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. Since 1985, however, 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 trend has recently been reversed in the United States because HIV is under better control. In fact, tuberculosis may be the first clinical manifestation of HIV infection (Barnes et al); among patients with full-blown AIDS, 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 the prevalence of HIV infection.
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 AIDS has led to a marked increase in cases caused by both the main organism and also by the two 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. Whether the meningitis always originates in this way is unlikely. It can be said, however, that the meningitis may occur as a terminal event in cases of miliary tuberculosis or as part of generalized tuberculosis with only a single focus (tuberculoma) in the brain.
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. 32-2) or a more uniform exudate in the leptomeninges. 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, 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.
MRI in tuberculous meningitis showing gadolinium enhancement of the basal meninges, reflecting microabscesses and intense inflammation, accompanied by hydrocephalus and cranial nerve palsies.
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 32-1). 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.
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.
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.
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 AIDS, but also in alcoholics, and in people who have emigrated from Asia, Africa, and 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 AIDS 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 should be started within 2 weeks of the onset of antituberculous therapy.
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; invariably, untreated, a fatal outcome then follows within 4 to 8 weeks of the onset.
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 pyogenic 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 and chloride and CSF chloride are often reduced, in most instances because of inappropriate ADH secretion or an addisonian state due to tuberculosis of the adrenals.
Most children with tuberculous meningitis have positive tuberculin skin tests (85 percent) but the rate is far lower in adults with or without AIDS: 40 to 60 percent in most series.
The previously 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 quantity 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.
More widely used test now 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.
Other diagnostic procedures (CT, MRI) are necessary in patients who present with or develop raised intracranial pressure, hydrocephalus, or focal neurologic deficits. One or more tuberculomas may also be visualized (Fig. 32-2 and 32-3) 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.
A tuberculoma of the pons on a gadolinium-enhanced MRI (top panel). There is a thick, uniform enhancing rim. The mass behaved clinically like a malignant brain tumor. The bottom panel shows the same lesion after antituberculous treatment.
Other Forms of Central Nervous System Tuberculosis
Tuberculous Serous Meningitis
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 but this form of meningitis is not always self-limited.
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 (Fig. 32-3). 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 AIDS 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.
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. 44.
Treatment of Central Nervous System Tuberculous Infections
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 countries (e.g., Vietnam, Haiti, Philippines, former Soviet Union) 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 drugs for the entire period).
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 (see Chap. 40) 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. 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.
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 AIDS, 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).
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 be valuable if they can be obtained safely.
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. 44.) 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 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.
The infectious etiology of sarcoidosis has never been established but the disease may suitably be considered at this point because of its close resemblance pathologically and clinically to tuberculosis and other granulomatous infections. Indeed, one still credible theory of causation considers sarcoidosis to be a modified form or product of the tubercle bacillus. This has not been proved, and the same can be said for various other infectious and noninfectious etiologies that from time to time have been proposed as the underlying cause. Current opinion favors the idea that sarcoidosis represents an exaggerated cellular immune response to a limited class of antigens or autoantigens (Baughman and Lower).
The essential lesion in sarcoidosis consists of focal collections of epithelioid cells surrounded by a rim of lymphocytes; frequently there are giant cells, but caseation is lacking. The sarcoid, noncaseating granuloma may be found in all organs and tissues, including the nerve roots, peripheral, and central nervous systems, but the most frequently involved are the mediastinal and peripheral lymph nodes, lungs, liver, skin, phalangeal bones, eyes, and parotid glands.
According to Iannuzzi and colleagues, sarcoidosis is accompanied by nervous system involvement (neurosarcoidosis) in approximately 25 percent of postmortem cases. This number overestimates the frequency of neurosarcoidosis because only a small percentage of all patients with sarcoidosis come to autopsy and among these, neurologic involvement is prevalent. Approximately 5 percent of patients with sarcoidosis prove to have nervous system involvement clinically. Primary neurosarcoidosis, by which is meant sarcoidosis isolated only to the nervous system, is even less common. If one excludes facial palsy, primary neurosarcoidosis is rare. Several other syndromes are caused by localized sarcoid involvement of the meninges, brain, and spinal cord (Table 32-5). In Scadding's series of 275 patients, only 3 developed CNS lesions; in other large series, the incidence of CNS involvement was greater but, as mentioned, most are in the range of 5 to 10 percent (of 285 studied by Chen and McLeod; and 33 of 649 studied by Stern et al). Delaney, in his review of the literature, found the neurologic involvement in sarcoidosis to be equally divided between the peripheral and central nervous systems.
Table 32-5 The Main Nervous System Manifestations of Sarcoidosis ||Download (.pdf)
Table 32-5 The Main Nervous System Manifestations of Sarcoidosis
Cranial neuropathy (see Chap. 47)
Facial palsy, unilateral, bilateral, or sequentiala
Hearing loss, vertigo
Facial sensory loss or pain
Spinal cord and roots (see Chap. 44)
Granulomatous meningomyelitis, subacute or chronic
Cauda equina syndrome
Peripheral nervous system (see Chap. 46)
Lumbar or brachial plexopathy
Mononeuropathy and mononeuropathy multiplex
Basal granulomas with diabetes insipidus
Subacute meningitis and pachymeningitis
Sarcoidosis in the nervous system may take one of several forms (see Table 32-5). As indicated in Chaps. 13, 46, and 47, isolated sarcoid granulomas may involve peripheral or cranial nerves, giving rise to a subacute or chronic polyradiculopathy, neuropathy, or plexopathy of asymmetrical type (Jefferson). Polyneuropathy may occur, but is infrequent; Zuniga and colleagues summarized our experience with this process. Of the cranial nerves, the facial is the most frequently involved, either as part of the uveoparotid syndrome (Heerfordt syndrome) or independently. The facial palsy may be unilateral or bilateral; if the latter, the nerves may be affected simultaneously or in succession. Blindness is a rare complication that follows basal infiltration that encompasses the optic nerves as noted later (Fig. 32-4). Other causes of visual disturbance include uveitis and optic neuropathy.
Cerebral sarcoid. Gadolinium-enhanced MRI of the brain. Top panel: Sarcoid lesions coat the base of the brain and cerebellum and surround the pituitary stalk. The patient had pulmonary sarcoid, marked abulia, and panhypopituitarism. Bottom panel: Sarcoid infiltration of the basal pachymeninges and both optic nerves causing blindness. Visual acuity returned almost to normal after 2 weeks of corticosteroid administration.
There is also a well-described myopathy associated with sarcoidosis; it is discussed below, and also considered in Chap. 49. The neuropathy of sarcoidosis is discussed further in Chap. 46.
In the CNS, sarcoidosis takes the form of a granulomatous infiltration of the meninges and underlying parenchyma, most frequent at the base of the brain (see Fig. 32-4). The process is subacute or chronic in nature, mimicking other granulomatous lesions and neoplasms. One particular syndrome that has been associated with sarcoidosis consists of a circumscribed lesion of the stalk of the pituitary gland, optic chiasm, and hypothalamus, it causes visual disturbances, polydipsia, polyuria, or somnolence. Hydrocephalus, seizures, cranial-nerve palsies, and corticospinal and cerebellar signs are other occasional manifestations.
Rarely, sarcoid can be a cause of a chronic recurrent or persistent meningitis, or severe, steroid-responsive headache. Granulomas may present as a mass or as one or more focal infiltrating cortical and subcortical lesions that tend to follow the course of superficial cortical veins. Focal cerebral signs, including seizures, presumably caused by deposits of sarcoid in the brain, are observed but are uncommon. Among the odd focal syndromes reported are an amnestic or dementing condition from infiltration of the medial temporal lobes and psychotic and related behavioral aberrations. In addition to this leptomeningitis, there is an infiltration of the dura, a pachymeningitis.
The spinal meninges and spinal cord may be infiltrated, usually independently of brain involvement, imparting a picture of chronic adhesive arachnoiditis or an inflammatory myelopathy. There is more prominent focal contrast enhancement and T2 signal abnormality on MRI than is usual for a demyelinating disease. It is one of the causes of a "longitudinally extensive myelopathy" (see Chap. 36). Characteristic of the spinal lesion is enhancement on the surface of the cord and a degree of expansion at the level of the myelitic lesion (see "Sarcoid Myelitis" in Chap. 44). We have had experience with several such cases in which the only evidence of sarcoid was a lesion in the thoracic cord. Biopsy of the spinal cord lesion, a risky procedure, was necessary for diagnosis in some of these cases.
A slight lymphocytic pleocytosis (10 to 200 cells/mm3) and a moderate increase in protein content (generally without oligoclonal bands), consistent with meningeal involvement are the usual CSF findings but many cases show no change. The glucose content is normal or slightly reduced. The spinal form may be associated with CSF block and a resultant greatly raised protein content.
The diagnosis of neurosarcoidosis is made on the basis of the clinical features together with clinical and biopsy evidence of sarcoid granulomas in other tissues (lymph nodes, lungs, bones, uvea, skin, and muscle). The history or presence of erythema nodosum or iritis further raises suspicion of this process. If a conventional chest radiograph does not disclose the characteristic bilateral hilar adenopathy of sarcoidosis, a thoracic CT scan may be obtained. In patients in whom the clinical suspicion remains high, positron emission tomography (PET) scanning may be useful to identify inflamed lymph nodes that are amenable to biopsy. If PET scanning is not available, radionuclide scanning with gallium-67 also shows uptake in the chest, spleen, and salivary or lacrimal glands in almost half of patients and can be a useful ancillary test.
The contrast-enhanced CT or MRI are useful means of detecting meningeal involvement and MRI may disclose periventricular and white matter lesions, although the latter pattern is usually not at all specific. Nodular or streak-like perivenular enhancement may be found on the contrast-enhanced MRI, as described by Sherman and Stern and by Christoforidis and colleagues. The intensity of enhancement may be reduced after the administration of corticosteroids.
Of historical interest is the Kveim-Siltzbach skin reaction, a granuloma in response to homogenate of spleen or lymph node from patients with known sarcoidosis. Most patients are allergic to multiple antigens including purified protein derivative (for tuberculosis) and Candida antigen, injected intradermally. Mild anemia, lymphocytopenia (occasional eosinophilia), slightly elevated sedimentation rate, hypercalcemia, and hyperglobulinemia are common findings in active disease. Serum levels of angiotensin-converting enzyme (ACE) are increased in two-thirds of patients with active pulmonary sarcoid but only one-fifth of those with chronic disease. Therefore it may not be helpful in instances of neurosarcoidosis. There is scant evidence that the concentration of ACE in the spinal fluid is helpful in the diagnosis of CNS sarcoidosis.
The differential diagnosis of neurosarcoidosis is broad and includes multiple sclerosis as well as entities such as Sjögren syndrome, systemic lupus, lymphoma, lymphomatoid granulomatosis, cryptococcosis and other fungal infections that cause abscesses and chronic meningitis, syphilis, Wegener granulomatosis, Whipple disease, and, of course, tuberculosis.
Administration of corticosteroids is the main therapy for neurosarcoidosis, but it has not been subjected to an adequate trial. Other immunosuppressive drugs are effective; methotrexate, cyclophosphamide, and the anti-TNF agents (infliximab, etanercept, and adalimumab). Radiation of focal lesions had in the past found favor but is now infrequently used.
The major problem is in knowing when to treat the patient, because neurosarcoid may remit spontaneously in about half the cases. The recent onset of neurologic symptoms, indicating an active phase of the disease, or a disabling syndrome such as myelopathy, is the most certain indication for steroid therapy. One approach is to use prednisone in daily doses of 40 mg, given for 2 weeks, followed by 2-week periods in which the dose is reduced by 5 mg, until a maintenance dose of 15 to 10 mg is reached. Therapy should be continued for at least several months and in many cases is required for several years. If patients become resistant or intolerant to corticosteroids, most often one of the anti-TNF drugs is added.
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 AIDS. Congenital syphilis represents a special problem, which is discussed with developmental diseases in Chap. 37.
Etiology and Pathogenesis
Syphilis is caused by Treponema pallidum, a slender, spiral, motile organism. In this chapter, only the basic facts regarding the neurosyphilitic infection are enumerated. Figure 32-5 summarizes the neurosyphilitic diseases.
Diagram of the evolution of neurosyphilis.
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, as shown by completely negative CSF, there is only one chance in 20 that the patient will develop neurosyphilis as a result of the original infection; if the CSF is negative at the end of 5 years, the likelihood of developing neurosyphilis falls to 1 percent. The initial event in the neurosyphilitic infection is meningitis, which occurs in approximately 25 percent of all cases of syphilis. 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 natural subsidence of the meningitis.
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 each case this pathologic sequence results from chronic syphilitic meningitis. The intermediate mechanisms, whereby transformation occurs from persistent asymptomatic syphilitic meningitis or relapsing meningitis, to the late forms of parenchymal neurosyphilis are unknown.
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. Because asymptomatic neurosyphilis can be recognized only by the changes in the CSF, it is advisable that all patients with syphilis should have a spinal fluid examination.
Clinical syndromes such as syphilitic meningitis, meningovascular syphilis, general paresis, tabes dorsalis, optic atrophy, and meningomyelitis seldom exist in pure form. Because all of them appear to have a common origin in meningitis, there is usually a combination of two or more syndromes with one predominating, e.g., 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.
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.
The CSF has been 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 AIDS 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. 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 and is recognized as the presence of oligoclonal banding of CSF protein. The glucose content is usually normal. 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. 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 AIDS. 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.
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.
Serologic Diagnosis of Syphilis
This depends on the demonstration of one of two types of antibodies: nonspecific or nontreponemal (reagin) antibodies and specific treponemal antibodies. The common tests for reagin are the Kolmer, which uses a complement fixation technique, and the Venereal Disease Research Laboratory (VDRL) slide test, which uses a flocculation technique. These 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 instance of neurosyphilis. The fluorescent treponemal antibody absorption (FTA-ABS) test is more than adequate for the majority of clinical situations. The 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. 14). The diagnosis is based entirely on the CSF findings, which vary, as mentioned above.
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.
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.
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 medium- and 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.
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)
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 and others long before Schaudinn'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).
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 a rarity. 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 AIDS; possibly the immunodeficiency has altered the biologic reaction to the organism.
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 critical faculties—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 Chap. 21, 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.
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.
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, 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.
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. The neuropsychiatric features of this disease create a picture unlike that of most degenerative diseases—with the notable exception of the category of frontotemporal dementias discussed in Chap. 39. It is well to remember that many of our ideas about the brain and the mind were shaped historically by this disease.
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.
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.
Tabetic Neurosyphilis (Tabes Dorsalis)
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, and the majority of patients show ptosis or some degree of ophthalmoplegia. 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. 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 impotence are other expressions of dysfunction of the sacral roots and ganglia.
In the established phase of the disease, now seldom seen, ataxia is the most prominent feature. 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. A Romberg sign is grossly manifest.
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 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. 46 in the context of sensory polyneuropathies. 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.
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.
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 the 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 found to be secondary.
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 relate to the partial loss of A and C fibers in the roots.
If the CSF is positive, the patient should be treated with penicillin, as described below. If, however, there is no pleocytosis, the CSF protein content is normal, and there is no evidence of cardiovascular or other types of syphilis, antisyphilitic treatment is not 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.
This takes the form of progressive blindness beginning in one eye and then involving the other. The usual finding is a constriction of the visual fields, but scotomata may occur in rare cases. The optic discs are gray-white. Other forms of neurosyphilis, particularly tabes dorsalis, not infrequently coexist. 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, with subpial gliosis and fibrosis replacing degenerated optic nerve fibers. Exceptionally there are vascular lesions with infarction of central parts of the nerve.
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. 39). 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 (see Chap. 44).
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, e.g., a spinal form of multiple sclerosis as a degenerative disease.
Syphilitic Nerve Deafness and Vestibulopathy
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
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. 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 leukocytosis.
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.
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 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.
Lyme Disease (Erythema Chronicum Migrans; Borreliosis)
Until comparatively recently, the nonvenereal spirochetes were of little interest to neurologists of the Western world. Yaws, pinta, and endemic syphilis rarely, if ever, affected the nervous system. Leptospirosis was essentially an acute liver disease with only one variant causing nonicteric lymphocytic meningitis; tick- and louse-borne relapsing fevers were medical curiosities that did not involve neurologists. However, in the late 1970s, a multisystem disease with prominent neurologic features was recognized in the eastern United States (it had been known in Northern Europe). It was named after the town of Lyme, Connecticut, where a cluster of cases was first recognized in 1975. An early skin manifestation of the disease had previously been described in Western Europe and referred to as erythema chronicum migrans. In 1982, Burgdorfer and colleagues identified the causative spirochetal agent, Borrelia burgdorferi. Later manifestations of the disease—taking the form of acute radicular pain followed by chronic lymphocytic meningitis and frequently accompanied by peripheral and cranial neuropathies—had long been known in Europe as the Bannwarth or Garin-Bujadoux syndrome. The identity of these diseases has been established, as well as their close relationship to relapsing fever—a disease that is also caused by spirochetes of the genus Borrelia and transmitted by ticks. The entire group is now classed as the borrelioses but there are notable clinical and serologic differences between the American and European varieties of the disease.
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. 46). Immune factors may be important in the later phases of the disease and in the development of the neurologic syndromes.
Lyme disease is less acute than leptospirosis (Weil disease) and less chronic than syphilis. It successively involves the skin, nervous system, heart, and articular structures over a period of a year or longer 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 ixodid tick. The precise roles of the infecting spirochete, the antibodies it induces, and other features of the human host response in the production of clinical symptoms and signs are not fully understood, but the development of an animal model by Pachner and colleagues suggests that there may be a chronic form of Borrelia infection.
Lyme borreliosis has a worldwide distribution but the typical neurologic manifestations differ slightly in Europe and America, as emphasized in the review by Garcia-Monico and Benach (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 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.
Weeks to months later, neurologic or cardiac symptoms appear in 15 and 8 percent of the cases, respectively. Still later, if the patient remains untreated, arthritis or, more precisely, synovitis develops in approximately 60 percent of the cases. Death from this disease does not occur; consequently, little is known of the pathology. A long period of disability is to be expected if the disease is not recognized and treated.
Diagnosis is not difficult during the summer season in regions where the disease is endemic and when all the clinical manifestations are present. But in some cases, a skin lesion is not observed or may have been forgotten, or there may have been only a few or no secondary lesions and the patient is first seen in the neurologic phase of the illness. Then clinical diagnosis may be difficult.
The usual pattern of neurologic involvement is one of aseptic meningitis or a fluctuating meningoencephalitis with cranial or peripheral neuritis, lasting for months (Reik). By the time the neurologic disturbances appear, the systemic symptoms and skin lesions may have long since receded, 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 an atrioventricular block.
The initial nervous system symptoms are rather nonspecific. They consist of headache, mild stiff neck, nausea and vomiting, malaise, and chronic fatigue, fluctuating over a period of weeks to months. 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, is also documented as another rare manifestation.
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. 46. In addition to facial palsies, a severe and painful meningoradiculitis of the cauda equina (Bannwarth syndrome) is particularly characteristic and seems to be more common in Europe than in the United States (there are other causes of this syndrome, including herpesvirus and cytomegalovirus). There is also an infrequent occurrence of Guillain-Barré syndrome following Lyme infection, 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.
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. 46) there are scattered lymphocytic infiltrates, without vasculitis. It seems likely to us that the organism will eventually be found in nervous tissue as the cause of disease, as there is active antibody production reflected in the CSF.
A problematic aspect of Lyme disease relates to the development in some patients of a mild chronic encephalopathy coupled with fatigue. That such a disorder may occur after a well-documented attack of Lyme disease is undoubted. However, in the absence of a history of the characteristic rash, arthritis, or aseptic meningitis, the attribution to Lyme disease of fatigue alone or various other vague mental symptoms, such as difficulty in concentration, is almost always erroneous, even if there is serologic evidence of exposure to the spirochete. It would be an understatement that a large number of patients are persuaded that various symptoms are the result of Lyme infection and seek and receive unnecessary treatment.
In acute and subacute cases that involve the spinal or cranial nerve roots or spinal cord, the CSF routinely shows a pleocytosis (20 to 250 lymphocytes/mm3) with moderately elevated protein; the glucose concentration is usually normal but may be slightly depressed. The majority of cases with facial palsy alone are associated with this CSF formula, but there are exceptions.
Serologic tests are of great value but must be interpreted with caution if there has not been an inciting clinical syndrome of erythema migrans or arthritis or a well- documented tick bite. The most valuable initial screening is performed by the ELISA; if both acute and convalescent sera are tested, approximately 90 percent of patients have a positive IgM response. After the first few weeks, most patients have elevated IgG antibody responses to the spirochete (Berardi et al); a positive test of this nature may simply reflect prior exposure. The ratio of IgG intrathecal anti-Borrelia antibody to that of the serum is greater than 2 in cases of neuroborreliosis; this elevated ratio is a necessary criterion for the diagnosis in Europe. However, Blanc and colleagues studied a sample of 123 consecutive patients with clinical signs of neurologic involvement and found the sensitivity of the index was only 75 percent and the specificity was 97 percent. These authors have proposed more pragmatic diagnostic, but somewhat contrived, criteria for neuroborreliosis, consisting of the presence of 4 of the following 5 items: no past history of neuroborreliosis, active CSF ELISA serology, anti-Borrelia antibody index greater than 2, favorable outcome after specific antibiotic treatment, and no alternative diagnosis. False-positive tests do occur in some of the conditions that react to syphilitic reagin; B. burgdorferi–specific antibodies can also be demonstrated in the CSF (these are also reflected by the presence of oligoclonal bands).
Positive ELISA testing should be pursued further with Western blot or immunoblot analysis or other more specific serologies in clinically uncertain cases. Although these latter tests are difficult to carry out and have not been 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 Golightly. 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.
In only approximately 30 percent of cases, the organism can be detected in the spinal fluid using PCR techniques, usually early in the neurologic illness.
In the chronic phase of the disease, CT and MRI in cases of encephalopathy may display multifocal and periventricular cerebral lesions but these are by no means indicative alone of Lyme disease, as they also appear in numerous other conditions.
The recommended treatment in the first stage of the disease, mainly referring to the initial rash and the subsequent presence of facial or other cranial nerve palsies alone, is oral or 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" that have undergone adequate early treatment. Once the meninges and central or peripheral nervous system are implicated probably most effective is ceftriaxone, 2 g daily, usually given intravenously for a similar period.
Tetracycline, 500 mg qid for 30 days, is recommended by Reik for patients who are allergic to these intravenous drugs. Other alternative drugs are cefotaxime 2 g IV q8h and penicillin G 18 to 20 million units per day in divided doses q4h. For late abnormalities, no treatment has proved to be effective. However, most of the symptoms tend to regress regardless of the type of treatment given.
According to Kaiser, more than 90 percent of subacute neuropathies and facial palsies resolve by 1 year after treatment, but a 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.