Neurology_Adams

Neurology_Adams. Localized inflammatory exudate, septic thrombosis of vessels, and aggregates of degenerating leukocytes represent the early reaction to bacterial invasion of the brain. Surrounding the necrotic tissue are macrophages, astroglia, microglia, and many small veins, some of which show endothelial hyperplasia, contain fibrin, and are cuffed with polymorphonuclear leukocytes. There is interstitial edema in the surrounding white matter. At this stage, which is rarely observed postmortem, the lesion is poorly circumscribed and tends to enlarge by a coalescence of inflammatory foci. The term cerebritis is loosely applied to this local suppurative encephalitis or immature abscess.


Neurology_Adams

Neurology_Adams. Within several days, the intensity of the reaction begins to subside and the infection tends to become delimited. The center of the abscess takes on the character of pus; at the periphery, fibroblasts proliferate from the adventitia of newly formed blood vessels and form granulation tissue, which is readily identified pathologically within 2 weeks of the onset of the infection but it is evident earlier as restriction of diffusion on MRI (see Fig. 31-2). As the abscess becomes more chronic, the granulation tissue is replaced by collagenous connective tissue. It has also been noted, both in experimental animals and in humans, that the capsule of the abscess is not of uniform thickness, frequently being thinner on its medial (paraventricular) aspect. These factors account for the propensity of cerebral abscesses to spread deeply into the white matter and to produce daughter abscesses or a chain of abscesses and extensive surrounding cerebral edema. In some instances, the process


Neurology_Adams

Neurology_Adams. of cerebral abscesses to spread deeply into the white matter and to produce daughter abscesses or a chain of abscesses and extensive surrounding cerebral edema. In some instances, the process culminates in a catastrophic rupture into the ventricles.


Neurology_Adams

Neurology_Adams. Headache is probably the most frequent initial symptom of intracranial abscess but this varies and a considerable number of cases are revealed incidentally. Other early symptoms, roughly in order of their frequency are drowsiness and confusion; focal or generalized seizures; and focal motor, sensory, or speech disorders. Fever and leukocytosis are not consistently present, depending on the phase of the development of the abscess at the time of presentation (see in the following text). In patients who harbor chronic ear, sinus, or pulmonary infections, a recent activation of the infection frequently precedes the onset of cerebral symptoms. In patients without an obvious focus of infection, headache or other cerebral symptoms may appear abruptly on a background of mild general ill health or congenital heart disease. In some patients, bacterial invasion of the brain may be asymptomatic or may be attended only by a transitory focal neurologic disorder, as might happen when a septic


Neurology_Adams

Neurology_Adams. or congenital heart disease. In some patients, bacterial invasion of the brain may be asymptomatic or may be attended only by a transitory focal neurologic disorder, as might happen when a septic embolus briefly lodges in a brain artery. Sometimes stiff neck accompanies generalized headache, suggesting the diagnosis of meningitis (especially a partially treated one).


Neurology_Adams

Neurology_Adams. Localizing neurologic signs become evident sooner or later, but, like papilledema, they occur relatively late in the course of the illness. The nature of the focal neurologic defect will, of course, depend on the location of the abscess as fully explicated in Chap. 21. In cerebellar abscess, the headache is generally postauricular or occipital; the signs are those expected for disease of this part of the brain.


Neurology_Adams

Neurology_Adams. The treacherous aspect of brain abscess is that the signs of systemic infection may be entirely absent. The invasive stage of cerebral infection may be so inconspicuous, and the course so indolent, that the entire clinical picture may not differ from that of malignant brain tumor. Although slight fever is characteristic of the early invasive phase of cerebral abscess, the temperature may return to normal as the abscess becomes encapsulated; the same is true of leukocytosis. The sedimentation rate is usually elevated. Although lumbar puncture is not recommended, in the early stages of abscess formation the CSF pressure is moderately increased; and there is a mild to moderate pleocytosis with 10 to 80 percent neutrophils; and the protein content is modestly elevated, rarely more than 100 mg/dL. Glucose values are not lowered, and the CSF is sterile unless there is concomitant bacterial meningitis. As already mentioned, the combination of brain abscess and acute bacterial meningitis


Neurology_Adams

Neurology_Adams. mg/dL. Glucose values are not lowered, and the CSF is sterile unless there is concomitant bacterial meningitis. As already mentioned, the combination of brain abscess and acute bacterial meningitis occurs only infrequently. In some patients, abscess is combined with subdural empyema; in these instances the clinical picture can be very complicated, although headache, fever, and focal signs again predominate. In a small number of cases, especially partially treated ones, there are no spinal fluid abnormalities and the sedimentation rate may be normal.


Neurology_Adams

Neurology_Adams. It is apparent from this overview that the clinical picture of brain abscess is far from stereotyped. Whereas headache is the most prominent feature in most patients, seizures or certain focal signs may predominate in others, and a considerable number of patients will present with only signs of increased intracranial pressure. In some instances the symptoms evolve swiftly over a week, new ones being added day by day. In such cases the abscess may become apparent only when cerebral imaging performed for the evaluation of headache or other symptoms discloses a ring-enhancing mass. Even then, the imaging identification is not always straightforward, depending often on the presence of a uniform, enhancing capsule that is typical of a mature abscess (see in the following text). An impressive feature of cerebral abscess is the unpredictability with which the symptoms may evolve, particularly in children. Thus, a patient whose clinical condition seems to have stabilized may, in a matter of


Neurology_Adams

Neurology_Adams. feature of cerebral abscess is the unpredictability with which the symptoms may evolve, particularly in children. Thus, a patient whose clinical condition seems to have stabilized may, in a matter of hours or a day or two, advance to an irreversible state of coma. Often this is caused by rupture of the abscess into the subarachnoid or ventricular CSF.


Neurology_Adams

Neurology_Adams. CT and MRI are the most important diagnostic tools. In the CT scan, the capsule of the abscess enhances and the center of the abscess and surrounding edematous white matter are hypodense. With MRI, in T1-weighted images, the capsule enhances and the interior of the abscess is hypointense and shows restricted diffusion; in T2-weighted images, the surrounding edema is apparent and the capsule is hypointense and there is variable diffusion restriction within the lesion (see Fig. 31-2, right). The abscess capsule tends to be thinner on the side directed to the lateral ventricle. Cerebritis appears as dot-sized areas of decreased density that enhance with gadolinium. Practically all abscesses larger than 1 cm produce positive scans. There is almost no likelihood of cerebral abscess if enhanced CT and MRI studies are negative. Blood cultures, sedimentation rate, and chest radiography are indispensable in the complete diagnosis of brain abscess, although it must be acknowledged that blood


Neurology_Adams

Neurology_Adams. CT and MRI studies are negative. Blood cultures, sedimentation rate, and chest radiography are indispensable in the complete diagnosis of brain abscess, although it must be acknowledged that blood cultures are likely to be unrevealing except in cases of acute endocarditis.


Neurology_Adams

Neurology_Adams. If there is no apparent source of infection and there are only signs and symptoms of a mass lesion, the differential diagnosis includes tuberculous or fungal abscess, glioma, metastatic carcinoma, toxoplasmosis, subdural hematoma, subacute infarction of the basal ganglia or thalamus, and resolving cerebral hemorrhage or infarction. Sometimes only surgical exploration will settle the issue, but one must be cautious in interpreting especially stereotactic biopsy if only inflammatory and gliotic tissue is obtained, as these changes may appear in the neighborhood of either abscess or tumor.


Neurology_Adams

Neurology_Adams. During the stage of cerebritis and early abscess formation, which is essentially an acute focal encephalitis, intracranial operation accomplishes little and probably adds only further injury and swelling of brain tissue and possibly dissemination of the infection. Some cases can be cured at this stage by the adequate administration of high-dose antibiotics. Even before bacteriologic examination of the intracerebral mass, certain antibiotics can be given, with the choice based on the predisposing condition (vancomycin, a secondor third-generation cephalosporin such as ceftriaxone, and either meropenem or metronidazole). If a penicillinor oxacillin-sensitive organism is suspected or isolated, those agents are superior to vancomycin. These drugs are given intravenously in divided daily doses. Metronidazole is so well absorbed from the gastrointestinal tract that it can be administered orally, 500 mg q6h.


Neurology_Adams

Neurology_Adams. This choice of antimicrobial agents is based on the fact that anaerobic streptococci and Bacteroides are often among the causative organisms and that most abscesses are polymicrobial. Evidence of staphylococcal infection can be presumed if there has been recent neurosurgery or head trauma or a demonstrable bacterial endocarditis with this organism. Abscesses caused by bacteria of oral origin must be considered to have a high frequency of gram- negative organisms; penicillin and metronidazole are usually adequate but a thirdor fourth-generation cephalosporin, such as cefotaxime or cefepime intravenously, is often used. In abscess of odontogenic origin, coverage of the gram negative organisms with a cephalosporin may not be necessary. In all cases, several weeks of treatment are advised.


Neurology_Adams

Neurology_Adams. The initial elevation of intracranial pressure and threatening temporal lobe or cerebellar herniation can be managed by the use of intravenous mannitol (or hypertonic saline) and dexamethasone, 6 to 12 mg q6h. If improvement does not begin promptly, it becomes necessary to aspirate the abscess stereotactically or remove it by an open procedure that also allows precise etiologic diagnosis by Gram stain and culture. The decision regarding aspiration or open removal of the abscess is governed by its location and the course of clinical signs and by the degree of mass effect and surrounding edema as visualized by repeated scans.


Neurology_Adams

Neurology_Adams. Only if the abscess is solitary, superficial, and well encapsulated or associated with a foreign body should total excision be attempted; if the abscess is deep, aspiration performed stereotactically and repeated if necessary is currently the method of choice. If the location of the abscess is such that it causes obstructive hydrocephalus, for example, in the thalamus adjacent to the third ventricle or in the cerebellum, it is advisable to remove or aspirate the mass and to drain the ventricles externally for a limited time. While it has been our practice to recommend either complete excision for posterior fossa and fungal abscesses or aspiration if they are deep, there is still a lack of unanimity as to the optimal surgical approach. Some neurosurgeons instill antibiotics into the abscess cavity following aspiration, but the efficacy of this treatment is difficult to judge.


Neurology_Adams

Neurology_Adams. The least satisfactory results are obtained if the patient is comatose before treatment is started; more than 50 percent of such patients in the past have died. If treatment is begun while the patient is alert, the mortality is in the range of 5 to 10 percent, and even multiple metastatic abscesses may respond. Approximately 30 percent of surviving patients are left with neurologic residua. Of these, focal epilepsy is the most troublesome. Following successful treatment of a cerebral abscess in a patient with congenital heart disease, correction of the cardiac anomaly is indicated to prevent recurrence. One may even consider closing a patent foramen ovale using interventional or open surgical methods if no other explanation for the abscess is apparent.


Neurology_Adams

Neurology_Adams. There are many infectious processes that induce an inflammation of the leptomeninges of lesser intensity and more chronicity than the acute forms described earlier. Included are some bacterial and most fungal infections, tuberculosis, syphilis, Lyme disease, HIV infection, and presumed noninfectious causes, such as lymphoma, sarcoidosis, Wegener granulomatosis, and others. As pointed out by Ellner and Bennett many decades ago, the clinical syndrome of chronic meningitis comprises confusion or cognitive decline, seizures, an absence of lateralizing and focal cerebral signs, with or without headache, and mild stiffness of the neck. In most cases, there is little or no fever or other manifestation of infection. The CSF will often not divulge the causative agent, as the organisms are usually by nature more difficult to detect and culture. The main identifiable forms of subacute and chronic meningitis are described below. Chapter 32 addresses the approach to the complicated problem of


Neurology_Adams

Neurology_Adams. by nature more difficult to detect and culture. The main identifiable forms of subacute and chronic meningitis are described below. Chapter 32 addresses the approach to the complicated problem of chronic nonbacterial meningitis (aseptic meningitis) in which no cause can be found, and should be referred to along with this section.


Neurology_Adams

Neurology_Adams. In the United States and in most western countries, the incidence of tuberculous meningitis, which parallels the frequency of systemic tuberculosis, has, until recently, decreased steadily and markedly since World War II. Beginning approximately 1985, there has been a moderate increase in the incidence of systemic tuberculosis (and tuberculous meningitis) in the United States—a 16 percent annual increase compared to an average annual decline of 6 percent during the preceding 30 years (Snider and Roper). This was partly due to the appearance of HIV. In fact, tuberculosis may be the first clinical manifestation of HIV infection (Barnes et al); among patients with full-blown HIV, the incidence of tuberculosis is almost 500 times the incidence in the general population (Pitchenik et al). In developing countries, particularly in sub-Saharan Africa, recent estimates of the incidence of tuberculosis suggest that it is 25 times more frequent than in the United States, again largely because of


Neurology_Adams

Neurology_Adams. countries, particularly in sub-Saharan Africa, recent estimates of the incidence of tuberculosis suggest that it is 25 times more frequent than in the United States, again largely because of the prevalence of HIV infection. The trend of increasing incidence has recently been reversed in regions of the world where HIV has been brought under better control.


Neurology_Adams

Neurology_Adams. Tuberculous meningitis is usually caused by the acid-fast organism Mycobacterium tuberculosis and exceptionally, by Mycobacterium bovis, Mycobacterium avian, Mycobacterium kansasii, and Mycobacterium fortuitum (the last of these after neurosurgical procedures and cranial trauma). The emergence of HIV has led to a marked increase in cases caused by both the main organism, and also by the atypical mycobacteria. In a monograph as informative today as it was 70 years ago, Rich described two stages in the pathogenesis of tuberculous meningitis: first a bacterial seeding of the meninges and subpial regions of the brain with the formation of tubercles, followed by the rupture of one or more of the tubercles and the discharge of bacteria into the subarachnoid space. The concept that tuberculous meningitis always originates in a tubercle (i.e., part of the miliary disease) in contrast to the conventional notion of hematogenous implantation in other bacterial meningitis, has been debated.


Neurology_Adams

Neurology_Adams. Small, discrete white tubercles are scattered over the base of the cerebral hemispheres and to a lesser degree on the convexities. The brunt of the pathologic process falls on the basal meninges, where a thick, gelatinous exudate accumulates, obliterating the pontine and interpeduncular cisterns and extending to the meninges around the medulla, the floor of the third ventricle and subthalamic region, the optic chiasm, and the undersurfaces of the temporal lobes. There may be multiple small abscesses (Fig. 31-3) or a more uniform exudate in the leptomeninges (Fig. 31-3). By comparison, the convexities are little involved, possibly because the associated hydrocephalus obliterates the cerebral subarachnoid space. Microscopically, the meningeal tubercles are like those in other parts of the body, consisting of a central zone of caseation surrounded by epithelioid cells and some giant cells, lymphocytes, plasma cells, and connective tissue. The exudate is composed of fibrin, lymphocytes,


Neurology_Adams

Neurology_Adams. body, consisting of a central zone of caseation surrounded by epithelioid cells and some giant cells, lymphocytes, plasma cells, and connective tissue. The exudate is composed of fibrin, lymphocytes, plasma cells, other mononuclear cells, and some polymorphonuclear leukocytes. The ependyma and choroid plexus are studded with minute glistening tubercles. The exudate also surrounds the spinal cord. Unlike the typical bacterial meningitides, the disease process is not confined to the subarachnoid space but frequently penetrates the pia and ependyma and invades the underlying brain, so that the process is truly a meningoencephalitis.


Neurology_Adams

Neurology_Adams. Other pathologic changes depend on the chronicity of the disease process and recapitulate the changes that occur in the subacute and chronic stages of the other bacterial meningitides (see Table 31-1). Cranial nerves are often involved by the inflammatory exudate as they traverse the subarachnoid space, indeed, far more often than with typical bacterial meningitis. Arteries may become inflamed and occluded, with infarction of brain. Blockage of the basal cisterns frequently results in a meningeal, obstructive hydrocephalus; marked ependymitis with blocking of the CSF in the aqueduct or fourth ventricle is a less-common cause. The exudate occasionally predominates around the spinal cord, leading to multiple spinal radiculopathies and compression of the cord.


Neurology_Adams

Neurology_Adams. Tuberculous meningitis occurs in persons of all ages. Formerly, it was more frequent in young children, but now it is more frequent in adults, at least in the United States. The early manifestations are usually low-grade fever, malaise, headache (more than 50 percent of cases), lethargy, confusion, and stiff neck (75 percent of cases), with Kernig and Brudzinski signs. Characteristically, these symptoms evolve much less rapidly in tuberculous than in bacterial meningitis, usually over a period of a week or two, sometimes longer. In young children and infants, apathy, hyperirritability, vomiting, and seizures are the usual symptoms; however, stiff neck may not be prominent or may be absent altogether.


Neurology_Adams

Neurology_Adams. Because of the inherent chronicity of the disease, signs of cranial nerve involvement (usually ocular palsies, less-often facial palsies or deafness) and papilledema may be present at the time that the infection is recognized (20 percent of cases). Occasionally, the disease may present with the rapid onset of a focal neurologic deficit because of hemorrhagic infarction, with signs of raised intracranial pressure or with symptoms referable to the spinal cord and nerve roots. Hypothermia and hyponatremia have been additional features in several of our cases at the time of discovery of the meningitis.


Neurology_Adams

Neurology_Adams. In approximately two-thirds of patients with tuberculous meningitis there is evidence of active tuberculosis elsewhere, usually in the lungs and occasionally in the small bowel, bone, kidney, or ear. In some patients, however, only inactive pulmonary lesions are found, and in others there is no evidence of tuberculosis outside of the nervous system. As mentioned, among our adult patients, tuberculous meningitis is now seen largely in those with HIV, but also in alcoholics, and in people who have emigrated from Asia, Africa, India, and certain locations in the former Soviet Union. Except for the emergence of drug-resistant organisms, the HIV infection does not appear to much change the clinical manifestations or the outcome of tuberculous meningitis. However, others disagree with this statement, pointing out that the course of the bacterial infection is accelerated in HIV patients, with more frequent involvement of organs other than the lungs. Whether or not HIV infection alters the


Neurology_Adams

Neurology_Adams. pointing out that the course of the bacterial infection is accelerated in HIV patients, with more frequent involvement of organs other than the lungs. Whether or not HIV infection alters the natural history of tuberculous meningitis, treatment of the HIV infection is of paramount importance and it has been recommended that it should be started within 2 weeks of the onset of antituberculous therapy.


Neurology_Adams

Neurology_Adams. If tuberculous meningitis is untreated, its course is characterized by confusion and progressively deepening stupor and coma, coupled with cranial-nerve palsies, pupillary abnormalities, focal neurologic deficits, raised intracranial pressure, and decerebrate postures; usually, untreated, a fatal outcome follows within 4 to 8 weeks of the onset.


Neurology_Adams

Neurology_Adams. The most important diagnostic test is lumbar puncture, which preferably should be performed before the administration of antibiotics. The CSF is usually under increased pressure and contains between 50 and 500 white cells per cubic millimeter, rarely more. Early in the disease there may be a more-or-less-equal number of polymorphonuclear leukocytes and lymphocytes, but after several days lymphocytes predominate in the majority of cases. In some cases, however, M. tuberculosis causes a persistent polymorphonuclear pleocytosis, the other usual causes of this CSF formula being Nocardia, Aspergillus, and Actinomyces (Peacock). The protein content of the CSF is always elevated, between 100 and 200 mg/dL in most cases, but much higher if the flow of CSF is blocked around the spinal cord. Glucose is reduced to levels below 40 mg/dL, but rarely to the very low values observed in conventional bacterial meningitis; the glucose falls slowly and a reduction may become manifest only several days


Neurology_Adams

Neurology_Adams. is reduced to levels below 40 mg/dL, but rarely to the very low values observed in conventional bacterial meningitis; the glucose falls slowly and a reduction may become manifest only several days after the patient has been admitted to the hospital. The serum sodium is often reduced, in most instances because of inappropriate ADH secretion or an addisonian state due to tuberculosis of the adrenals. In the past, much was made of a low concentration of CSF chloride.


Neurology_Adams

Neurology_Adams. Most children with tuberculous meningitis have positive tuberculin skin tests (85 percent) but the rate is far lower in adults with or without HIV: 40 to 60 percent in most series. In the current era, interferon-gamma-release assay is used to document previous or current tuberculosis infection. The blood test appears to be highly, but not perfectly, sensitive and about 90 percent specific for active tuberculous infection in patients with meningitis as indicated by Sali and coworkers but caution must be observed in endemic areas where there are high rates of positivity. The test has been used in CSF with similar results but it is not clear if this is valuable as a routine test.


Neurology_Adams

Neurology_Adams. The previously used conventional methods of demonstrating tubercle bacilli in the spinal fluid are inconsistent and often too slow for immediate therapeutic decisions. Success with the traditional identification of tubercle bacilli in smears of CSF sediment stained by the Ziehl-Neelsen method is a function not only of their number but also of the persistence with which they are sought. There are effective means of culturing the tubercle bacilli; because their the quantity of bacteria is usually small, however, attention must be paid to proper technique. The amount of CSF submitted to the laboratory is critical; the more that is cultured, the greater the chances of recovering the organism. Unless one of the newer techniques is used, growth in culture media is not seen for 3 to 4 weeks.


Neurology_Adams

Neurology_Adams. Now widely used is polymerase chain reaction amplification from the CSF, which rapidly permits the detection of small amounts of tubercle bacilli. The sensitivity of this test is stated to be close to 80 percent but there is a 10 percent false-positive rate. There is also a rapid culture technique that allows identification of the organisms in less than 1 week. However, even these new diagnostic methods may give uncertain results or take several days to demonstrate the organism and they cannot be counted on to exclude the diagnosis. For these reasons, if a presumptive diagnosis of tuberculous meningitis has been made and cryptococcosis and other fungal infections and meningeal neoplasia have been reasonably excluded, treatment can be instituted without waiting for the results of bacteriologic study.


Neurology_Adams

Neurology_Adams. Imaging procedures are informative in patients who present with or develop raised intracranial pressure, hydrocephalus, or focal neurologic deficits. One or more tuberculomas may be visualized (Figs. 31-3 and 31-4) or there may be deep cerebral infarction from occlusion of vessels of the circle of Willis or one of its primary branches. MR or CT angiography may demonstrate vascular occlusive disease from granulomatous infiltration of the walls of arteries. Other Forms of Central Nervous System Tuberculosis


Neurology_Adams

Neurology_Adams. Other Forms of Central Nervous System Tuberculosis This condition, which is essentially a self-limited meningitis, is observed with some frequency in countries where tuberculosis is prevalent. The CSF shows a modest pleocytosis in some, but not all, cases, a normal or elevated protein content, and normal glucose levels. Headache, lethargy, and confusion are present in some cases and there are mild meningeal signs. Lincoln, who was the first to call attention to this syndrome, believed it to be a meningeal reaction to an adjacent tuberculous focus that did not progress to frank meningitis.


Neurology_Adams

Neurology_Adams. These are tumor-like masses of tuberculous granulation tissue, most often multiple but also occurring singly, that form in the parenchyma of the brain and range from 2 to 12 mm in diameter (see Fig. 31-4). The larger ones may produce symptoms of a space-occupying lesion and periventricular ones may cause obstructive hydrocephalus, but many are unaccompanied by symptoms of focal cerebral disease. In the United States, tuberculomas are rare; in developing countries, however, they constitute from 5 to 30 percent of all intracranial mass lesions. In some tropical countries, cerebellar tuberculomas are the most frequent intracranial tumors in children. Because of their proximity to the meninges, the CSF often contains a small number of lymphocytes and increased protein (serous meningitis), but the glucose level is not reduced. True tuberculous abscesses of the brain are rare except in HIV patients. In two of our patients who presented with a brainstem tuberculoma, there was a serous


Neurology_Adams

Neurology_Adams. but the glucose level is not reduced. True tuberculous abscesses of the brain are rare except in HIV patients. In two of our patients who presented with a brainstem tuberculoma, there was a serous meningitis that progressed to a fatal generalized tuberculous meningitis.


Neurology_Adams

Neurology_Adams. The spinal cord may be affected in a number of ways in the course of tuberculous infection. In addition to compressing spinal roots and cord, causing spinal block, the inflammatory meningeal exudate may invade the underlying parenchyma, producing signs of posterior and lateral column and spinal root disease. Spinal cord symptoms may also accompany tuberculous osteomyelitis of the spine with compression of the cord by an epidural abscess, a mass of granulation tissue (Pott disease, “Pott paraplegia”), or, less frequently, by the mechanical effects of angulation of the vertebral column. Pott disease, a tuberculous osteomyelitis of the spine that leads to compression of vertebral bodies and a highly characteristic kyphotic deformity at the thoracic or upper lumbar level, is discussed in Chap. 42. Treatment of Central Nervous System Tuberculous Infections


Neurology_Adams

Neurology_Adams. The treatment of tuberculous meningitis consists of the administration of a combination of four drugs—isoniazid (INH), rifampin (RMP), ethambutol (EMB), and/or pyrazinamide (PZA) for the first 2 months. Some regimens omit the last drug but recent recommendations from various U.S. societies prefer the four-drug combination. An alternative regimen is INH, PZA, high-dose RMP, and moxifloxacin. All of these drugs have the capacity to penetrate the blood–brain barrier, with INH and PZA ranks higher than the others in this respect. Resistant strains of tuberculous organisms are emerging, requiring the use of second-line drugs. It has been pointed out that individuals from certain regions have high rates of INH, and sometimes EMB-resistant organisms. In these cases of multidrug resistance, ethionamide (ETA) must be added as a fifth drug. Antibiotics must be given for a prolonged period, 9 to 12 months if first-line treatment has been given (although it may not be necessary to give all 3 or 4


Neurology_Adams

Neurology_Adams. (ETA) must be added as a fifth drug. Antibiotics must be given for a prolonged period, 9 to 12 months if first-line treatment has been given (although it may not be necessary to give all 3 or 4 drugs for the entire period).


Neurology_Adams

Neurology_Adams. INH is the single most effective drug. It can be given in a single daily dose of 5 mg/kg in adults and 10 mg/kg in children. Its most important adverse effects are neuropathy and hepatitis, particularly in alcoholics. Neuropathy can be prevented by the administration of 50 mg pyridoxine daily. In patients who develop the symptoms of hepatitis or who have abnormal liver function tests, INH should be discontinued. The usual dose of RMP is 10 mg/kg daily for adults, 15 mg/kg for children. Ethambutol is given in a single daily dose of 15 mg/kg. The dosage of ETA is 15 to 25 mg/kg daily for adults; because of its tendency to produce gastric irritation, it is given in divided doses, after meals. The latter two drugs (EMB and ETA) may cause optic neuropathy, so that patients taking them should have regular examinations of visual acuity and red-green color discrimination. Ethambutol dependably causes optic neuropathy when used in doses above 20 m/kg and is a major cause of preventable optic


Neurology_Adams

Neurology_Adams. have regular examinations of visual acuity and red-green color discrimination. Ethambutol dependably causes optic neuropathy when used in doses above 20 m/kg and is a major cause of preventable optic neuropathy in developing countries. Renal failure and weight loss are risks for toxic levels of the drug. Pyrazinamide is given once daily in doses of 20 to 35 mg/kg. Rash, gastrointestinal disturbances, and hepatitis are the main adverse effects. Except for INH, all these drugs can be given only orally or by stomach tube. INH and rifampin may be given parenterally.


Neurology_Adams

Neurology_Adams. Corticosteroids may be used in patients whose lives are threatened by the effects of subarachnoid block or raised intracranial pressure but only in conjunction with antituberculous drugs. A randomized study conducted in Vietnam, including patients with and without HIV, showed that the addition of intravenous dexamethasone (0.4 mg/kg daily for a week and then tapering doses for 3 to 6 weeks) reduced mortality from 41 percent to 32 percent but had no effect on residual disability (Thwaites et al).


Neurology_Adams

Neurology_Adams. Intracranial tuberculoma calls for a similar course of antibiotics, as outlined above. Under the influence of these drugs, the tuberculoma(s) may decrease in size and small ones ultimately disappear or calcify, as judged by the CT scan; if they do not, and especially if there is “mass effect,” excision may be necessary. Patients with spinal osteomyelitis or localized granulomas with instability or spinal cord compression (Pott paraplegia) should be explored surgically after an initial course of chemotherapy, and an attempt should be made to excise the tuberculous focus. We have, however, dealt successfully with tuberculous osteomyelitis of the cervical spine (without significant abscess or cord compression) by immobilizing our patient in a hard collar and administering triple-drug therapy (at the suggestion of the patient’s father, who was a physician in India), once it was established that the spinal column was stable, the collar could be removed. Thus, flexion–extension x-rays can


Neurology_Adams

Neurology_Adams. (at the suggestion of the patient’s father, who was a physician in India), once it was established that the spinal column was stable, the collar could be removed. Thus, flexion–extension x-rays can be valuable if they can be obtained safely.


Neurology_Adams

Neurology_Adams. The overall mortality of patients with CNS tuberculosis is still significant (approximately 10 percent), infants and the elderly being at greatest risk. Among HIV-infected patients, the mortality from tuberculous meningitis is considerably higher (21 percent in the series of Berenguer et al)—the result of delays in diagnosis and, more importantly, of resistance to antituberculous drugs in some patients (Snider and Roper). Most resistant tuberculosis in developed countries is a result of intermittent, ineffective therapy. Therefore, directly observed therapy for at least 2 months–“short course” (DOTS) has become routine for patients in many areas. (See also “Tuberculous Myelitis” in Chap. 42.) Early diagnosis, as one might expect, enhances the chances of survival. In patients who are treated late in the disease, when coma has supervened, the mortality rate is nearly 50 percent. Between 20 and 30 percent of survivors manifest a variety of residual neurologic sequelae, the most important


Neurology_Adams

Neurology_Adams. late in the disease, when coma has supervened, the mortality rate is nearly 50 percent. Between 20 and 30 percent of survivors manifest a variety of residual neurologic sequelae, the most important of which are diminished intellectual function, psychiatric disturbances, recurrent seizures, visual and oculomotor disorders, deafness, and hemiparesis. A detailed account of these has been given by Wasz-Hockert and Donner.


Neurology_Adams

Neurology_Adams. The incidence of neurosyphilis, like that of CNS tuberculosis, declined dramatically in the decades following World War II, with the advent of penicillin. In the United States, for instance, the rate of first admissions to mental hospitals because of neurosyphilis fell from 4.3 per 100,000 population (in 1946) to 0.4 per 100,000 (in 1960). However, in more recent years, the number of reported cases of early syphilis has increased, both in nonimmunocompromised individuals and particularly in HIV-infected ones. Notable also is the shift in clinical presentation of neurosyphilis from parenchymal damage, now quite rare, to one of chronic meningovascular disease, particularly in patients with HIV. Congenital syphilis represents a special problem, which is discussed with developmental diseases in Chap. 37.


Neurology_Adams

Neurology_Adams. Syphilis is caused by Treponema pallidum, a slender, spiral, motile organism. Figure 31-5 summarizes the evolution from the primary infection to the various forms of neurosyphilitic diseases.


Neurology_Adams

Neurology_Adams. The initial event in the neurosyphilitic infection is meningitis, which occurs in approximately 25 percent of all cases of syphilis. The treponeme usually invades the CNS within 3 to 18 months of inoculation with the organism. If the nervous system is not involved by the end of the second year, there is only one chance in 20 that the patient will develop neurosyphilis as a result of the original infection. At the end of 5 years, the likelihood of developing neurosyphilis falls to 1 percent. Usually the meningitis is asymptomatic and can be discovered only by lumbar puncture. Exceptionally, it is more intense and causes cranial-nerve palsies, seizures, stroke, and symptoms of increased intracranial pressure. In the current era, clinicians understandably neglect to consider the possibility of neurosyphilis with these syndromes. The meningitis may persist in an asymptomatic state and, ultimately, after a period of years, may lead to parenchymal damage. In some cases, however, there is a


Neurology_Adams

Neurology_Adams. of neurosyphilis with these syndromes. The meningitis may persist in an asymptomatic state and, ultimately, after a period of years, may lead to parenchymal damage. In some cases, however, there is a natural subsidence of the meningitis.


Neurology_Adams

Neurology_Adams. All forms of neurosyphilis begin as meningitis (and meningeal inflammation) are the invariable accompaniment of all forms of neurosyphilis. The early clinical syndromes are aseptic meningitis and meningovascular syphilis; the late (secondary) ones are vascular syphilis (1 to 12 years), followed even later by tertiary syphilis, general paresis, tabes dorsalis, optic atrophy, or subacute myelitis. In all cases of tertiary neurosyphilis, the pathologic sequence results from chronic syphilitic meningitis and subpial recruitment of microglia and other inflammatory cells. The clinical syndromes are the result of chronic and progressive damage to subadjacent neurons and supporting tissues. The intermediate mechanisms, whereby transformation occurs from persistent asymptomatic syphilitic meningitis or relapsing meningitis, to the late forms of parenchymal neurosyphilis are unknown.


Neurology_Adams

Neurology_Adams. From a clinical point of view, asymptomatic neurosyphilis is perhaps the most important form because, if discovered and adequately treated, the symptomatic varieties would be prevented in most instances. Asymptomatic neurosyphilis can be recognized only by the changes in the CSF. Clinical syndromes such as syphilitic meningitis, meningovascular syphilis, general paresis, tabes dorsalis, optic atrophy, and meningomyelitis often exist in mixed form. Because all of them appear to have a common origin in chronic meningitis, there is usually a combination of two or more syndromes with one predominating, for example, meningitis and vascular syphilis, tabes and paresis. Even though the patient’s symptoms may have been referable to only one part of the nervous system, postmortem examination usually discloses diffuse changes, in both brain and spinal cord, which were of insufficient severity to be detected clinically.


Neurology_Adams

Neurology_Adams. The clinical syndromes and pathologic reactions of congenital syphilis are similar to those of the late-acquired forms, differing only in the age at which they occur. All the aforementioned biologic events are equally applicable to congenital and childhood neurosyphilis.


Neurology_Adams

Neurology_Adams. The CSF is a sensitive indicator of the presence of active neurosyphilitic infection. The CSF abnormalities consist of (1) a pleocytosis of up to 100 cells/mm3, sometimes higher, mostly lymphocytes and a few plasma cells and other mononuclear cells (the counts may be lower in patients with HIV and those with leukopenia); (2) elevation of the total protein, from 40 to 200 mg/dL; (3) an increase in gamma globulin (IgG), usually with oligoclonal banding; and (4) positive serologic tests for syphilis. Elevated gamma globulin in the CSF is produced intrathecally and has been shown to be adsorbed to T. pallidum (Vartdal et al). Hence the gamma globulin represents a specific antibody response to this organism. The glucose content is usually normal.


Neurology_Adams

Neurology_Adams. Later, the CSF changes may vary. With either spontaneous or therapeutic remission of the disease, the cells disappear first; next the total protein returns to normal; then the gamma globulin concentration is reduced. The positive serologic tests are the last to revert to normal. Some caution is advisable in interpreting the CSF results in patients with concurrent HIV. On the one hand, an aseptic reaction may be the result of HIV alone; on the other hand, those with profound leukopenia or T-cell deficiencies may show little or no cellular reaction in the CSF (see Katz and Berger). In congenital (but not adult) neurosyphilis, the earliest changes in the CSF, consisting of pleocytosis and an elevation of protein, may occur in the first few weeks of the infection, before the serologic tests become positive.


Neurology_Adams

Neurology_Adams. Frequently, the CSF serology remains positive, despite repeated courses of therapy and the subsidence of all signs of inflammatory activity. When this occurs, it may be safely concluded that the syphilitic inflammation in the nervous system is burned out and that further progression of the disease probably will not occur. If treatment restores the CSF to normal, particularly the cell count and protein, arrest of the clinical symptoms almost always occurs. A return of cells and elevation of protein precedes or accompanies clinical relapse.


Neurology_Adams

Neurology_Adams. Serologic diagnosis of syphilis This depends on the demonstration of one of two types of antibodies: nonspecific or nontreponemal (regain, RPR) antibodies and specific treponemal antibodies. The common tests for reagin, which uses a rapid complement fixation technique, and the venereal disease research laboratory (VDRL) slide test, which uses a flocculation technique. The reagin tests, if positive in the CSF, are virtually diagnostic of neurosyphilis. Serum reactivity alone demonstrates exposure to the organism in the past, but does not imply the presence of neurosyphilis. However, serum reagin tests are negative in a significant proportion of patients with late syphilis and in those with neurosyphilis in particular (seronegative syphilis). In such patients (and in patients with suspected false-positive test in the serum) it is essential to employ tests for antibodies that are directed specifically against treponemal antigens. The latter are positive in the serum of practically every


Neurology_Adams

Neurology_Adams. false-positive test in the serum) it is essential to employ tests for antibodies that are directed specifically against treponemal antigens. The latter are positive in the serum of practically every instance of neurosyphilis. The fluorescent treponemal antibody absorption (FTA-ABS) test is more than adequate for most clinical situations. The


Neurology_Adams

Neurology_Adams. T. pallidum immobilization (TPI) test is the most reliable, but it is expensive, difficult to perform, and available in only a few laboratories. Principal Types of Neurosyphilis In this condition, there are no symptoms or physical signs except, in rare cases, abnormal pupils, which are light-unreactive but constrict as part of the near response (accommodate with convergence) (Argyll Robertson pupils, Chap. 13). The diagnosis is based entirely on the CSF findings, which vary, as mentioned above.


Neurology_Adams

Neurology_Adams. Symptoms of meningeal involvement may occur at any time after infection but typically does so within the first 2 years. The most common symptoms are headache, stiff neck, cranial-nerve palsies, convulsions, and mental confusion. Occasionally, headache, papilledema, nausea, and vomiting—as a result of the presence of increased intracranial pressure—are added to the clinical picture. The patient is afebrile, unlike the case in tuberculous meningitis. The CSF always has a lymphocytic reaction, more so than in asymptomatic syphilitic meningitis. Obviously, the meningitis is more intense in the symptomatic type and may be associated with hydrocephalus. With adequate treatment, the prognosis is good. The symptoms usually disappear within days to weeks, but if the CSF remains abnormal, it is likely that some other form of neurosyphilis will subsequently develop if treatment is not continued.


Neurology_Adams

Neurology_Adams. As indicated earlier, this clinical syndrome is now probably the most common form of neurosyphilis. Whereas in the past, strokes from syphilitic meningitis accounted for only 10 percent of neurosyphilitic syndromes, their frequency is now estimated to be 35 percent. The most common time of occurrence of meningovascular syphilis is 6 to 7 years after the original infection, but it may be as early as 9 months or as late as 10 to 12 years. It is therefore the main manifestation of what has been termed “secondary syphilis.” The CSF almost always shows some abnormality, usually an increase in cells, protein content, and gamma globulin, as well as a positive serologic test.


Neurology_Adams

Neurology_Adams. The CSF almost always shows some abnormality, usually an increase in cells, protein content, and gamma globulin, as well as a positive serologic test. The pathologic changes in this disorder consist not only of meningeal infiltrates but also of inflammation and fibrosis of small arteries (Heubner arteritis), which lead to narrowing and, finally, occlusion. Most of the infarctions occur in the distal territories of mediumand small-caliber lenticulostriate branches that arise from the stems of the middle and anterior cerebral arteries. Most characteristic perhaps is an internal capsular lesion, extending to the adjacent basal ganglia. The presence of multiple small but not contiguous lesions adjacent to the lateral ventricles is another common pattern. Small, asymptomatic lesions are often seen in the caudate and lenticular nuclei. Several of our patients have had transient prodromal neurologic symptoms.


Neurology_Adams

Neurology_Adams. The neurologic signs that remain after 6 months will usually be permanent but adequate treatment will prevent further vascular episodes. If repeated strokes occur despite adequate therapy, one should consider the possibility of nonsyphilitic vascular disease of the brain. Paretic Neurosyphilis (General Paresis, Dementia Paralytica)


Neurology_Adams

Neurology_Adams. The general setting of this form of cerebral syphilis is long-standing meningitis hence, with tabes, it is a form of tertiary syphilis. As remarked above, some 15 to 20 years usually separate the onset of general paresis from the original infection. The history of the disease is entwined with many of the major historical events in neuropsychiatry. Haslam in 1798 and Esquirol at about the same time first delineated the clinical state. Bayle in 1822 commented on the arachnoiditis and meningitis, and Calmeil, on the encephalitic lesion. Nissl and Alzheimer added details to the pathologic descriptions. The syphilitic nature of the disease was suspected by Lasegue, by Fournier, and by others before Schaudinn’s and Hoffman’s discovery of the spirochete; it was finally confirmed by Noguchi in 1913. Kraepelin’s monograph General Paresis (1913) is one of the classic reviews (see Merritt et al for these and other historical references).


Neurology_Adams

Neurology_Adams. Once a major cause of various forms of mental illness, accounting for some 4 to 10 percent of admissions to asylums (hence the term “general paresis of the insane,” or GPI), general paresis is now seen less frequnetly. Because syphilis is acquired mainly in late adolescence and early adult life, the middle years (35 to 50) are the usual time of onset of the paretic symptoms. There have not been many cases of this process in patients with HIV; possibly the immunodeficiency has altered the biologic reaction to the organism.


Neurology_Adams

Neurology_Adams. The clinical picture in its fully developed form includes progressive dementia, dysarthria, myoclonic jerks, action tremor, seizures, hyperreflexia, Babinski signs, and Argyll Robertson pupils. However, greater importance attaches to diagnosis at an earlier stage, when few of these manifestations are conspicuous. The insidious onset of memory defect, impairment of reasoning, and reduction in executive function—along with minor oddities of deportment and conduct, irritability, and lack of interest in personal appearance—are not too different from the general syndrome of dementia outlined in Chaps. 20 and 38, especially of the frontotemporal variety. One can appreciate how elusive the disease may be at any one point in its early evolution. Indeed, with the currently low index of suspicion of the disease, diagnosis at this predemented stage is more often accidental than deliberate.


Neurology_Adams

Neurology_Adams. Although former writings have stressed the development of delusional systems, most dramatically in the direction of mania, such symptoms are exceptional in the early or preparalytic phase. More usual has been a simple dementia with reduction of intellectual capacities, forgetfulness, disorders of speaking and writing, and vague concerns about health. In a few patients the first hint of a syphilitic encephalitis, as mentioned earlier, may be facial quivering; tremulousness of the hands; indistinct, hurried speech; myoclonus; and seizures—reminiscent of delirium or acute viral encephalitis. As the deterioration continues into the paralytic stage, intellectual function progressively declines, and aphasias, agnosias, and apraxias intrude themselves.


Neurology_Adams

Neurology_Adams. Physical dissolution progresses concomitantly—impaired station and gait, debility, unsteadiness, dysarthria, and tremor of the tongue and hands. All these disabilities lead eventually to a bedridden state; hence the term paretic. Other symptoms are hemiplegia (hence the term “paresis”), hemianopia, aphasia, cranial-nerve palsies, and seizures with prominent focal signs of unilateral frontal or temporal lobe disease—a syndrome known pathologically as Lissauer cerebral sclerosis.


Neurology_Adams

Neurology_Adams. Agitated, delirious, depressive, and schizoid psychoses are special psychiatric syndromes that can be differentiated from general paresis by the lack of mental decline, neurologic signs, and CSF findings in the primary psychiatric disorders. The neuropsychiatric features of this disease create a picture unlike that of most degenerative diseases—with the notable exception that it may simulate the category of degenerative frontotemporal dementias as mentioned and discussed in Chap. 38. It is well to remember that many of our ideas about the brain and the mind were shaped historically by this disease.


Neurology_Adams

Neurology_Adams. Pathologic changes This consists of meningeal thickening, brain atrophy, ventricular enlargement, and granular ependymitis. Microscopically, the perivascular spaces are filled with lymphocytes, plasma cells, and mononuclear cells; nerve cells have disappeared; there are numerous rod-shaped microgliacytes and plump astrocytes in parts of the cortex devastated by neuronal loss; iron is deposited in mononuclear cells; and, with special stains, spirochetes are visible in the cortex. The changes are most pronounced in the frontal and temporal lobes. The ependymal surfaces of the ventricles are studded with granular elevations protruding between ependymal cells (granular ependymitis). Meningeal fibrosis with obstructive hydrocephalus is present in many cases.


Neurology_Adams

Neurology_Adams. Treatment The prognosis in early treated cases with antibiotics has in the past been fairly good; 35 to 40 percent of patients made some occupational readjustment; in another 40 to 50 percent, the disease was arrested but left the patient dependent. Without treatment as discussed below there is progressive mental decline, and death occurs within 3 to 4 years.


Neurology_Adams

Neurology_Adams. This type of neurosyphilis, described by Duchenne in his classic monograph L’ataxie locomotrice progressive (1858), usually develops 15 to 20 years after the onset of the infection. The major symptoms are lightning pains, ataxia, and urinary incontinence; the chief signs are absent tendon reflexes at knee and ankle, impaired vibratory and position sense in feet and legs, and a Romberg sign. The ataxia is purely a result of the sensory defect. Power, by contrast, is fully retained in most cases. The pupils are abnormal in more than 90 percent of cases, usually Argyll Robertson in type (see Chap. 13). Optic atrophy is frequent. The lancinating or lightning pains (present in more than 90 percent of cases) are, as their name implies, sharp, stabbing, and brief, like a flash of lightning. They are more frequent in the legs than elsewhere but roam over the body from face to feet, sometimes playing persistently on one spot “like the repeated twanging of a fiddle string,” as Wilson remarked.


Neurology_Adams

Neurology_Adams. are more frequent in the legs than elsewhere but roam over the body from face to feet, sometimes playing persistently on one spot “like the repeated twanging of a fiddle string,” as Wilson remarked. They may come in bouts lasting several hours or days. “Pins and needles” feelings, coldness, numbness, tingling, and other paresthesias are also present and are associated invariably with impairment of tactile, pain, and thermal sensation. The bladder is insensitive and hypotonic, resulting in unpredictable overflow incontinence. Constipation and megacolon as well as erectile dysfunction are other expressions of dysfunction of the sacral roots and ganglia.


Neurology_Adams

Neurology_Adams. In the late established phase of the disease, now seldom seen, ataxia is the most prominent feature. A Romberg sign is grossly manifest. The patient totters and staggers while standing and walking. In mild form, it is best seen as the patient walks between obstacles or along a straight line, turns suddenly, or halts. To correct the instability, the patient places his feet and legs wide apart, flexes his body slightly, and repeatedly contracts the extensor muscles of his feet as he sways (la danse des tendons). In moving forward, the patient flings his stiffened leg abruptly, and the foot strikes the floor with a resounding thump in a manner quite unlike that seen in the ataxia of cerebellar disease. The patient clatters along in this way with eyes glued to the floor. If his vision is blocked, he is rendered helpless. When the ataxia is severe, walking becomes impossible despite relatively normal strength of the leg muscles.


Neurology_Adams

Neurology_Adams. Trophic lesions, perforating ulcers of the feet, and Charcot joints are characteristic complications of the tabetic state. The deformity of deafferented Charcot joints occurs in less than 10 percent of tabetics (the most common cause nowadays is diabetic neuropathy, which is also a cause of lancinating pains). Most often the hips, knees, and ankles are affected, but occasionally also the lumbar spine or upper limbs are affected. The process generally begins as an osteoarthritis, which, with repeated injury to the insensitive joint, progresses to destruction of the articular surfaces. Osseous architecture disintegrates, with fractures, dislocations, and subluxations, only some of which occasion discomfort. The arthropathy has been observed to occur as frequently in the burned-out as in the active phase of tabes; hence it is only indirectly related to the syphilitic process. Although the basic abnormality appears to be repeated injury to an anesthetic joint, the process need not be


Neurology_Adams

Neurology_Adams. the active phase of tabes; hence it is only indirectly related to the syphilitic process. Although the basic abnormality appears to be repeated injury to an anesthetic joint, the process need not be painless. Presumably a deep and incomplete hypalgesia and loss of autonomic function are enough to interfere with protective mechanisms. The Charcot joint is addressed further in Chap. 43 in the context of sensory polyneuropathies.


Neurology_Adams

Neurology_Adams. Visceral crises represent another interesting manifestation of this disease, now rarely seen. The gastric ones are the best known. The patient is seized abruptly with epigastric pain that spreads around the body or up over the chest. There may be a sense of thoracic constriction as well as nausea and vomiting—the latter repeated until nothing but blood-tinged mucus and bile are raised. The symptoms may last for several days; a barium swallow sometimes demonstrates pylorospasm. The attack subsides as quickly as it came, leaving the patient exhausted, with a soreness of the epigastric skin. Intestinal crises with colic and diarrhea, pharyngeal and laryngeal crises with gulping movements and dyspneic attacks, rectal crises with painful tenesmus, and genitourinary crises with strangury and dysuria are all less frequent but well-documented types.


Neurology_Adams

Neurology_Adams. In most cases now seen, the CSF is normal when the patient is first examined (so-called burned-out tabes). It is abnormal less often than in general paresis.


Neurology_Adams

Neurology_Adams. Pathology Pathologic study reveals a striking thinness and grayness of the posterior roots, principally lumbosacral, and thinning of the spinal cord mainly as a result of wallerian degeneration of the posterior columns. Only a slight outfall of neurons is observed in the dorsal root ganglia; the peripheral nerves are essentially normal. For many years, there was an argument as to whether the spirochete first attacked the posterior columns of the spinal cord, the posterior root as it pierced the pia, the more distal part of the radicular nerve where it acquires its arachnoid and dural sheaths, or the dorsal root ganglion cell. The observations of our colleagues of rare active cases have shown the inflammation to be all along the posterior root; the slight dorsal ganglion cell loss and posterior column degeneration were considered to be secondary.


Neurology_Adams

Neurology_Adams. The hypotonia, areflexia, and ataxia relate to destruction of proprioceptive fibers in the sensory roots. The hypotonia and insensitivity of the bladder are caused by deafferentation at the S2 and S3 levels; the same is true of the impotence and obstipation. Lightning pains and visceral crises cannot be fully explained but are probably attributable to incomplete posterior root lesions at different levels. Analgesia and joint insensitivity that lead to Charcot joints relate to the partial loss of A and C fibers in the roots.


Neurology_Adams

Neurology_Adams. Treatment If the CSF serology is positive and the patient has not been treated before, the patient should be treated with penicillin, as described below. (The CSF VDRL may remain positive for many years after treatment.) If, however, CSF serology is negative, there is no pleocytosis, the CSF protein content is normal, and there is no evidence of cardiovascular or other types of syphilis, antisyphilitic treatment may not be necessary. We are uncertain of the proper course of treatment in patients with tabes who have survived many decades with HIV. Residual symptoms in the form of lightning pains, gastric crises, Charcot joints, or urinary incontinence frequently continue long after all signs of active neurosyphilitic infection have disappeared. These should be treated symptomatically rather than by antisyphilitic drugs.


Neurology_Adams

Neurology_Adams. This takes the form of progressive blindness beginning in one eye and then involving the other and may occur within months of the primary infection as part of meningovascular syphilis, or as a later manifestation. The usual finding is a constriction of the visual fields, but scotomata may occur in rare cases. The optic discs are gray-white. The CSF is almost invariably abnormal, although the degree of abnormality may be slight in some cases. The prognosis is poor if vision in both eyes is greatly reduced. If only one eye is badly affected, sight in the other eye can usually be saved. In exceptional cases, visual impairment may progress, even after the CSF becomes negative. The pathologic changes consist of perioptic meningitis (inflammatory reaction surrounding the optic nerves, chiasm and tracts), with subpial gliosis and fibrosis replacing degenerated optic nerve fibers. Exceptionally there are vascular lesions with infarction of central parts of the nerve.


Neurology_Adams

Neurology_Adams. There are several types of spinal syphilis other than tabes. Two of them, syphilitic meningomyelitis (formerly called Erb spastic paraplegia because of the predominance of bilateral corticospinal tract signs) and spinal meningovascular syphilis, are observed from time to time, although less often than tabes. Spinal meningovascular syphilis may occasionally take the form of an anterior spinal artery syndrome. In meningomyelitis, there is subpial loss of myelinated fibers and gliosis as a direct result of the chronic fibrosing meningitis. Gumma of the spinal meninges and cord seldom is found. It was not present in a single case in Merritt and Adams’ study of spinal syphilis. Progressive muscular atrophy (syphilitic amyotrophy) is a very rare disease of questionable syphilitic etiology; most cases are degenerative (see Chap. 38). Also rare is syphilitic hypertrophic pachymeningitis or arachnoiditis, which allegedly gives rise to radicular pain, amyotrophy of the hands, and signs of long


Neurology_Adams

Neurology_Adams. cases are degenerative (see Chap. 38). Also rare is syphilitic hypertrophic pachymeningitis or arachnoiditis, which allegedly gives rise to radicular pain, amyotrophy of the hands, and signs of long tract involvement in the legs (syphilitic amyotrophy with spastic-ataxic paraparesis). In all these syndromes there is an abnormal CSF, unless, of course, the neurosyphilitic infection is burned out.


Neurology_Adams

Neurology_Adams. The prognosis in spinal neurosyphilis is uncertain. There is improvement or at least an arrest of the disease process in most instances, although a few patients may progress slightly after treatment is begun. A steady advance of the disease in the face of a negative CSF usually means that there has been a secondary constrictive myelopathy or that the original diagnosis was incorrect and the patient suffers from some other disease, for example, a spinal form of multiple sclerosis as a degenerative disease.


Neurology_Adams

Neurology_Adams. This may occur in either early or late syphilitic meningitis and may be combined with other syphilitic syndromes. Because this may produce a treatable vestibular syndrome of vertigo, with or without hearing loss, syphilis serology should be tested in patients with cryptic vestibular dysfunction. Some of the characteristics of vestibular neurosyphilis are identical to those of Ménière disease, including episodic loss of function (Baloh and Honrubia). Curiously, there is seldom a history of clear primary syphilitic infection. The pathology, mainly endarteritis in the cochlea and labyrinths, is identical to the more common congenital syphilitic deafness, which is described in Chap. 37. Treatment of Neurosyphilis


Neurology_Adams

Neurology_Adams. Treatment of Neurosyphilis The treatment of all of these forms of neurosyphilis consists of the administration of penicillin G, given intravenously in a dosage of 18 to 24 million units daily (3 to 4 million units q4h) for 10 to 14 days. The CDC recommends procaine penicillin and probenecid, and ceftriaxone as an alternative to penicillin if there is an allergy to either drug. Penicillin is so much preferred that even these patients are ideally desensitized to the drug. The Jarisch-Herxheimer reaction, which occurs after the first dose of penicillin and is a matter of concern in the treatment of primary syphilis, is of little consequence in neurosyphilis; it usually consists of no more than a mild temperature elevation and systemic leukocytosis.


Neurology_Adams

Neurology_Adams. In patients who have neurosyphilis and are co-infected with HIV, longer treatment and surveillance for relapse, which is more common in this group than patients without HIV, has been recommended An alternative to penicillin in these patients is doxycycline orally for 30 days. The effects of treatment on certain symptoms of neurosyphilis, especially of tabetic neurosyphilis, are unpredictable and often little influenced by treatment with penicillin; they require symptomatic measures. Lightning pains may respond to gabapentin or carbamazepine. Analgesics may be helpful, but opiates should generally be avoided. Neuropathic (Charcot) joints require bracing or fusion. Atropine and phenothiazine derivatives are said to be useful in the treatment of visceral crises.


Neurology_Adams

Neurology_Adams. In all forms of neurosyphilis, the patient should be reexamined every 3 to 6 months after treatment and the CSF should be retested after a 6-month interval. If after 6 months the patient is free of symptoms and the CSF abnormalities have been reversed (disappearance of cells as well as reduction in protein, gamma globulin, and serology titers), no further treatment is indicated. Followup should include clinical examinations at approximately 12 months and another lumbar puncture. If a pleocytosis remains, these procedures should be repeated every 6 months. In the opinion of most experts, a persistent weakly positive serologic (VDRL) test after the cells and protein levels have returned to normal does not constitute an indication for additional treatment. Such a CSF formula ensures that the disease is quiescent or arrested. Others are not convinced of the reliability of this concept and prefer to give more penicillin. If at the end of 6 months there are still an increased number of


Neurology_Adams

Neurology_Adams. the disease is quiescent or arrested. Others are not convinced of the reliability of this concept and prefer to give more penicillin. If at the end of 6 months there are still an increased number of cells and an elevated protein in the fluid, another full course of penicillin should be given. Clinical relapse is almost invariably attended by recurrence of cells and increase in protein levels. Rapid clinical progression in the face of a negative CSF suggests the presence of a nonsyphilitic disease of the brain or cord.


Neurology_Adams

Neurology_Adams. 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; tickand 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


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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 but there are notable clinical and serologic differences between the American and European varieties of the disease.


Neurology_Adams

Neurology_Adams. In humans, all these spirochetoses, if untreated, 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 small a proportion of such cases. The early neurologic complications are mainly derivations of meningitis. Unlike syphilis, peripheral and cranial nerves are often damaged (see further on and Chap. 43). Immune factors may be important in the later phases of the disease and in the development of the neurologic syndromes.


Neurology_Adams

Neurology_Adams. 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 although one aspect or another may predominate. The responsible organism, as stated earlier, is the spirochete B. burgdorferi and the vector in the United States is the common deer tick (Ixodes dammini). 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 may be a chronic form of Borrelia infection.


Neurology_Adams

Neurology_Adams. 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 (as does the serologic testing). 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 (B. burgdoferii) than the European form of the illness (Borrelia afzelii and Borrelia garinii)—possibly attributable to a more


Neurology_Adams

Neurology_Adams. associated, and these seem to be more prominent in the North American (B. burgdoferii) than the European form of the illness (Borrelia afzelii and Borrelia garinii)—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. The European variant has a propensity to cause the painful lymphocytic meningoradiculitis, Bannwarth syndrome, as summarized in the review by Pachner and Steiner.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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, usually by many weeks or months. A cardiac disorder, which may accompany or occur independently of the neurologic changes, takes the form of myocarditis, a pericarditis, or atrioventricular block.


Neurology_Adams

Neurology_Adams. 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. Mild meningism without pleocytosis has been seen early in the syndrome and it may be worth repeating the studies in highly suspicious cases. 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,


Neurology_Adams

Neurology_Adams. 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 as another rare manifestation.


Neurology_Adams

Neurology_Adams. In about half the cases, cranial neuropathies become manifest within weeks of onset of the meningitic 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. 43. 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, again apparently more common in Europe, but there is no reason to believe that the illness then differs from other cases of the acute


Neurology_Adams

Neurology_Adams. occurrence of Guillain-Barré syndrome following Lyme infection, again apparently more common in Europe, 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.


Neurology_Adams

Neurology_Adams. 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. 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. 43) 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.


Neurology_Adams

Neurology_Adams. A problematic aspect of Lyme disease relates to the development in some patients of a mild chronic encephalopathy coupled with 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. A comment is made below about imaging findings in Lyme.


Neurology_Adams

Neurology_Adams. 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 is associated with this CSF formula, but there are exceptions.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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 to explain positive serology, 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;


Neurology_Adams

Neurology_Adams. 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 entirely 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 laboratory diagnostic issues are discussed and put in perspective by Steere and colleagues (2016). If the European variety of borreliosis is suspected, different serologic tests are required but the general principles of diagnosis are the same as for cases in the United States and elsewhere.


Neurology_Adams

Neurology_Adams. 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. There are no characteristic imaging findings for neuroborreliosis. In some acute cases one may find enhancement of an affected cranial nerve or spinal nerve root. In the chronic phase of the disease, CT and MRI may display multifocal and periventricular cerebral lesions but these are not specific to Lyme disease, as they also appear in numerous other conditions. The relationship of these lesions, when they do occur in Lyme, to encephalopathy, is unproved.


Neurology_Adams

Neurology_Adams. The recommended treatment in the first stage of the disease, mainly referring to the initial rash and the subsequent presence of facial or other cranial nerve palsies alone, is oral doxycycline (100 mg bid) for 14 days. Alternate therapies include amoxicillin 500 mg tid, used sometimes in children, 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” in patients who have undergone adequate early treatment. Once the meninges and central or peripheral nervous system are implicated, treatment in the U.S has been ceftriaxone, 2 g daily, usually given intravenously for 4 weeks. In other regions, oral treatment has been used.


Neurology_Adams

Neurology_Adams. Tetracycline, 500 mg qid for 30 days, is recommended 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 or persistent clinical features ostensibly attributed to Lyme, antibiotics have not been shown 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 smaller proportion of spastic and ataxic myelopathy cases are improved. In other studies, up to a fifth of children with facial palsies have residual weakness.


Neurology_Adams

Neurology_Adams. 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 but viral infections that cause meningitis are capable of producing the same eye signs. 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 (ELISA, indirect hemoglutination assay, followed by specific agglutination tests and culture).


Neurology_Adams

Neurology_Adams. Treatment Antibiotic treatment seems to be effective only if implemented during the initial febrile phase. Penicillin, doxycycline, or ceftriaxone have been used. The meningitis is usually self-limited.


Neurology_Adams

Neurology_Adams. 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 in the following text), 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


Neurology_Adams

Neurology_Adams. 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 HIV and in patients on immunosuppression medications.


Neurology_Adams

Neurology_Adams. Fungal infections of the CNS may arise without obvious predisposing cause, but they typically complicate some other disease process that suppresses immune function such as HIV, cancer chemotherapy, organ transplantation, severe burns, leukemia, lymphoma or other malignancy, diabetes, rheumatologic disease, or prolonged corticosteroid therapy. They are referred to as opportunistic. 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. In these circumstances, other infectious agents including bacteria (Pseudomonas and other gram-negative organisms, L. monocytogenes), protozoa (Toxoplasma), and viruses (cytomegalovirus, herpes simplex, and varicella zoster) may also be opportunistic and should be considered in the aforementioned clinical situations.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. The spinal fluid changes in fungal meningitis are also 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 (also seen with the bacterial infections, nocardia, and actinomycosis). On the other hand, in patients with HIV 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.


Neurology_Adams

Neurology_Adams. 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 later. Cryptococcosis (Torulosis, European Blastomycosis)


Neurology_Adams

Neurology_Adams. Cryptococcosis (Torulosis, European Blastomycosis) Cryptococcosis is one of the more frequent fungal infections of the CNS and it occurs in both normal and immunocompromised hosts. The causative organism is usually Cryptococcus neoformans but Cryptococcus gattii has also been implicated. 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.


Neurology_Adams

Neurology_Adams. 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 HIV). 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 HIV are particularly vulnerable to cryptococcal infection; estimates are that 6 to 12 percent of HIV patients are subject to meningoencephalitis with the organism.


Neurology_Adams

Neurology_Adams. The spinal fluid shows a variable lymphocytic pleocytosis, usually fewer than 50 cells/mm3, but there may be few or no cells in a patient with HIV (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 HIV patients) and the protein may reach high levels.


Neurology_Adams

Neurology_Adams. Specific diagnosis in developed regions depends on finding C. neoformans antigens in the CSF. The organism may be seen as spherical cells, 5 to 15 μm 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 HIV patients, in whom the CSF values for cells, glucose, and proteins may be entirely normal but difficulties interpreting the India ink preparation have led to its being used less often.


Neurology_Adams

Neurology_Adams. 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 HIV 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 used. 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).


Neurology_Adams

Neurology_Adams. Treatment In patients without HIV, this consists of intravenous administration of amphotericin B, given in a dose of 0.7 to 1.0 mg/kg/d, or 3–4 mg/kg/d of liposomal amphotericin. 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 (100 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. Both medications are usually continued for at least 6 weeks—longer if CSF cultures remain positive.


Neurology_Adams

Neurology_Adams. 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 HIV. The recommended treatment in these circumstances is amphotericin supplemented by flucytosine for 2 weeks. Subsequently, fluconazole, an oral triazole antifungal agent, is given (or less preferably, oral itraconazole), for up to 1 year or indefinitely to prevent relapse (Saag et al; Powderly et al). The medication can be discontinued if the CD4 exceeds 100/mm3 and HIV viral load is suppressed. The optimum use of these drugs has not been settled, and some trials have yielded ambiguous results in both HIV and other patients. Details of a randomized trial in HIV comparing amphotericin as above to a regimen of additional flucytosine is given by Day and colleagues. They showed no advantage to an initial regimen of both drugs over amphotericin alone.


Neurology_Adams

Neurology_Adams. Mortality from cryptococcal meningoencephalitis, even in the absence of HIV or other disease, is high. Candidiasis is probably the most frequent 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 grave.


Neurology_Adams

Neurology_Adams. In most instances, this 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; that 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 and galactomannan are detectable in the blood.


Neurology_Adams

Neurology_Adams. Treatment Liposomal amphotericin in combination with voriconazole, and echinocandins in some cases, 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 an aggressive infection of soft tissues or sinuses, spreading to cerebral vessels with one of the Mucorales family. It occurs as a rare complication in patients with diabetes, especially during diabetic acidosis, in drug addicts, and in those with leukemia and lymphoma, particularly those treated with corticosteroids and cytotoxic agents.