuberculosis, and other debilitating diseases that alter the immune responses are predisposing factors in as many as half the patients. As already emphasized, patients with AIDS are particularly vulnerable to cryptococcal infection; estimates are that 6 to 12 percent of AIDS patients are subject to meningoencephalitis with the organism.
The spinal fluid shows a variable lymphocytic pleocytosis, usually less than 50 cells/mm3, but there may be few or no cells in a patient with AIDS (two-thirds have 5 or fewer cells/mm3). The initial CSF formula may display polymorphonuclear cells but it rapidly changes to a lymphocytic predominance. The glucose is reduced in three-fourths of cases (again, it may be normal in AIDS patients) and the protein may reach high levels.
Specific diagnosis in developed regions depends upon finding Cryptococcus neoformans antigens in the CSF. The organism may also be seen as spherical cells, 5 to 15 m in diameter, which retain Gram stain and are surrounded by a thick, refractile capsule. India ink preparations are distinctive and diagnostic in experienced hands (debris and talc particles from the gloves used in lumbar puncture may be mistaken for the organism) but the rate of positive tests under the best circumstance is 75 percent. The carbon particles of the dye fail to penetrate the capsule, leaving a wide halo around the doubly refractile wall of the organism. Large volumes of CSF (20 to 40 mL) may be needed to find the organism, but in others they are prolific. The search for these organisms is particularly important in AIDS patients, in whom the CSF values for cells, glucose, and proteins may be entirely normal. A latex agglutination test for the cryptococcal polysaccharide antigen in the CSF is now widely available and gives rapid results. The latter test, if negative, excludes cryptococcal meningitis with approximately 90 percent reliability in AIDS patients and slightly less in others (Chuck and Sande). In most cases the organisms grow readily in Sabouraud glucose agar at room temperature and at 37°C (98.6°F), but these results may not appear for days. Newer enzyme-linked immunoadsorption tests are being evaluated.
The principal diseases to be considered in diagnosis are tuberculous meningitis; granulomatous cerebral vasculitis (normal glucose values in CSF); unidentifiable forms of viral meningoencephalitis (normal CSF glucose values); sarcoidosis; and lymphomatosis or carcinomatosis of meninges (neoplastic cells in CSF).
In patients without AIDS, this consists of intravenous administration of amphotericin B, given in a dose of 0.5 to 0.7 mg/kg/d. Intrathecal administration of the drug in addition to the intravenous route appears not to be essential. Administration of the drug should be discontinued if the blood urea nitrogen reaches 40 mg/dL and resumed when it descends to normal levels. Renal tubular acidosis also frequently complicates amphotericin B therapy. The addition of flucytosine (150 mg/kg/d) to amphotericin B results in fewer failures or relapses, more rapid sterilization of the CSF, and less nephrotoxicity than the use of amphotericin B alone because it permits the reduction of the amphotericin dose to 0.3 to 0.5 mg/kg/d. Both medications are usually continued for at least 6 weeks—longer if CSF cultures remain positive.
However, this regimen, which has a success rate of 75 to 85 percent in immunocompetent patients, has proven to be much less effective in patients with AIDS. The recommended treatment in these circumstances is amphotericin supplemented by flucytosine for 2 weeks. Subsequently, fluconazole, an oral triazole antifungal agent, is given in a dosage up to 400 mg daily (or less preferably, oral itraconazole), for up to 1 year or indefinitely to prevent relapse (Saag et al; Powderly et al). The optimum use of these drugs has not been settled, and some trials have yielded ambiguous results in both AIDS and other patients. A current perspective on treatment can be obtained in the reference of Tunkel and Scheld.
Mortality from cryptococcal meningoencephalitis, even in the absence of AIDS or other disease, is approximately 40 percent.
Candidiasis is probably the most frequent type of opportunistic fungus infection. The notable antecedents of Candida sepsis are severe burns and the use of total parenteral nutrition, especially in children. Urine, blood, skin, and particularly the heart (myocardium and valves) and lungs (alveolar proteinosis) are the usual sites of primary infection. No special features distinguish this fungal infection from others; meningitis, meningoencephalitis, and cerebral abscess, usually multiple and small, are the main modes of clinical presentation. Generally, the CSF contains several hundred (up to 2,000) cells/mm3. Yeast can be seen on direct microscopy in half the cases. Even with treatment (intravenous amphotericin B), the prognosis is extremely grave.
In most instances, this fungal infection has presented as a chronic sinusitis (particularly sphenoidal), with osteomyelitis at the base of the skull or as a complication of otitis and mastoiditis. Cranial nerves adjacent to the infected bone or sinus may be involved. We have also observed brain abscesses and cranial and spinal dural granulomas. In one of our patients, the Aspergillus organisms had formed a granulomatous mass that compressed the cervical spinal cord. Aspergillosis does not present as meningitis but hyphal invasion of cerebral vessels may occur, with thrombosis, necrosis, and hemorrhage; i.e., it is an infectious vasculitis. In some cases, the infection is acquired in the hospital, and in most it is preceded by a pulmonary infection that is unresponsive to antibiotics. Diagnosis can often be made by finding the organism in a biopsy specimen or by culturing it directly from a lesion. Also, specific antibodies are detectable in the blood.
Amphotericin B in combination with 5-fluorocytosine and imidazole drugs is the recommended treatment, but this regimen is not as effective for aspergillosis as it is for cryptococcal disease. The addition of itraconazole, 200 mg bid, in less-immunocompromised patients is recommended. If amphotericin B is given after surgical removal of the infected material, some patients recover.
Mucormycosis (Zygomycosis, Phycomycosis)
This is a malignant infection of cerebral vessels with one of the Mucorales. It occurs as a rare complication in patients with diabetic acidosis, in drug addicts, and in those with leukemia and lymphoma, particularly those treated with corticosteroids and cytotoxic agents.
The cerebral infection begins in the nasal turbinates and paranasal sinuses and spreads from there along infected vessels to the retroorbital tissues (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 amphotericin B have resulted in recovery in some patients.
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.
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.
A similar type of meningitis may occasionally complicate histoplasmosis, blastomycosis, and 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. 33). The CSF yields an organism in a minority of patients, so that diagnosis depends upon 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. Penicillin is the treatment for actinomycosis; amphotericin B and supplemental antifungal agents are used in the others. Intrathecal amphotericin is administered in patients who relapse.
Infections Caused by Rickettsias, Protozoa, and Worms
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 200 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.
The following are the major rickettsial diseases:
Epidemic typhus, small pockets of which are present in many undeveloped parts of the world. It is transmitted from lice to humans and from person to person.
Murine (endemic) typhus, which is present in the same areas as Rocky Mountain spotted fever (see below). It is transmitted by rat fleas from rats to humans.
Scrub typhus or tsutsugamushi fever, which is confined to eastern and southeastern Asia. It is transmitted by mites from infected rodents or humans.
Rocky Mountain spotted fever, first described in Montana, is most common in Long Island, Tennessee, Virginia, North Carolina, and Maryland. It is transmitted by special varieties of ticks.
Q fever, which has a worldwide distribution (except for the Scandinavian countries 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.
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.
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.
Q fever, unlike the other rickettsioses, is not associated with an exanthem or agglutinins for the Proteus bacteria (Felix-Weil reaction). 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 the illness usually recover completely; a few are left with residual neurologic signs.
This consists of the administration of chloramphenicol or tetracycline, which is 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.
This disease is caused by Toxoplasma gondii, a tiny (2- to 5-m), obligate, intracellular parasite that is readily recognized in Wright- or Giemsa-stained preparations. It has assumed great importance in recent decades because of the frequency with which it involves the brain in patients with AIDS. 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. (Mothers can be assured, therefore, that there is no 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 in AIDS patients occur in the absence of an obvious source.
The congenital infection has attracted attention because of its severe destructive effects on the neonatal brain, as discussed in Chap. 38. 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 only several weeks or months later. Most infants succumb; others survive with varying degrees of the aforementioned abnormalities.
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 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, collagen vascular 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 AIDS (see Chap. 33). Frequently, the symptoms and signs of infection with Toxoplasma are assigned to the primary disease with which toxoplasmosis is associated, and an opportunity for effective therapy is missed.
The clinical picture in patients without AIDS varies. There may be a fulminant, widely disseminated infection with a rickettsia-like rash, encephalitis, myocarditis, and polymyositis. Or the neurologic signs may consist only of myoclonus and asterixis, suggesting a metabolic encephalopathy. Often, there are signs of a meningoencephalitis, i.e., seizures, mental confusion, meningeal irritation, coma, and a lymphocytic pleocytosis and increased CSF protein. The brain in such cases shows foci of inflammatory necrosis (Fig. 32-7), 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. Or a nodular lesion is detected on MR or CT imaging that is performed for other reasons.
A presumptive diagnosis can be made on the basis of a rising antibody titer or a positive IgM indirect fluorescent antibody or other serologic test. The diagnosis may be confirmed by the infrequent finding of organisms in CSF sediment and in biopsy specimens of muscle or lymph node. Patients with AIDS and those who are otherwise immunocompromised, however, usually do not display an antibody response or an elevation of titers (those with lymphoma do have positive serologic tests). Excepting AIDS cases, a clinical syndrome and radiologic features that are consistent with toxoplasmosis and a greatly elevated IgG titer are thought to be diagnostic. In the setting of AIDS, patients with multiple nodular or ring-enhancing brain lesions are treated initially with antibiotics for toxoplasmosis, and further evaluation (mainly for cerebral lymphoma) is undertaken only if there is no response, as discussed in Chap. 33.
All patients with a presumptive diagnosis should be treated with oral sulfadiazine (4 g initially, then 2 to 6 g daily) and pyrimethamine (100 to 200 mg initially, then 25 mg daily). Leucovorin, 2 to 10 mg daily, should be given to counteract the antifolate action of pyrimethamine. Treatment must be continued for at least 4 weeks. In patients with AIDS, treatment is continued until the CD4 count exceeds 200 to 250 for 6 months or more; otherwise treatment must be lifelong so as to prevent relapses.
This disease is caused by free-living flagellate amebae, usually of the genus Naegleria and less frequently of the genus Hartmannella (Acanthamoeba and Balamuthia mandrillaris). They are acquired by swimming in ponds or lakes where the water is contaminated. One outbreak in Czechoslovakia followed swimming in a chlorinated indoor swimming pool. Most of the cases in the United States have occurred in the Southeastern states. As of 1989, more than 140 cases of primary amebic meningoencephalitis caused by Naegleria fowleri and more than 40 cases caused by the less-virulent Acanthamoeba had been reported (Ma et al).
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. 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.
Autopsy discloses purulent meningitis and numerous quasigranulomatous microabscesses in the underlying cortex.
Subacute and chronic amebic meningoencephalitis is a rare disease in humans. Isolated instances, caused by Hartmannella species, have been reported in debilitated and immunosuppressed patients (Gonzalez et al). Usually these patients will have amebic abscesses in the liver, and sometimes in the lung and brain. The organism can be cultured from the CSF during periods of recurrent seizures and confusion. 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 amebae that could have been easily mistaken for macrophages or cellular debris; the organism proved to be Balamuthia.
Treatment with the usual antiprotozoal agents is largely ineffective. Because of the in vitro sensitivity of Naegleria to amphotericin B, this drug should be used by the same schedule as for cryptococcal meningitis. With such a regimen in combination with rifampin, recovery is sometimes possible.
A number of other protozoal diseases are of great importance in tropical regions. One is cerebral malaria, which complicates approximately 2 percent of cases of falciparum 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. Cerebral capillaries and venules are packed with parasitized erythrocytes and the brain is dotted with small foci of necrosis surrounded by glia (Dürck nodes). 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).
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, 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.
Quinine, chloroquine, 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. It has been stated that the administration of large doses of dexamethasone, given as soon as cerebral symptoms appear, may be lifesaving, but most studies, including those of our colleagues, express the view that corticosteroids are ineffective. Exchange transfusions may confer a small benefit on survival in severe cases.
This is a common disease in equatorial Africa and in Central and South America. The African type ("sleeping sickness") is caused by Trypanosoma brucei and is transmitted by several species of the tsetse fly. There has been an alarming increase in this disease in sub-Saharan Africa during the last two decades. The infection begins with a chancre at the site of inoculation and localized lymphadenopathy. Posterior cervical adenopathy is highly characteristic of 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 stage of dissemination, usually in the second year of the infection, the trypanosomes 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, vacant facial expression, and in some, ptosis and ophthalmoplegia, dysarthria, and then muteness, seizures, progressive apathy, stupor, and coma.
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. The sequence of local lymphadenopathy, hematogenous dissemination, and chronic meningoencephalitis is like that of African trypanosomiasis. Serologic tests are available to confirm the diagnosis.
Treatment is with pentavalent arsenicals, mainly melarsoprol, which are more effective in the African than in the South American form of the disease. An encephalopathy occurs in 10 percent of cases during the institution of treatment. 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, lethal in between 50 and 75 percent of cases. Unusually high rates of relapse are being reported after treatment. A review of the subject of trypanosomiasis has been given by Barrett and colleagues, who also discuss the important topic of vector control.
Diseases Caused by Nematodes
Parasitic Causes of Central Nervous System Lesions