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Tuberculosis meningitis

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Tuberculous meningitis

I. What every physician needs to know.

Tuberculous (TB) meningitis is a rare disease in developed countries and is often difficult to diagnose. The presentation is variable and patients often do not present with classic symptoms. While it is often described as a subacute meningitis with symptoms occurring over several weeks, patients often present with other symptoms. The diagnosis is difficult to establish and the clinician must have a high index of suspicion. Delay in diagnosis results in complications, and failure to establish the diagnosis results in death.

In developed countries, TB meningitis is rare, and accounts for about 1% of all TB cases. It can occur following primary infection or as part of disseminated disease with reactivation of TB. In developing countries, TB meningitis most often occurs in children aged 0-4 years and follows primary infection. However, with the advent of human immunodeficiency virus (HIV), TB meningitis is becoming much more common in adults, and may be the most common cause of meningitis in areas of the world with a high prevalence of HIV infection.

II. Diagnostic Confirmation: Are you sure your patient has Tuberculous Meningitis?

Typically, the diagnosis of TB meningitis is considered when patients present with a change in mental status and are found to have lymphocytic pleocytosis. The typical cerebrospinal fluid (CSF) profile demonstrates a predominance of lymphocytes, low glucose and elevated protein. If the CSF acid-fast bacillus (AFB) smear is positive, this is very helpful, but is usually not the case. Culture can take up to 8 weeks, and even the tests that are supportive for the diagnosis are often not available without some delay. Because of this, treatment must be started prior to confirmation of diagnosis in suspected cases. Neuroimaging, particularly magnetic resonance imaging (MRI) can be helpful early on, and may demonstrate basilar meningitis.

TB infection occurs by inhalation of bacilli through droplets. The bacteria typically infects alveolar macrophages and localized proliferation of bacteria occur followed by spread to regional lymph nodes. This is referred to as a primary complex. While this is occurring, there is a brief period of bacteremia during which TB can spread to other organs in the body, including the central nervous system. TB bacilli can spread to the meninges and from subpial or subependymal foci of infection. These may heal or may rupture into the subarachnoid space. If rupture into the subarachnoid space occurs, there is an intense inflammatory response, along with symptoms of infection.

The resultant inflammation can cause an intense basilar meningitis, obliterative vasculitis, encephalitis, and obstruction of CSF flow with resultant hydrocephalus. A thick exudate often involving the basal parts of the brain can result in adhesions and resultant cranial neuropathies. The vasculitis may involve small or large arteries, and stroke syndromes may occur. Blockage of the basilar cisterns can result in hydrocephalus. Inflammation may extend to involve the brain parenchyma, and encephalitis may occur.

A. History Part I: Pattern Recognition:

TB meningitis is often described in three stages, but patients don't necessarily progress from one stage to the next in an orderly fashion. Stage 1 is considered alert, stage 2 is lethargy, and stage 3 is coma. The typical patient will present with several weeks of headache, fever, and a subacute alteration in mental status. They may have night-sweats and fever along with weight loss, and there may be evidence of pulmonary TB or other extrapulmonary disease.

Following the initial symptoms, patients develop more pronounced meningeal symptoms, and may present with worsening headache, nuchal rigidity, vomiting, fever, and cranial neuropathies. If the disease goes unrecognized, patients will progress to stupor and coma, along with neurological complications such as infarcts, focal signs from tuberculomas, hydrocephalus, seizures, and paralysis. For patients who are untreated, death may occur within about 2 months of initial symptoms, but the time course is variable and can be prolonged.

B. History Part 2: Prevalence:

The exact prevalence of TB meningitis is unknown, but it is estimated to account for about 1% of all TB cases annually. The risk factors for developing TB meningitis are the same as the risk factors for other forms of TB. In developing countries, age is the greatest predictor for development of TB meningitis, but in developed countries, it is usually an adult disease.

Approximately 5-10% of all individuals infected with TB will eventually develop active disease. In individuals with HIV infection, this number is much higher. Being immunocompromised or immunosuppressed, alcoholism, diabetes, severe kidney disease, silicosis, head and neck cancer, malnutrition and substance abuse are all risk factors for development of active TB. Genetic factors may also influence the risk for development of TB meningitis. It has been demonstrated that a polymorphism in the Toll-interleukin 1 receptor confers increased risk of developing TB meningitis.

C. History Part 3: Competing diagnoses that can mimic Tuberculous Meningitis.

The differential diagnosis depends on the presentation of TB meningitis. In patients who present with the classic subacute meningitis syndrome, other diseases to consider will include fungal meningitis (cryptococcal meningitis, histoplasmosis and coccidioidomycosis), carcinomatous meningitis, neurosyphilis, brucellosis, and parasitic infections.

A meticulous travel history becomes essential, as the risk factors for developing specific diseases will depend on exposure. Infections such as trypanosomiasis, schistosomiasis and Angiostrongylus cantonensisshould be considered given specific travel history. Also, some parasitic infections and coccidioidomycosis may demonstrate an eosinophilic pleocytosis, which aids in narrowing the differential diagnosis. Neurosyphilis is relatively easy to diagnose with serological tests, and carcinomatous meningitis is diagnosed with cytology. Other diseases to consider include central nervous system (CNS) lupus and sarcoidosis. Neurosarcoidosis may be suggested by neuroimaging, but it may also present with cranial nerve involvement and biopsy may be necessary for definitive diagnosis.

For patients who present with syndromes resulting from tuberculomas, the differential diagnosis will include diseases that cause mass lesions including brain abscess, neoplasm, and fungal infection. Patients who present with vasculitis due to TB may present with stroke syndromes, although this will be rare.

D. Physical Examination Findings.

Patients will most often present with fever, headache and altered mental status. Nuchal rigidity may be present, and in more advanced disease, patients will have cranial nerve palsies, focal neurological deficits, and signs of raised intracranial pressure.

In elderly patients, meningeal signs are less frequently present. Fever and headache are the most common presenting signs, and symptoms are present on average for about 2 weeks prior to presentation. Change in mental status is seen in about 70%. Older adults may present with memory loss and personality changes, while pediatric patients often present with raised intracranial pressure and seizures. Cranial nerve palsies are present in about 25% of patients. In advanced disease, paraplegia may be present. Movement disorders have also been described and are more common in children than adults.

E. What diagnostic tests should be performed?

The most important diagnostic test is CSF examination. This will generally yield a low glucose, lymphocytic pleocytosis, and elevated protein. It is important to obtain a serum glucose at the same time as the CSF glucose, as diabetic patients may have elevated serum glucose and the CSF glucose may be relatively low when compared to serum. The AFB smear is positive in 5-30% of cases, and is virtually diagnostic when present. Culture of CSF is positive in 45-90% of cases, but can take up to 8 weeks to grow. Polymerase chain reaction (PCR) for detection of TB deoxyribonucleic acid (DNA) has variable sensitivity, but is highly specific when positive. Yield for both AFB smears and culture is greater when a larger volume of CSF is obtained. Repeated samples may also be necessary.

Neuroimaging, especially MRI can be helpful in establishing the diagnosis.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

As stated above, examination of the CSF is critical for diagnosis. Patients with the appropriate history or CSF formula should have CSF sent for AFB smear, culture, and consider PCR for detection of Mycobacterium tuberculosis DNA. The sensitivity for these tests increases when a combination of tests is used and when repeated samples are sent for evaluation. In addition, patients with tuberculous meningitis may also have extra-pulmonary disease elsewhere, and AFB blood cultures may be helpful. This is especially true in the setting of HIV infection.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Neuroimaging is helpful both for evaluating patients for TB meningitis as well as for determining whether complications are present. MRI and or computed tomography (CT) will often demonstrate basilar meningeal enhancement and hydrocephalus. In addition, patients may have periventricular infarcts, cerebral edema, tuberculomas, and contrast enhancement of the basilar cisterns. MRI is considered more sensitive than CT, and gadolinium contrast can demonstrate basilar meningeal enhancement early on.

Patients with TB meningitis may also have pulmonary TB, and the diagnosis of TB meningitis is often established by diagnosing TB elsewhere. Chest X-ray often shows hilar lymphadenopathy, pulmonary infiltrates, or miliary disease. If chronic meningitis occurs in the setting of pulmonary TB, a presumptive diagnosis of TB meningitis can be made.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

This disease is difficult to diagnose, and because of the length of time it takes for confirmatory tests to return or for patients to respond to therapy, many other tests may be ordered while waiting for results. There is no specific over-utilized test in establishing this diagnosis. However, it must be recognized that this diagnosis may be made on a clinical basis alone without laboratory confirmation.

III. Default Management.

The medications used to treat TB meningitis are the same as those used for pulmonary TB. Isoniazid, rifampin, pyrazinamide, and ethambutol are the drugs that are used initially. After the first 2 months of therapy, ethambutol and pyrazinamide can be discontinued for drug-susceptible strains. Treatment is continued for 9-12 months total. If patients are unable to take oral medication, intravenous isoniazid, rifampin, aminoglycosides, capreomycin, or fluoroquinolones can be used. Some individuals advocate even longer course of therapy, such as up to 2 years for tuberculous meningitis.

In addition, patients who have altered mental status at presentation are at high risk for permanent neurological sequelae and death. There have been studies demonstrating a decrease in mortality in individuals who present with lethargy or altered mental status when dexamethasone is administered with TB therapy. In those individuals who present with coma, no difference in outcome has been noted. However, the current recommendation is to treat all individuals with suspected/proven TB meningitis with dexamethasone 8 milligram (mg)/day for children weighing less than 25 kilogram (kg) and 12 mg/day for children weighing greater than 25 kg and adults. This dose is continued daily for 3 weeks and then gradually decreased over the next 3 weeks.

A. Immediate management.

By far the most important thing in management of TB meningitis is to include this disease in the differential diagnosis of an individual presenting with subacute meningitis. Treatment is empiric, often for weeks or even months before diagnosis is established, and as mentioned, it is not always possible to establish a definite diagnosis. Starting antituberculous therapy as soon as TB meningitis is suspected is the first step in management.

B. Physical Examination Tips to Guide Management.

There are no specific physical exam findings that lead to diagnosis. However, because TB meningitis often causes a basilar meningitis with thick exudate, patients may present with multiple cranial neuropathies. Other focal neurological signs may be present, and patients may have altered mental status and meningismus. Also, signs of increased intracranial pressure may be present.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Once the diagnosis of TB meningitis is suspected and therapy is started, it is often necessary to obtain repeat CSF to evaluate response to treatment. For individuals who improve on clinical basis after starting therapy, this may not be needed. However, for patients who present with altered mental status, it can be difficult to gauge response without repeat CSF evaluation.

All of the antituberculous drugs have side effects including hepatotoxicity and some renal toxicity. Isoniazid can cause peripheral neuropathy and other CNS effects. Drug hypersensitivity and lupus-like reaction are also possible.

Rifampin also can cause hepatotoxicity, orange discoloration of urine and has multiple drug interactions. Ethambutol can cause retrobulbar neuritis which is seen as loss of color vision. Color perception must be monitored during treatment. Pyrazinamide can also cause hepatotoxicity, dermatitis, acute gouty flares and other side effects. All of the drugs used to treat TB can have multiple side effects, and there should be familiarity with drugs prior to prescribing them. In the event that severe drug reactions occur, it may be necessary to halt therapy temporarily. Alternate regimens may be necessary with severe reactions.

D. Long-term management.

Long-term management involves management of any complications that occur from TB meningitis such as neurological deficits or memory impairment. Some individuals may develop increased intracranial pressure and may require CNS shunts. Also, side effects from antituberculous drugs are common and must be monitored.

E. Common Pitfalls and Side-Effects of Management.

The standard treatment of drug-susceptible tuberculosis consists of four drugs for the initial 2 months, followed by modification of the regimen when drug susceptibility is known.

  • Isoniazid 5mg/kg (maximum 300 mg), rifampin 10 mg/kg (maximum 600 mg), pyrazinamide 15-30 mg/kg (maximum dose 2000 mg) and ethambutol 15-20 mg/kg (maximum dose 1600 mg).

The treatment for TB meningitis is the same as for pulmonary TB except that the treatment is prolonged to 9-12 months. Also, studies have demonstrated a decrease in mortality in children and adults with TB meningitis who received corticosteroid therapy. Dexamethasone 12 mg/kg for adults more than 25 kg given daily for 3 weeks and then gradually tapered over the next 3 weeks, or prednisone 60 mg/day for adults for 3 weeks and then tapered over the next 3 weeks is given in addition to anti-tuberculous therapy.

The most important aspect of treating TB is to avoid exposure to inadequate therapy which can lead to development of resistance. Individuals should have directly observed therapy. Drugs used to treat TB are fairly expensive, and individuals should not be given prescriptions and left to take the medications on their own. It is very important to ensure that patients have access to medications and that they are actually taking them as directed. Directly observed therapy has been demonstrated to be highly beneficial in the treatment of tuberculosis.

Drug side effects are common and any new problem should be evaluated for the possibility of adverse drug reaction.

The biggest pitfall in treatment of TB is lack of familiarity with medications and administration of inadequate drug regimens which can lead to resistance. Expert assistance should be sought in the management of any form of tuberculosis, but especially TB meningitis.

IV. Management with Co-Morbidities.

Management of TB is not altered due to specific co-morbidities. Rifampin, which is one of the cornerstones of TB therapy, has many drug interactions, and dosage adjustment for other drugs may be required. If severe drug interactions exist, an alteration in the regimen used to treat TB may be considered.

A. Renal Insufficiency.

Pyrazinamide is mostly metabolized by the liver, but there are metabolites that build up in individuals with end-stage renal disease. For individuals on hemodialysis, the medication is administered 3 times weekly after dialysis.

B. Liver Insufficiency.

The medications used to treat tuberculosis, particularly isoniazid and rifampin can cause hepatitis, so increased monitoring of liver function tests is recommended. All drug regimens that are used to treat tuberculosis can cause drug-induced liver injury. Patients should be advised to avoid other hepatotoxic medications and abstain from alcohol. Individuals who have underlying hepatitis C or chronic hepatitis B infection are at increased risk for drug-induced hepatitis. TB treatment should be held if patients develop an increase in transaminases more than 3 times the upper limit of normal, and potential causes should be sought. Rechallenge may be considered if the cause of transaminase elevation is unclear. Change in the treatment regimen may be necessary.

In addition, pyrazinamide may be avoided in individuals with severe liver disease.

C. Systolic and Diastolic Heart Failure.

No change in standard management. If patients are being anticoagulated with oral warfarin, dosage adjustment for warfarin and increased monitoring will be necessary.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management. If patients are being anticoagulated with oral warfarin, dosage adjustment for warfarin and increased monitoring will be necessary.

E. Diabetes or other Endocrine issues.

No change in standard management. Excellent glucose control is helpful in controlling infection.

F. Malignancy.

No change in standard management. There may be drug interactions with chemotherapeutic agents and regimen or dose adjustment may be necessary.

G. Immunosuppression (HIV, chronic steroids, etc).

Caution should be used when initiating antiretroviral therapy in the setting of tuberculous meningitis, as more serious adverse events have been described in HIV-infected individuals who were started on antiretroviral therapy within 2 weeks of initiation of TB therapy in the setting of TB meningitis. It is not recommended to start antiretroviral therapy within the first 8 weeks of initiation of treatment for TB in the setting of HIV infection. Immune reconstitution inflammatory syndrome may worsen TB meningitis.

The drugs that are used to treat HIV infection often have significant drug interactions with rifampin, and may need to be changed to alternate regimens. Since treatment of tuberculosis is more urgent than the treatment of HIV infection, the HIV regimen is adjusted in order to allow treatment of tuberculosis. Efavirenz is preferred over protease inhibitors when rifampin is being administered for the treatment of tuberculosis. Integrase inhibitor therapy may have less drug interactions than protease inhibitor regimens or non-nucleoside regimens. Due to extensive drug interactions, dosage adjustment may be necessary for antiretrovirals.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management. If patients are unable to take oral medications due to malabsorption, intravenous medications may be used such as fluoroquinolones and aminoglycosides. Both isoniazid and rifampin are also available in intravenous formulations, although isoniazid may be difficult to obtain.

J. Hematologic or Coagulation Issues.

No change in standard management. If patients are being anticoagulated with oral warfarin, dosage adjustment for warfarin and increased monitoring will be necessary.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management. Directly observed therapy is recommended for all patients with disease due to TB, and is especially important in patients with memory impairment.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Patients with TB meningitis may develop paradoxical enlargement of tuberculomas during treatment for TB meningitis. The symptoms will depend on the location of the lesion. Other complications of TB meningitis have been discussed previously. Any worsening headache or decline in mental status should prompt repeat neuroimaging to determine whether there is hydrocephalus or an expanding mass lesion is present.

Patients receiving isoniazid and rifampin may develop hepatitis, although this is often noted on blood tests prior to the development of any symptoms. If patients develop nausea, emesis, or abdominal pain, liver function tests should be checked.

B. Anticipated Length of Stay.

Due to the difficulties in establishing the diagnosis of TB meningitis, it is not unusual for patients to have a prolonged length of stay. Two weeks or more would be considered within the normal range for this illness.

C. When is the Patient Ready for Discharge.

The patient is ready for discharge when other illnesses have been ruled out and the patient is able to tolerate the TB regimen. Because patients often have neurological problems related to this illness, it is common for patients to be discharged to long-term care facilities.

D. Arranging for Clinic Follow-up.

Ideally, patients should be seen for follow-up by an individual who is very knowledgeable about the treatment of TB. Patients should be linked with the provider who will be providing directly observed therapy prior to discharge. Patients should be seen by the physician who will be managing the TB meningitis within one week after discharge. Often this will be a specific TB clinic or an Infectious Disease physician.

1. When should clinic follow up be arranged and with whom.

See above

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Patients should have a complete blood count (CBC) and liver function tests (LFT) prior to the clinic visit. HIV testing should be done if not already completed in the hospital.

E. Placement Considerations.

As mentioned above, patients often have neurological problems due to TB meningitis. Often this will require placement in a skilled nursing facility for a period of time.

F. Prognosis and Patient Counseling.

The prognosis depends on the stage of presentation at which treatment was begun and which complications occurred. This will be variable. If patients present early in the course of illness and a diagnosis is established promptly, they may not have any long-term sequelae of infection. However, mortality rates for TB meningitis remain high.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

The most common cause for readmission is management of hydrocephalus. Should a patient develop hydrocephalus, readmission will be required. The other main reason for readmission is drug toxicity. Individuals and their caretakers should be counseled about medication side effects and toxicities and should be advised to call immediately in the event these occur. All of the drug regimens used for the treatment of TB can cause drug induced liver injury, and individuals should be counseled to stop taking all medications and call in the event that abdominal pain, nausea, emesis or jaundice occur.

VII. What's the Evidence?

"Treatment of tuberculosis". MMWR Recomm Rep. vol. 52. 2003 Jun 20. pp. 1-77.

Thwaites, GE, Nguyen, DB, Nguyen, HD, Hoang, TQ, Do, TT, Nguyen, TC. "Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults". N Engl J Med.. vol. 351. 2004 Oct 21. pp. 1741-51.

Garg, RK. "Tuberculosis of the central nervous system". Postgrad Med J.. vol. 75. 1999 Mar. pp. 133-40.

Havlir, DV, Kendall, MA, Ive, P, Kumwenda, J, Swindells, S, Qasba, SS. "AIDS Clinical Trials Group Study A5221. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis". N Engl J Med.. vol. 365. 2011 Oct 20. pp. 1482-91.

Christie, LJ, Loeffler, AM, Honarmand, S, Flood, JM, Baxter, R, Jacobson, S, Alexander, R, Glaser, CA. "Diagnostic challenges of central nervous system tuberculosis". Emerg Infect Dis.. vol. 14. 2008 Sep. pp. 1473-5.

Christensen, A-SH, Roed, C, Omland, LH, Andersen, PH, Obel, N. "Long-Term Mortality in Patients with Tuberculous Meningitis: A Danish Nationwide Cohort Study". PLoS ONE. vol. 6. 2011. pp. e27900.

Gupta, BK, Bharat, A, Debapriya, B, Baruah, H. "Adenosine Deaminase Levels in CSF of Tuberculous Meningitis Patients". J Clin Med Res.. vol. 2. 2010 Oct 11. pp. 220-4.

Nahid, P, Dorman, SE, Alipanah, N. "Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: treatment of drug-susceptible tuberculosis". Clin Infect Dis. 2016.

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