AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Skeletal tuberculosis (TB) was present in Egypt as early as 3500 BCE. TB is also described in ancient Chinese and Indian texts. Presently, more than 2 billion (2000 million) people in the world are infected with TB (ie, one third of the world's population), of which approximately 10% will develop clinical disease. The incidence of CNS TB is related to the prevalence of TB in the community, and it is still the most common type of chronic CNS infection in developing countries.

Despite great advances in immunology, microbiology, and drug development, TB remains among the great public health challenges. Poverty; lack of functioning public health infrastructure; lack of funding to support basic research aimed at developing new drugs, diagnostics, and vaccines; and the co-epidemic of HIV continue to fuel the ongoing epidemic of TB.

Pathophysiology

Many of the symptoms, signs, and sequelae of tuberculous meningitis (TBM) are the result of an immunologically directed inflammatory reaction to the infection. The development of TBM is a 2-step process. Mycobacterium tuberculosis bacilli enter the host by droplet inhalation, the initial point of infection being the alveolar macrophages. Localized infection escalates within the lungs, with dissemination to the regional lymph nodes to produce the primary complex. During this stage, a short but significant bacteremia is present that can seed tubercle bacilli to other organs in the body.

In persons who develop TBM, bacilli seed to the meninges or brain parenchyma, resulting in the formation of small subpial or subependymal foci of metastatic caseous lesions. These are termed Rich foci, after the original pathologic studies of Rich and McCordick. Tuberculous pneumonia develops with heavier and more prolonged tuberculous bacteremia. Dissemination to the CNS is more likely, particularly if miliary TB develops.

The second step in the development of TBM is an increase in size of a Rich focus until it ruptures into the subarachnoid space. The location of the expanding tubercle (ie, Rich focus) determines the type of CNS involvement. Tubercles rupturing into the subarachnoid space cause meningitis. Those deeper in the brain or spinal cord parenchyma cause tuberculomas or abscesses. While an abscess or hematoma can rupture into the ventricle, a Rich focus does not.

A thick gelatinous exudate infiltrates the cortical or meningeal blood vessels, producing inflammation, obstruction, or infarction. Basal meningitis accounts for the frequent dysfunction of cranial nerves (CNs) III, VI, and VII, eventually leading to obstructive hydrocephalus from obstruction of basilar cisterns. Subsequent neurological pathology is produced by 3 general processes: adhesion formation, obliterative vasculitis, and encephalitis or myelitis.

Tuberculomas are conglomerate caseous foci within the substance of the brain (see Image 1). Centrally located, active lesions may reach considerable size without producing meningitis (Rich, 1933). Under conditions of poor host resistance, this process may result in focal areas of cerebritis or frank abscess formation, but the usual course is coalescence of caseous foci and fibrous encapsulation (ie, tuberculoma). Paradoxical development or enlargement of tuberculomas during antituberculous chemotherapy has also been reported; it possibly has an immunological basis (Hejazi, 1997).

In the tuberculous process, the spinal meninges may be involved, owing to the spread of infection from intracranial meningitis, primary spinal meningitis in isolation as a result of a tuberculous focus on the surface of the cord rupturing into the subarachnoid space, or transdural extension of infection from caries of the spine.

Pathologically, a gross granulomatous exudate fills the subarachnoid space and extends over several segments. Vasculitis involving arteries and veins occurs, sometimes resulting in ischemic spinal cord infarction.

The earliest lesion in the vertebra is invariably due to hematogenous spread, often involving the body of the vertebra near an intervertebral disk. The intervertebral disk is almost always involved with the spread of the disease to the adjacent vertebra and eventually along the anterior or posterior longitudinal ligaments or through the end plate. Soon, a cold abscess develops, either as a paraspinal abscess in the dorsal and lumbar regions or as a retropharyngeal abscess in the cervical region. As the disease progresses, increasing decalcification and erosion result in progressive collapse of the bone and destruction of intervertebral disks, involving as many as 3-10 vertebrae in one lesion, resulting in kyphosis. The abscess may rupture intraspinally, resulting in primary spinal meningitis, hyperplastic peripachymeningitis, intraspinal abscess, or tuberculoma.

Pathological effects

Papilledema is the most common visual effect of TBM. In children, papilledema may progress to primary optic atrophy and blindness resulting from direct involvement of the optic nerves and chiasma by basal exudates (ie, opticochiasmatic arachnoiditis). In adults, papilledema may progress more commonly to secondary optic atrophy, provided the patient survives long enough. Other causes of visual impairment include chorioretinitis, optic neuritis, internuclear ophthalmoplegia, and, occasionally, an abrupt onset of painful ophthalmoplegia.

CN VI is affected most frequently by TBM, followed by CNs III, IV, VII, and, less commonly, CNs II, VIII, X, XI, and XII (Zuger, 1997).

Sudden onset of focal neurological deficits, including monoplegia, hemiplegia, aphasia, and tetraparesis, has been reported. Although these could be postictal phenomena, they mostly are due to vasculitic changes resulting in ischemia. While some of these could be the result of proliferative arachnoiditis or hydrocephalus, vasculitis still appears to be the leading cause.

Vasculitis with resultant thrombosis and hemorrhagic infarction may develop in vessels that traverse the basilar or spinal exudate or lie within the brain substance. Mycobacterium also may invade the adventitia directly and initiate the process of vasculitis. An early neutrophilic reaction is followed by infiltration of lymphocytes, plasma cells, and macrophages, leading to progressive destruction of the adventitia, disruption of elastic fibers, and, finally, intimal destruction. Eventually, fibrinoid degeneration within small arteries and veins produces aneurysms, multiple thrombi, and focal hemorrhages, alone or in combination (Dastur, 1995).

Tremor is the most common movement disorder seen in the course of TBM. In a smaller percentage of patients, abnormal movements, including choreoathetosis and hemiballismus, have been observed, more so in children than in adults. In addition, myoclonus and cerebellar dysfunction have been observed. Deep vascular lesions are more common among patients with movement disorders.

Frequency

United States

TB is the seventh leading cause of death and disability worldwide. In 1997, TBM was the fifth most common form of extrapulmonary TB. TBM accounted for 5.2% (186) of all cases of exclusively extrapulmonary disease and 0.7% of all reported cases of TB. The 2003 "Tuberculosis Advocacy Report" from the World Health Organization stated that 8 million new cases of TB are reported annually and 2 million deaths occur each year (World Health Organization, 2003).

More recent data suggest that TBM accounts for 2.1% of pediatric cases and 9.1% of extrapulmonary TB cases (Nelson, 2004). TB accounts for approximately 0.04% of all cases of chronic suppurative otitis media (Jeang, 1983). The "Tuberculosis Advocacy Report" of 2003 suggests the persistence of TB otitis, as well as possibly an increase in the incidence of TB otitis. Tuberculomas account for 10-30% of intracranial masses in TB-endemic areas.

Data published in 2000 revealed that the risk increased with age across racial and ethnic groups and that case rates were consistently higher in minority racial and ethnic groups than in non-Hispanic whites. Case rates in Asians and Pacific Islanders were the highest, particularly in adults. In 2000, approximately 75% of all reported TB cases occurred in racial and ethnic minorities, including 32% in non-Hispanic blacks, 23% in Hispanics, 21% in Asians and Pacific Islanders, and 1% in Native Americans and Alaskan Natives. Approximately 22% of all reported cases occurred in non-Hispanic whites.

Several important factors likely contribute to the disproportionate burden of TB in minorities. In foreign-born persons from countries where TB is common, active TB disease may result from infection acquired in the country of origin. Approximately 95% of cases in the Asian/Pacific Islander group occurred in foreign-born persons, compared with 70% of cases in Hispanics and 20% of cases in non-Hispanic blacks. In racial and ethnic minorities, unequal distribution of TB risk factors, such as HIV infection, also may contribute to an increased exposure to TB or to the risk of developing active TB once infected with M tuberculosis. However, much of the increased risk of TB in minorities has been linked to lower socioeconomic status and the effects of crowding, particularly among US-born persons.

International

The worldwide prevalence of TB in children is difficult to assess because data are scarce and poorly organized. The available reports grossly underestimate the true incidence. Lack of surveillance testing in most areas of the world restricts the ability to assess the prevalence of the disease. In many areas of Africa and Asia, the annual incidence of TB infection for all ages is approximately 2%, which would yield an estimated 200 cases of TB per 10,000 population per year. Approximately 15-20% of these cases occur in children younger than 15 years. In the developing world, 10-20% of persons who die of TB are children.

The developing world has 1.3 million cases of TB and 40,000 TB-related deaths annually among children younger than 15 years. TBM complicates approximately 1 of every 300 untreated primary TB infections.

Mortality/Morbidity

• Mortality: The number of deaths due to TB has decreased dramatically since 1953. In 1953, 19,707 deaths from TB were reported in the United States, for a rate of 12.4 deaths per 100,000 population. In 1997, 1,166 deaths were reported, for a rate of 0.4 deaths per 100,000 population. The number of TB deaths and the TB death rate increased slightly during a recent TB resurgence, reaching a high in 1989 of 1,970 deaths and a rate of 0.8 deaths per 100,000 population before decreasing again.
• Morbidity: Between 1969 and 1973, TBM accounted for approximately 4.5% of the total extrapulmonary TB morbidity in the United States. Between 1975 and 1990, 3,083 cases of TBM were reported by the US Centers for Disease Control and Prevention (CDC), an average of 193 cases per year, accounting for 4.7% of total extrapulmonary TB cases during that 16-year period. In 1990, however, 284 cases of TBM were reported, constituting 6.2% of the morbidity attributed to extrapulmonary TB. This increase in TBM was most likely due to increasing CNS TB among patients with HIV/AIDS and to the increasing incidence of TB among infants, children, and young adults of minority populations.

Race

Rates in whites are lowest at all age groups, and rates in Asians and Pacific Islanders are the highest. Rates among Blacks, Hispanics, and Native Americans/Alaskan Natives are intermediate. Black men have appreciably higher rates than Hispanic and Native American/Alaskan Native men, except in the oldest age group.

Sex

Among persons younger than 20 years, TB infection rates are similar for both sexes; the lowest rates are observed in children aged 5-14 years. During adulthood, TB infection rates are consistently higher for men than for women; the male-to-female ratio is approximately 2:1.

Age

Prior to the appearance of HIV, the most important determinant for the development of TBM was age.

• In populations with a low prevalence of TB, most cases of TBM occur in adults. In the United States in 1996, case rates were low in infancy and decreased somewhat during early childhood. After the age of puberty, they showed a steady increase with age.
• In general, however, TBM is more common in children than in adults, especially in the first 5 years of life. In fact, children aged 0-5 years are affected more commonly with TBM than any other age group. TBM is uncommon, however, in children younger than 6 months and almost unheard of in infants younger than 3 months because the causative pathological sequence takes at least 3 months to develop.
• Children aged 5-14 years often have been referred to as the favored age because they have lower rates of TB than any other age group.
• Childhood TB has a limited influence on the immediate epidemiology of the disease because children rarely are a source of infection to others.
• Younger children are more likely to develop meningeal, disseminated, or lymphatic TB, whereas adolescents more frequently present with pleural, genitourinary, or peritoneal disease.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

TBM is difficult to diagnose, and a high index of suspicion is needed to make an early diagnosis.

• Elucidate the following:
• • Inquire about the patient's medical and social history, including recent contact with patients with TB.
  • Elicit any known history of a positive result on the purified protein derivative test, especially a recent conversion.
  • Determine if the patient has a history of immunosuppression from a known disease or from drug therapy.
  • Check if the patient has a negative history for BCG vaccination.
• Usually, the prodrome is nonspecific, including headache, vomiting, photophobia, and fever. In one study, only 2% of patients reported meningitic symptoms. The duration of presenting symptoms may vary from 1 day to 9 months, although 55% presented with symptoms of less than 2 weeks in duration.
• In an immunocompetent individual, CNS TB usually takes the form of meningitis that causes an acute-to-subacute illness characterized by fever, headache, drowsiness, meningism, and confusion over a period of approximately 2-3 weeks.
• • During the prodromal period, nonspecific symptoms are present, including fatigue, malaise, myalgia, and fever.
  • Often, in the first stage of meningitis, patients have infection of the upper respiratory tract, a fact that should be remembered when the concurrent fever and irritability or lethargy seem out of proportion to the obvious infection or when general symptoms persist after improvement in the local manifestations. Fever and headache can be absent in 25% of patients and malaise can be absent in as many as 60% of patients. Headache and mental status changes are much more common in elderly persons.
• Visual symptoms include visual impairment or blindness and, occasionally, abrupt onset of painful ophthalmoplegia.
• Sudden onset of focal neurological deficits, including monoplegia, hemiplegia, aphasia, and tetraparesis, has been reported.
• Tremor and, less commonly, abnormal movements, including choreoathetosis and hemiballismus, have been observed, more so in children than adults. Myoclonus and cerebellar dysfunction have also occurred.
• The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is a common complication and is linked to a poor prognosis.
• Less frequent presentations include atypical febrile seizures in children, isolated CN palsies, bilateral papilledema, and acute confusional state.
• Tuberculous spinal meningitis may manifest as an acute, subacute, or chronic form.
• • The clinical picture in primary spinal meningitis is often characterized by myelopathy, with progressive ascending paralysis, eventually resulting in basal meningitis and associated sequelae.
  • In some cases with acute onset, in addition to variable constitutional symptoms, patients develop acute paraplegia with sensory deficits and urinary retention. The clinical picture often mimics transverse myelitis or Guillain-Barré syndrome.
  • The subacute form is often dominated by myeloradiculopathy, with radicular pain and progressive paraplegia or tetraplegia.
  • A less virulent chronic form might mimic a very slowly progressive spinal cord compression or a nonspecific arachnoiditis.
  • The dorsal cord seems to be affected most commonly, followed by the lumbar and the cervical regions.
• Tuberculous spondylitis is also known as Pott disease or spinal caries.
• • In regions where the disease is endemic, such as Asia and Africa, this condition still accounts for 30-50% of all cases of compressive myelopathy resulting in paraplegia. Spinal TB also accounts for approximately 50% of all bone and joint TB cases.
  • In the lumbar region, tuberculous spondylitis may result in a psoas abscess that often calcifies.
  • It usually runs a subacute or a chronic course, with back pain and fever and variable neurological deficits.
  • Spondylitis can also result in various symptoms, including local and radicular pain, limb motor and sensory loss, and sphincter disturbances.
  • Eventually, complete spinal cord compression with paraplegia, the most dreaded complication, may supervene.
• Tuberculous radiculomyelitis (TBRM) is a complication of TBM that has been reported only rarely in the modern medical literature.
• • TBRM develops at various periods after TBM, even in adequately treated patients after sterilization of the cerebrospinal fluid (CSF).
  • The most common symptoms are subacute paraparesis, radicular pain, bladder disturbance, and subsequent paralysis.
  • As in other forms of paradoxical reactions to anti-TB treatment, evidence shows that steroid treatment might have a beneficial effect.
• Two rare forms of TBM are serous TB meningitis and TB encephalopathy.
  • Serous TB meningitis is characterized by signs and symptoms of a mild meningitis with spontaneous recovery.
  • TB encephalopathy usually occurs in a young child with progressive primary TB; the presentation is that of reduced levels of consciousness with few focal signs and minimal meningism. Diffuse edema and white matter pallor with demyelination are found upon pathologic examination. The pathogenesis is uncertain but is presumed to be immune mediated. Diagnosis is important because anecdotal reports suggest a good response to corticosteroids.

Physical

Perform careful general, systemic, and neurologic examinations, looking especially for a BCG vaccination scar, lymphadenopathy, papilledema and tuberculomas during funduscopy, and meningismus.

• Visual findings
• • Apart from papilledema, fundus examination occasionally reveals a retinal tuberculoma or a small grayish-white choroidal nodule, highly suggestive of TB. These lesions are believed to be more common in miliary TB than in other forms of TB.
  • In children, fundus examination may reveal pallor of the disc.
  • Examination may elicit visual impairment.
• Neurologic findings
• • Cranial neuropathies, most often involving CN VI, may be noted. CNs III, IV, VII, and, less commonly, CNs II, VIII, X, XI, and XII, also may be affected.
  • Focal neurological deficits may include monoplegia, hemiplegia, aphasia, and tetraparesis.
  • Tremor is the most common movement disorder seen in the course of TBM. In a smaller percentage of patients, abnormal movements, including choreoathetosis and hemiballismus, have been observed, more so in children than adults. In addition, myoclonus and cerebellar dysfunction have been observed. Deep vascular lesions are more common among patients with movement disorders.

Causes

• Mycobacterium tuberculosis
• • The first description of TBM is credited to Robert Whytt, on the basis of his 1768 monograph, Observations of Dropsy in the Brain. TBM first was described as a distinct pathological entity in 1836, and Robert Koch demonstrated that TB was caused by M tuberculosis in 1882.
  • M tuberculosis is an aerobic gram-positive rod that stains poorly because of its thick cell wall that contains lipids, peptidoglycans, and arabinomannans.
    • Mycobacteria vary in appearance from spherical to short filaments, which may be branched. Although they appear as short to moderately long rods, they can be curved and frequently are seen in clumps. Individual bacilli generally are 0.5-1 µm in diameter and 1.5-10 µm long. They are nonmotile and do not form spores.
    • One of the distinct characteristics of mycobacteria is their ability to retain dyes within the bacilli that usually are removed from other microorganisms by alcohols and dilute solutions of strong mineral acids such as hydrochloric acid. This ability is attributed to a waxlike layer composed of long-chain fatty acids, the mycolic acids, in their cell wall. As a result, mycobacteria are termed acid-fast bacilli.
  • The mechanisms by which neurovirulence may occur are unknown.
• Risk factors
• • Human migration plays a large role in the epidemiology of TB. Massive human displacement during wars and famines has resulted in increased case rates of TB and an altered geographic distribution. With the advent of air travel, TB has a global presence. In the United States, the prevalence of TB, mostly in foreign-born persons, has steadily increased.
  • Once infected with M tuberculosis, HIV co-infection is the strongest risk factor for progression to active TB; the risk has been estimated to be as great as 10% per year, compared with 5-10% lifetime risk among persons with TB but not HIV infection.
    • Although patients who are HIV infected and also have TB are at increased risk for TBM, the clinical features and outcomes of TB do not seem to be altered by HIV.
    • Patients infected with HIV, especially those with AIDS, are at very high risk of developing active TB when exposed to a person with infectious drug-susceptible or drug-resistant TB. They have a higher incidence of drug-resistant TB, in part due to Mycobacterium avium-intracellulare, and have worse outcomes.
  • Predisposing factors for the development of active TB include malnutrition, alcoholism, substance abuse, diabetes mellitus, corticosteroid use, malignancy, head trauma, and HIV infection.
  • Homeless persons, people in correctional facilities, and residents of long-term care facilities also have a higher risk of developing active TB compared with the general population.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

TBM must be differentiated from other forms of acute and subacute meningitis, viral infections, and cerebral abscess. The radiological differential diagnosis includes cryptococcal meningitis, cytomegalovirus encephalitis, sarcoidosis, meningeal metastases, and lymphoma.

Diagnostic confusion often exists between TBM and other meningoencephalitides. In one study, 5 features were independently predictive of the diagnosis of TBM (P <.007), including (1) prodromal stage lasting 7 days or longer, (2) optic atrophy upon fundal examination, (3) focal deficit, (4) abnormal movements, and (5) CSF leukocytes comprising less than 50% polymorphs. Validation of these criteria on another set of 128 patients revealed a sensitivity of 98.4% if at least one feature was present and a specificity of 98.3% if 3 or more were present. This simple rule is useful for physicians working in regions where TB is prevalent.

TBM continues to be an important disease and should be considered in the differential diagnosis in any patient presenting with fever and a change in sensorium.

• Infections
  • Fungal - Cryptococcus, histoplasmosis, actinomycetic, nocardiasis, Arachnia infection, candidiasis, coccidiosis
  • Spirochetal - Lyme disease, syphilis, leptospirosis
  • Bacterial - Partially treated bacterial meningitis, brain abscess, listeriosis, Neisseria species infection, tularemia
  • Brucellosis
  • Parasitic - Cysticercosis, acanthamebiasis, angiostrongylosis, toxoplasmosis, trypanosomiasis
  • Viral - Herpes, mumps, retrovirus (HIV type 1, human T-lymphotropic virus type 1), enterovirus infection (in hypogammaglobulinemics)
• Acute hemorrhagic leukoencephalopathy
• Behçet disease
• Chemical meningitis
• Chronic benign lymphocytic meningitis
• Neoplastic - Metastatic, lymphoma
• Systemic lupus erythematosus
• Vascular - Multiple emboli, subacute bacterial endocarditis, sinus thrombosis
• Vasculitis - Isolated CNS angiitis, systemic giant cell arteritis, Wegener granulomatosis, polyarteritis nodosa, noninfectious granulomatosis, lymphomatoid granulomatosis
• Vogt-Koyanagi-Harada syndrome

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Complete blood cell count
• Erythrocyte sedimentation rate
• Electrolytes: Mild-to-moderate hyponatremia is present in roughly 45% of patients, in some cases constituting a true SIADH.
• Serum glucose level
• BUN and creatinine levels
• Serology for syphilis
• Complementation test or its equivalent for fungal infections
• Urinalysis
• CSF analysis (also see Procedures)
• • Cell counts, differential count, cytology
  • Glucose level, with a simultaneous blood glucose level
  • Protein level
  • Acid-fast stain, Gram stain, appropriate bacteriologic culture and sensitivity, India ink stain
  • Cryptococcal antigen and herpes antigen testing
  • Culture for M tuberculosis (50-80% of known cases of TBM yield positive results)
  • Polymerase chain reaction (PCR): Results imply that PCR can provide a rapid and reliable diagnosis of TBM, although false-negative results potentially occur in samples containing very few organisms (<2 colony forming units per mL).
  • Syphilis serology
• Tuberculin test: Negative results from the purified protein derivative test do not rule out TB; if the 5-tuberculin test skin test result is negative, repeat the test with 250-tuberculin test. Note that this test is often nonreactive in persons with TBM.
• • Despite its many limitations, tuberculin skin testing, by necessity, remains in widespread use. The CDC, the American Thoracic Society, and the Infectious Disease Society of America have updated the guidelines, and they are quite useful in practice (American Thoracic Society, 2000).
  • These guidelines stress that in general, one should not obtain a tuberculin skin test unless treatment would be offered in the event of a positive test result. Cutoff points for induration (5, 10, or 15 mm) for determining a positive test result vary based on the pretest category into which the patient falls. While this approach might decrease the specificity of the test, it increases the sensitivity for capturing those at highest risk for developing the disease in the short term.

Imaging Studies

• Chest radiography posteroanterior and lateral views may reveal hilar lymphadenopathy, simple pneumonia, infiltrate, fibronodular infiltrate/cavitation, and/or pleural effusion/pleural scar.
• CT scanning and MRI of the brain reveal hydrocephalus, basilar meningeal thickening, infarcts, edema, and tuberculomas (see Image 2).
• • The characteristic CT finding is a nodular, enhancing lesion with a central hypodense lesion (Weisberg, 1984). Contrast enhancement is essential. Early stages are characterized by low-density or isodense lesions, often with edema out of proportion to the mass effect and little encapsulation. At a later stage, well-encapsulated tuberculomas appear as isodense or hyperdense lesions with peripheral ring enhancement.
  • Although CT scanning and MRI lack specificity, they help in monitoring complications that require neurosurgery.
  • MRI and CT scanning are critical for the diagnosis of TBRM, revealing loculation and obliteration of the subarachnoid space along with linear intradural enhancement.
  • For tuberculous spinal meningitis, MRI shows that the subarachnoid space is obliterated, with focal or diffusely increased intramedullary signal on T2-weighted images and variable degrees of edema and mass effect.
  • • With gadolinium, contrast enhancement is often seen surrounding the spinal cord and the roots. The nerve roots may appear clumped and show contrast enhancement, secondary to inflammation and edema, depending on the degree of involvement.
    • Rarely, tuberculomas occur in the spinal cord, and they may occur on the surface of the cord, as dural lesions, or deep inside in an intramedullary location.
    • Less frequently, intramedullary tuberculous abscesses have been reported.
  • Tuberculous spondylitis neuroimaging invariably reveals bone destruction and fragmentation with involvement of the disk space and calcified paravertebral mass.
  • • MRI has an accuracy of 94% in vertebral osteomyelitis. It reveals hypointense T1-weighted areas in the vertebral bodies, alternating with areas of hyperintense T2-weighted signal in the disk spaces and the paravertebral soft tissue. Infected bone and disk often reveal contrast enhancement.
    • CT scanning is superior to MRI in detecting psoas abscess calcification that, when present, strongly raises the suspicion of a tuberculous etiology. Epidural deposits are best shown by MRI, which reveals a soft-tissue mass that is isointense to hypointense compared with the spinal cord on T1-weighted images and hyperintense on proton-density and T2-weighted images and has variable degrees of contrast enhancement.
    • Tuberculous myelitis and radiculomyelitis are predominantly diseases of the thoracic spinal cord. Most spinal cord lesions appear hyperintense on T2-weighted images and isointense or hypointense on T1-weighted images. MRI findings in patients with spinal cord TB have both diagnostic and prognostic significance. Cord atrophy or cavitation and the presence of syrinx on MRIs may be associated with a poor outcome (Wasay et al, 2006).
• Perform magnetic resonance angiography and venography if indicated.
• • Findings on conventional 4-vessel angiography and magnetic resonance angiography most typically have included evidence of hydrocephalus, narrowing of the arteries at the base of the brain, and narrowed or occluded small and medium-sized arteries.
  • Imaging studies, both CT scanning and MRI, are performed with and without enhancement, as long as the renal function of the patient is not compromised.
  • Basal cisterns often enhance strikingly, corresponding to the thick exudate that is observed pathologically. The quadrigeminal cistern, interpeduncular fossa, ambient cistern, and chiasmatic region are particularly involved, owing to associated arachnoiditis. Meningeal enhancement is more common in HIV-infected patients.
  • Contrast enhancement further delineates focal parenchymal and space-occupying lesions, with or without associated hydrocephalus.
• Skull radiography may reveal evidence of increased intracranial tension in children, in the form of sutural diastasis. During follow-up of patients with TBM, intracranial calcification may be evident.
• • Calcification occurs in 2 main sites, (1) more commonly in the basal meninges and, (2) to a lesser extent, within brain substance.
  • Calcification is generally in the sellar region, either as a single lesion or as a cluster of small calcifications. These calcifications sometimes harbor tubercle bacilli, which may be responsible for a relapse of the disease.

Other Tests

• The diagnosis of TBM cannot be made or excluded on the basis of clinical findings. Tuberculin testing is of limited value. Variable natural history and accompanying clinical features of TBM hinder the diagnosis. Ziehl-Neelsen staining lacks sensitivity, and culture results are often too late to aid clinical judgment. Semiautomated radiometric culture systems, such as the Bactec 460, and automated continuously monitored systems have reduced culture times. Newer methods involving amplification of bacterial DNA by PCR and comparable systems have not been assessed completely and may not be suitable for laboratories in developing countries with limited resources. The duration of chemotherapy for TBM is unclear, and the benefits of adjuvant corticosteroids remain in doubt. Death may occur as a result of missed diagnoses and delayed treatment.
• In one study, EEG findings were abnormal in 24 patients. The EEG abnormalities included diffuse theta-to-delta slowing in 22 patients, intermittent rhythmic delta activity in the frontal region in 15 patients, right-to-left asymmetry in 5 patients, and epileptiform discharges in 4 patients. At the end of 3 months, 5 patients had died, while recovery was poor in 13 patients, partial in 3, and complete in 11. EEG findings correlated with severity of meningitis and degree of coma; outcome at 3 months was assessed using the Barthel index score.
• In the same study, brainstem auditory evoked potential abnormalities were observed in more than 50% of patients with TBM. Motor and somatosensory evoked potentials may be helpful in objective documentation of respective motor and sensory functions in patients with TBM and altered sensorium.
• A dot-immunobinding assay (Dot-Iba) has been standardized to measure circulating antimycobacterial antibodies in CSF specimens for the rapid laboratory diagnosis of TBM (Sumi, 2000).
• • Specific CSF immunoglobulin G antibody to M tuberculosis from a patient with culture-proven TBM was isolated and coupled with activated cyanogen bromide-Sepharose 4B. A 14-kd antigen present in the culture filtrates of M tuberculosis was isolated by immunosorbent affinity chromatography and used in the Dot-Iba to quantitate specific antimycobacterial antibodies. The Dot-Iba gave positive results in all 5 patients with culture-proven TBM; no false-positive results were obtained from CSF specimens from patients with partially treated pyogenic meningitis.
  • In the opinion of Sumi et al, the Dot-Iba developed in their laboratory is a simple, rapid, and specific method and, more importantly, is suited for the routine application in laboratories with limited resources. This is not yet available for routine use, and proof of its utility requires further studies.
• Use of neurochemical markers has been investigated in patients with aseptic meningitis or TBM.
• • CSF levels of amino acids, nitrite (a metabolite of nitric oxide), vitamin B-12, and homocysteine were quantitated in both groups of patients.
  • Levels of excitatory amino acids aspartic acid and glutamic acid, GABA, glycine, and tryptophan all were increased significantly in both groups, whereas levels of taurine were decreased and levels of phenylalanine were increased only in patients with TBM.
  • Levels of nitrite and its precursor arginine were significantly higher in patients with TBM, whereas they were unchanged in patients with aseptic meningitis.
  • Levels of homocysteine were increased significantly, and levels of vitamin B-12 decreased only in patients with TBM, whereas these levels were unchanged in patients with aseptic meningitis. This indicates that patients with TBM are particularly prone to vitamin B-12 deficiency, resulting in increased levels of homocysteine and free radicals, showing the importance of these biological markers in the development and design of therapeutic approaches.

Procedures

• For more information about CSF studies, see Lab Studies.
• Spinal tap carries some risk of herniation of the medulla in any instance when intracranial pressure is increased (eg, TBM), but if meningitis is suspected, the procedure must be performed regardless of the risk, using suitable precautions and obtaining informed consent before the procedure.
• • Use manometrics to check CSF pressure. Typically, the pressure is higher than normal.
  • Inspect the CSF visually and note its gross appearance. It typically is clear or slightly turbid. If the CSF is left to stand, a fine clot resembling a pellicle or cobweb may form. This faintly visible "spider's web clot" is due to the very high level of protein in the CSF (ie, 1-8 g/L, or 1000-8000 mg/dL) typical of this condition.
  • Hemorrhagic CSF also has been recorded in proven cases of TBM; this is attributed to fibrinoid degeneration of vessels resulting in hemorrhage (Smith, 1947).
  • Abnormalities in the CSF depend on a tuberculin reaction within the subarachnoid space. Acellular CSF has been reported in elderly patients and patients who are HIV positive.
  • CSF typically has an elevated protein level, marked hypoglycorrhachia, and a pleocytosis, initially polymorphs then lymphocytes.
  • • In adults, mean the WBC count averages around 223 cells/µL (range, 0-4000 cells/µL), while the proportion with neutrophilic pleocytosis (>50% neutrophils) averages 27% (range, 15-55%) and the proportion with normal cell count averages 6% (range, 5-15%). In children, these numbers are 200 cells/µL (range, 5-950 cells/µL), 21% (range, 15-30%), and 3% (range, 1-5%), respectively.
    • The mean protein level in adults averages 224 mg/dL (range, 20-1000 mg/dL), and in children it is 219 mg/dL (range, 50-1300 mg/dL). The proportion with normal a protein content averages 6% (range, 0-15%) for adults and 16% (range, 10-30%) for children. The proportion with depressed glucose levels ( <45 mg/dL or 40% of serum glucose) averages 72% (range, 50-85%) for adults and 77% (range, 65-85%) for children.
  • A positive smear result is present in an average of 25% (range, 5-85%) of adults and only 3% (range, 0-6%) of children, whereas the numbers with a positive CSF culture average 61% (range, 40-85%) and 58% (range, 35-85%) for adults and children, respectively. Failure to respond to treatment should prompt a search for fungal infections or malignancy.
  • For patients with HIV and/or immunosuppression, while the mean WBC count in the CSF is 230 cells/µL, as many as 16% of HIV-infected patients may have acellular CSF, compared with 3-6% of HIV-negative patients. Patients whose CSF samples are acellular may show pleocytosis if a spinal tap is repeated 24-48 hours later. The proportion who have neutrophilic pleocytosis of the CSF (>50% neutrophils) is 42% (range, 30-55%). While HIV-infected patients generally have a mean protein level of 125 mg/dL (range, 50-200 mg/dL), as many as 43% of these patients may have a normal CSF protein content. The proportion who have depressed CSF glucose levels ( <45 mg/dL or 40% of serum glucose) averages around 69% (range, 50-85%). The number who have a positive CSF culture results averages 23%.
• Within a few days after commencement of anti-TB therapy, the initial mononuclear pleocytosis may change briefly in some patients to one of polymorphonuclear predominance, which may be associated with clinical deterioration, coma, or even death. This therapeutic paradox has been regarded by some authors as virtually pathognomonic of TBM. This syndrome is probably the result of an uncommon hypersensitivity reaction to the massive release of tuberculoproteins into the subarachnoid space.
• When CSF analysis offers no clues and the diagnosis remains elusive, a brain biopsy may be warranted under appropriate circumstances. This carries significant risks, however, including epidural hematoma and hydrocephalus.

Histologic Findings

The Ziehl-Neelsen stain uses the properties of the cell wall to form a complex that prevents decolorization by acid or alcohol. Fluorochrome tissue stains also can be helpful in the diagnosis of TBM (see Image 3).

Hematogenous spread leads to perivascular microscopic foci that form tubercles. These characteristically are associated with central caseation and epithelioid and giant cells. Gradually they enlarge to form numerous small macroscopic tuberculomas, which then may coalesce. In essence, tuberculomas are conglomerate caseous foci within the substance of the brain that develop from deep-seated tubercles (see Image 4).

Clinically silent single or multiple enhancing granulomata are observed in a significant minority of cases of TBM and in some cases of miliary TB without meningitis (Stevens, 1978).

Staging

• In 1948, the British Medical Research Council developed a method for staging the severity of the disease.
• • Stage I describes the early nonspecific symptoms and signs, including apathy, irritability, headache, malaise, fever, anorexia, nausea, and vomiting, without any alterations in the level of consciousness.
  • Stage II describes altered consciousness without coma or delirium but with minor focal neurological signs. Symptoms and signs of meningism and meningitis are present, in addition to focal neurological deficits, isolated CN palsies, and abnormal involuntary movements.
  • Stage III describes an advanced state with stupor or coma, severe neurological deficits, seizures, posturing, and/or abnormal movements.
  • Prognosis is related directly to the clinical stage at diagnosis.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

The duration of chemotherapy for TBM is unclear, and the benefits of adjuvant corticosteroids remain in doubt. Death may occur as a result of missed diagnoses and delayed treatment.

• The best antimicrobial agents in the treatment of TBM include isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and streptomycin (SM), all of which enter CSF readily in the presence of meningeal inflammation. Ethambutol is less effective in meningeal disease unless used in high doses. The second-line drugs include ethionamide, cycloserine, ofloxacin, and para-amino salicylic acid (PAS). INH, RIF, and PZA are bactericidal. RIF and SM achieve optimal CSF levels only when the meninges are inflamed. Usually, intrathecal drugs are not necessary. Treatment is best started with INH, RIF, and PZA. The addition of a fourth drug is left to the choice of the local physicians and their experience, with little evidence to support the use of one over the other.
• Evidence concerning the duration of treatment is conflicting. The duration of conventional therapy is 6-9 months, although some investigators still recommend as many as 24 months of therapy. No guidelines exist as to the components and duration of treatment in the case of multidrug-resistant TBM.
• Studies have shown that young children with TBM can be treated safely for 6 months with high doses of anti-TB agents without overt hepatotoxicity and with a low risk of relapse. Children must be treated for 12 months with combination antibiotic therapy and adjunctive corticosteroids. Twelve months is probably a conservative estimate of the time required for bacterial cure. The rationale behind the use of adjuvant corticosteroids lies in reducing the harmful effects of inflammation as the antibiotics kill the organisms. The use of corticosteroids in adults is controversial; they may be indicated in the presence of increased intracranial pressure, altered consciousness, focal neurological findings, spinal block, and tuberculous encephalopathy. Treatment of tuberculoma consists of high-dose steroids and continuation of antituberculous therapy, often for a prolonged course.
• Hyaluronidase has been used in spinal arachnoiditis with good results. Gourie-Devi and Satish Chandra (1980) recommend the use of hyaluronidase administered intrathecally in cases of arachnoiditis complicating TBM.
• In 2006, Walker et al report that BCG vaccination is partially protective against TB meningitis; therefore, a history of BCG vaccination or the presence of a BCG vaccination scar affords some degree of reassurance when considering a diagnosis of TBM (grade C). In patients in whom TBM is suspected clinically, the diagnosis must be rigorously investigated; a history of BCG vaccination does not rule out the diagnosis (grade C). In 2005, Kumar et al report that children with TBM who have been vaccinated with BCG appear to maintain better mentation and have superior outcomes. They believe this may be explained, in part, by the better immune response to infection, as is reflected in the higher CSF cell counts in their patient group.

Surgical Care

• In patients with evidence of obstructive hydrocephalus and neurological deterioration who are undergoing treatment for TBM, placement of a ventricular drain or ventriculoperitoneal or ventriculoatrial shunt should not be delayed.
• Studies suggest that prompt ventriculoatrial or ventriculoperitoneal shunting improves outcome, particularly in patients presenting with minimal neurological deficit.
• Unless a mass effect is compromising vital structures, surgical intervention is rarely required in the treatment of tuberculomas.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

First-line therapy includes INH, RIF, PZA, SM, and ethambutol. Second-line therapy includes ethionamide, cycloserine, PAS, aminoglycosides, capreomycin, and thiacetazone.

Potential new agents include oxazolidinone and isepamicin. Fluoroquinolones useful in the treatment of TBM include ciprofloxacin, ofloxacin, and levofloxacin. A new rifamycin called rifapentine has been developed.

Trials for novel agents for the treatment of TB are under way. Long-acting rifamycin derivatives and potent fluoroquinolone antibiotics have been studied, and they lead the way for improved regimens against active and latent TB. The recent rapid increase in knowledge of mycobacterial pathogenesis is likely to lead to the advent of potent new drugs in latent disease and against the phenomenon of persistence. Without a doubt, sustained and increased funding for basic research plays a key role in eradicating this global epidemic altogether.

Finally, because of the intensity of the inflammatory and fibrotic reactions at the meningeal site, adjunctive corticosteroids, in addition to standard antituberculous therapy, is recommended in TM.

Studies have confirmed the benefit of adjunctive corticosteroid therapy on survival and intellectual outcome in children with TBM, with enhanced resolution of basal exudates but no effect on intracranial pressure or the incidence of basal ganglia infarction (Schoeman, 1997).

Wasay, in his 2006 editorial, discusses at length CNS TB and the paradoxical response. The paradoxical response to antituberculous therapy is well known; it usually develops after approximately 2 weeks of treatment. It is characterized by the clinical or radiological worsening of preexisting tuberculous lesions or the development of new lesions not attributable to the normal course of disease in a patient who initially improved with antituberculous therapy. Up to 10% of patients with CNS TB report the paradoxical response, and this number may be as high as 30% in HIV-infected patients (Wasay, 2003; Gupta, 2003).

The paradoxical response has been attributed as a component of immune reconstitution inflammatory syndrome or immune restoration syndrome, which results from an exuberant inflammatory response toward incubating opportunistic pathogens (Shelburne, 2003). An increase in the incidence and severity of the paradoxical response is noted in HIV-infected patients on highly active antiretroviral therapy (Breen, 2004). Patients demonstrating a paradoxical response are more likely to have lower baseline lymphocyte counts, followed by a surge (Cheng, 2003).

Drug Category: Antitubercular agents

Any regimen must contain multiple drugs to which the mycoplasma is susceptible. In addition, the therapy must be taken regularly and continued for a sufficient period.

Drug Category: Fluoroquinolones

Several fluoroquinolones have shown in vitro activity against M tuberculosis. The target of the quinolones is the enzyme DNA gyrase. Ofloxacin and ciprofloxacin are compounds of this family that are licensed for use in the United States. However, neither of these drugs is licensed for treatment of TB.

The minimal inhibitory concentration of ofloxacin and ciprofloxacin is approximately 1 mcg/mL for a wide range of strains of M tuberculosis, compared with a peak serum concentration of 4.3 mcg/mL 1-2 h after a 750-mg dose of ciprofloxacin, and a 4.6 mcg/mL peak serum concentration after multiple 400-mg doses of ofloxacin. One study showed a similar minimal inhibitory concentration for ofloxacin in the macrophage model, and minimal bactericidal concentration was found to be 2 mcg/mL; however, the bactericidal activity of ofloxacin was less than that of RIF. Another study found i