Ersin Tan, MD
DESCRIPTION 
Tuberculous involvement of the nervous system occurs as meningitis, encephalitis, tuberculoma, spinal arachnoiditis, tuberculous brain abscess, or rarely in other forms such as acute disseminated encephalomyelitis.
EPIDEMIOLOGY
- Incidence/prevalence
- CNS disease caused by mycobacterium tuberculosis is an uncommon yet highly devastating manifestation of tuberculosis. CNS tuberculosis accounts for approximately 1% of all cases of tuberculosis and 5–10% of extrapulmonary tuberculosis cases.
- Tuberculous meningitis develops in 1–2% of tuberculosis cases. Immunodeficiency increases the incidence. From 5 to 10% of AIDS patients have tuberculosis, and up to 10% of these patients develop CNS involvement.
- Race
- American Indians have higher rates than African Americans, who in turn have higher rates than Caucasians.
- Age
- Seen at any age, but peaks in the pediatric and elderly populations.
- Sex
- More common in males than females.
RISK FACTORS
Pregnancy Considerations
A pregnant woman with tuberculosis should be treated because the infection is more hazardous to the patient and fetus than are the drugs. Isoniazid, rifampin, and ethambutol cross the placenta but have not demonstrated teratogenic effects. Streptomycin can cause congenital deafness. There are no adequate data on pyrazinamide. Tuberculosis during pregnancy is not an indication for therapeutic abortion.
ETIOLOGY
Mycobacterium tuberculosis is an aerobic, nonmotile, nonspore forming, acid-fast bacillus. Transmission of the disease from person-to-person is through air. Bacilli are expelled as droplet nuclei from patients while they are coughing, sneezing, and talking. Droplet nuclei can stay in the air for hours before they enter the body through the respiratory tract or rarely through the skin and gastrointestinal tract. Bacilli reach the central nervous system by hematogenous dissemination from a primary focus.
[Outline]
- CNS tuberculosis mainly presents as 4 different clinical pictures.
- Tuberculous meningitis results from hematogenous dissemination or, more frequently, rupture of granulomas into the subarachnoid space. The cause of the neurological symptoms is the thick fibrous exudate that especially fills the basal cisterns. Inflammation and compression of blood vessels cause cerebral infarctions. Cranial nerves traversing the exudate are affected. A communicating type of hydrocephalus commonly develops.
- The onset of symptoms is subacute. Signs of meningeal irritation (headache, vomiting, neck stiffness) are preceded by a prodromal phase lasting 2–3 weeks. Prodromal symptoms are fatigue, night sweats, low-grade fever, anorexia, malaise, and myalgia. Altered consciousness follows meningeal irritation signs. Cranial nerve palsies, especially involvement of cranial nerves III, IV, and VI, are seen in 20–30% of patients. Papilledema, seizures, and hemiparesis occur in 10–15% of patients. Signs of pulmonary or extrapulmonary tuberculosis are often present. If not treated, coma and death occur within 5–8 weeks.
- Tuberculomas are slow-growing granulomas that can be found in the cerebrum, cerebellum, brainstem, subarachnoid, subdural and epidural spaces, and rarely within the spinal cord. They more commonly arise as solitary lesions, but multiple tuberculomas are seen. They cause headache, seizures, and focal neurological deficits.
- Spinal arachnoiditis usually follows intracranial meningitis. Resultant root and cord compression causes pain, paralysis, sensory loss, and sphincter disturbances.
- Tuberculous brain abscess, which is a rare manifestation, develops either from parenchymal tubercular granulomas or via the spread of foci from the meninges. Although clinic manifestations largely depend on their location, patients often present with headache, seizures, papilledema, or other signs of increased intracranial pressure.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Imaging
- Chest x-ray film shows findings of pulmonary tuberculosis in about 50–90% of patients with meningitis.
- Cranial CT with contrast and postgadolinium magnetic MRI demonstrate uniform and intense enhancement of basal cisterns and meninges early in the disease.
- Hydrocephalus is seen as the disease evolves, more commonly in children. Serial CT examinations help to follow the progression of hydrocephalus.
- Tuberculomas are seen as hypodense, avascular, solid, or ring-enhancing lesions on CT scans. Occasionally they may have central calcification surrounded by a hypodense area with ring enhancement (target sign). On MRI, tuberculomas appear isointense to gray matter on T1-weighted images and are either hyperintense (noncaseating lesions) or isointense to hypointense (caseating tuberculomas) on T2-weighted images. They may have surrounding edema. Tuberculomas tend to be infratentorial in children but supratentorial in adults.
Diagnostic Procedures/Other
- CSF examination is the most important investigation. CSF pressure is increased, usually over 300 mm H2O, and there is pleocytosis. Polymorphonuclear leukocytes predominate in the earlier stages. Lymphocytic pleocytosis is seen within 24–48 hours. White cell count is between 100 and 400 cells/mm3. CSF protein concentration is high (between 100 and 200 mg/dL) and glucose is decreased (<45 mg/dL). Acid-fast bacilli can be detected by Ziehl–Neelsen stain on CSF examination. The chance of detection of acid-fast bacilli increases with repeated examinations.
- CSF cultures reveal the microorganism in 50–60% of patients; however, it takes several weeks to obtain the results. Cultures are important for drug sensitivity studies.
- Detection of bacterial DNA with polymerase chain reaction amplification is more sensitive than cultures and provides results within 24–72 hours.
- The detection of mycobacterium tuberculosis-specific antibodies in the CSF is rapid, but the techniques are limited by the inability to differentiate acute infection from previous one and problems with cross-reactivity.
- In tuberculomas without meningitis, CSF is either normal or may show lymphocytic pleocytosis with elevated protein and normal glucose.
DIFFERENTIAL DIAGNOSIS
[Outline]
MEDICATION
- Multiple-drug therapy is necessary because of the possibility of resistant strains of bacteria. Isoniazid and pyrazinamide are the key components of the regimen. Isoniazid penetrates the CSF freely and has potent early bactericidal activity. Rifampicin penetrates the CSF less well (maximum concentrations around 30% of plasma), but the high mortality from rifampicin-resistant tuberculous meningitis has confirmed its central role in the treatment of CNS disease. Penetration of rifampin, streptomycin, and ethambutol through noninflamed meninges is poor.
- British Infection Society guidelines for the treatment of CNS tuberculosis recommends 4 drugs (isoniazid, rifampicin, pyrazinamid, ethambutol) for 2 months followed by 2 drugs (isoniazid, rifampicin) for at least 10 months for all forms of CNS tuberculosis (1)[A].
- Isoniazid: Daily dose 300 mg in adults, 10–20 mg/kg (maximum 500 mg) in children, oral, for 12 months).
- Rifampicin: Daily dose 450 mg (<50 kg) and 600 mg (≥50 kg) in adults, 10–20 mg/kg (maximum 600 mg) in children, oral, for 12 months).
- Pyrazinamide: Daily dose 1.5 g (<50 kg) and 2 g (≥50 kg) in adults, 30–35 mg/kg (maximum 2 g) in children, oral, for 2 months).
- Ethambutol: 15 mg/kg in adults, 15–20 mg/kg (maximum 1 g) in children, oral, for 2 months.
- Although it has been suggested that short-duration (6 months) treatment is as effective as long-duration treatment, it is recommended to continue for 12 months prompted by the uncertain influences of disease severity, CNS drug penetration, undetected drug resistance, and patient compliance on response to therapy.
- All patients with suspected or proven tuberculosis should be offered testing for HIV infection. The treatment principals for HIV-infected and -uninfected individuals are the same, however, since anti-retroviral treatment can complicate the management, a combined approach between HIV and tuberculosis experts is needed.
- British Infection Society guidelines recommend that all patients with tuberculous meningitis receive adjunctive corticosteroids regardless of disease severity at presentation.
- Adults (>14 years) should start treatment with dexamethasone 0.4 mg/kg/day with a reducing course over 6–8 weeks. Children (≤14 years) should be given prednisolone 4 mg/kg/day (or equivalent dose dexamethasone: 0.6 mg/kg/day) for 4 weeks, followed by a reducing course over 4 weeks. Although there is insufficient evidence to recommend routine corticosteroids for tuberculomas without meningitis or with spinal cord tuberculosis, they may be helpful when the symptoms are not controlled or are worsening under treatment or may help those who have acute spinal cord compression due to vertebral tuberculosis.
- Contraindications: Drug allergy
- Precautions
- Side effects
- Isoniazid causes an axonal sensorimotor polyneuropathy by interfering with pyridoxine metabolism. Supplemental pyridoxine should be administered. Slow acetylators of the drug are more susceptible to neuropathy, whereas fast acetylators are prone to hepatotoxicity. Rifampin causes orange discoloration of body fluids, leukopenia, thrombocytopenia, and hemolytic anemia. Streptomycin is ototoxic, and ethambutol carries a risk of optic neuropathy.
- Alternative drugs
- If resistance or allergy to the standard regimen exists, susceptibility studies should guide treatment.
ADDITIONAL TREATMENT
General Measures
Routine supportive care of the unconscious or paralyzed patient, maintenance of fluid and electrolyte balance and nutrition, and care of urinary bladder are important.
COMPLEMENTARY AND ALTERNATIVE THERAPIES
- Symptomatic treatment
- Symptomatic treatment for headaches, vomiting, fever, and seizures is necessary.
SURGERY/OTHER PROCEDURES
- Indications for neurosurgical referral are hydrocephalus, tuberculous cerebral abscess, and vertebral tuberculosis with paraparesis.
- Early ventriculo-peritoneal shunting should be considered in noncommunicating hydrocephalus and in communicating hydrocephalus failing medical management. Communicating hydrocephalus may be initially treated with furosemide (40 mg/day adults) and acetazolamide (1–20 mg/kg adults) or repeated lumbar punctures.
- Urgent surgical decompression should be considered in all patients with extradural lesions causing paraparesis.
- Surgery for tuberculomas is indicated in the presence of intolerably high intracranial pressure or in medical failures.
IN-PATIENT CONSIDERATIONS
Admission Criteria
Tuberculosis patients with neurological involvement must be hospitalized.
[Outline]
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Repeat lumbar punctures are necessary to monitor response to treatment, and CSF pressure should be measured. Serial CT scans are used to follow hydrocephalus and resolution of tuberculomas. Patients receiving isoniazid should be followed monthly for hepatotoxicity. Color vision and visual acuity should be followed in patients receiving ethambutol, and patients should be asked to report any decrease in acuity.
PATIENT EDUCATION
PROGNOSIS
- Tuberculosis of the CNS is associated with higher mortality rates than other forms of tuberculosis.
- Although discovery of antituberculosis agents increased survival, tuberculosis meningitis still carries a 20% mortality risk. The prognosis mainly depends on the severity of findings at the initiation of therapy. Empiric therapy should be started as soon as tuberculosis meningitis is suspected. Other factors that affect the prognosis are
- Age of the patient (children and the elderly have worse prognosis)
- Nutritional status
- Presence of miliary tuberculosis
- Presence of hydrocephalus or cerebral infarction
[Outline]
