Tuberculous Meningitis

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Tuberculous meningitis (TBM) manifests extrapulmonary tuberculosis caused by the seeding of the meninges with the bacilli of Mycobacterium tuberculosis (MTB). MTB is first introduced into the host by droplet inhalation infecting the alveolar macrophage. The primary infection localizes in the lung with dissemination to the lymph nodes. At this point in the infectious process, a high degree of bacteremia can seed the entire body. In tuberculous meningitis, the meninges are seeded by MTB and form sub-ependymal collections called Rich foci. These foci can rupture into the subarachnoid space and cause an intense inflammatory response that causes meningitis symptoms. The exudates caused by this response can encase cranial nerves and cause nerve palsies. They can entrap blood vessels causing vasculitis, and block cerebral spinal fluid (CSF) flow leading to hydrocephalus. These immune responses can lead to complications associated with tuberculous meningitis and chronic sequela in patients who recover from TBM. This activity reviews evaluation, management, and current public health preventative measures to prevent tuberculous meningitis. This activity highlights the interprofessional teams involved in preventing and managing this global health threat.

Objectives:

  • Describe the etiology of tuberculous meningitis.

  • Review the risk factors for developing tuberculous meningitis.

  • Outline the typical presentation of tuberculous meningitis.

  • Summarize the importance of improving care coordination among the interprofessional team to enhance care delivery for patients with tuberculous meningitis.

Introduction

Mycobacterium tuberculosis infection in the central nervous system (CNS) may manifest as meningitis, tuberculoma, and spinal arachnoiditis. Tuberculous meningitis (TBM) is caused by the seeding of the meninges with the bacilli of Mycobacterium tuberculosis (MTB) and is characterized by inflammation of the membranes (meninges) around the brain or spinal cord. Approximately one-third of the world’s population is presumed to be infected with MTB. The number of persons infected with tuberculosis continues to increase despite advances in treatment and worldwide efforts to provide accessibility to medications and universal standard protocoled treatment programs.

Etiology

Predicting which patients with TB infection will develop tuberculous meningitis is difficult. Children with MTB, especially that aged 0 to 4, have a higher incidence of TBM. This infection is more prevalent in the developing world, with a higher incidence of MTB in children. By contrast, in the developed world, TBM is more often seen in adults who experience the reactivation of TB. Other immunocompromised states like chronic steroid use, diabetes mellitus, and chronic alcoholism carry the same risk of developing TBM.[1] The highest correlation remains with HIV co-infection, with reports that these patients are five to ten times more likely to develop CNS disease.[2]

Epidemiology

Despite being a preventable and curable disease, tuberculosis is the leading worldwide cause of death due to infectious etiology. Approximately one-third of the world’s population is presumed to be infected with MTB. Tuberculous meningitis carried a fatal prognosis before the development of anti-tuberculous medications, and it remains the number one cause of death and disability in children infected with MTB. TBM may also occur during immune reconstitution syndrome that can occur shortly after treatment initiation for HIV with antiretrovirals when undiagnosed MTB infection is present.

Tuberculous meningitis presents in 1% of all cases of extra-pulmonary TB. In the developed world, where there is a lower prevalence of TB in the population, estimates are that TBM accounts for 6% of all causes of meningitis. In locations with a higher prevalence of MTB in the population, estimates are that TBM accounts for up to one-third to one-half of all bacterial meningitis.[3] Those with a concurrent HIV infection have a five-fold increased risk of having CNS involvement and disseminated TB, and the risk increases among patients with CD4 count <100 cells/microL.[4]

Pathophysiology

MTB is first introduced into the host by droplet inhalation infecting the alveolar macrophage. The primary infection localizes in the lung with dissemination to the lymph nodes. At this point in the infectious process, a high degree of bacteremia can seed the entire body. In tuberculous meningitis, the meninges are seeded by MTB and form sub-ependymal collections called Rich foci. These foci can rupture into the subarachnoid space and cause an intense inflammatory response that causes meningitis symptoms. The exudates caused by this response can encase cranial nerves and cause nerve palsies. They can entrap blood vessels causing vasculitis, and block cerebral spinal fluid (CSF) flow leading to hydrocephalus, which may be communicating or non-communicating. These immune responses can lead to complications associated with tuberculous meningitis and chronic sequela in patients who recover from TBM.[5]

Tuberculous vasculitis leads to constriction, spasm, thrombosis, and occlusion of intracerebral vessels. This ultimately causes multiple, small, bilateral infarcts, frequently located in the periventricular regions. The basal ganglia, thalamus, and internal capsule are most frequently involved. These infarcts can cause stroke syndromes of the cerebral cortex, basal ganglia, pons, and/or cerebellum.[6]

History and Physical

The clinical presentation of tuberculous meningitis is similar to other forms of chronic meningitis, making the diagnosis difficult and the differential broad. The clinical presentation is associated with fever, headache, altered sensorium, and focal neurologic deficits. Typical neurologic deficits include facial palsy.[2] The additional diagnostic difficulty is that the symptoms can be present anywhere from a few days to six months. The clinical presentation of TBM is similar regardless of HIV status.[1]

Three distinct phases of clinical presentation are usually found:[7]

  1. The early prodromal phase is characterized by the insidious onset of low-grade fever, malaise, headache, and personality change. It usually lasts for one to three weeks.
  2. It is followed by the meningitic phase, characterized by prominent neurologic features, such as protracted headache, vomiting, meningismus, lethargy, confusion, and varying presentation of cranial nerve and long-tract signs.
  3. Confusion gives way to stupor, seizures, coma, and often hemiparesis in the paralytic phase. Death frequently ensues within five to eight weeks of the onset of untreated illness.

Atypical manifestations include rapidly progressive meningitic syndrome suggesting pyogenic meningitis, slowly progressive dementia over months, personality change, social withdrawal, memory deficits, and loss of libido. Patients may sometimes also present with an encephalitic course characterized by convulsions, stupor, and coma without overt signs of meningitis.[8]

Evaluation

Tuberculous meningitis assessment is done by obtaining cerebrospinal fluid (CSF) for analysis. Typically, the CSF reveals low glucose, elevated protein, and modestly elevated WBC count with a lymphocytic predominance. The CSF analysis most closely resembles the CSF analysis of viral meningitis.[3]

Confirming the diagnosis of TB is a difficult diagnostic dilemma; this is especially true in resource-poor areas. Definitive diagnosis results from the identification of MTB in the CSF. Standard Ziehl-Neelsen acid-fast bacilli (AFB) identification smears from CSF are highly unreliable. The positive yield of the AFB smear is broad, with results ranging from 0% to 87%.[2] CSF mycobacterium cultures vary in their yield and are only positive 40 to 83% of the time and can take from 6 to 8 weeks to grow.[3] Over several days, daily large-volume spinal taps sent for microbiological analysis can improve the culture sensitivity by greater than 85%.[9] 

Various new sophisticated modalities for testing for antigens and antibodies specific for TB exist using PCR, but they have not won wide acceptance or utilization; this is due to a lack of access to the testing and high variability in the specificity of the results of the tests. The choice of diagnosis in most cases is going to depend on the resources available. Despite advances in developing improved and accurate diagnostic modalities MTB, confirmation by culture in the CSF remains the gold standard globally.[2][3][9] Culture allows for the assessment of drug sensitivity results. Drug-resistant MTB carries up to twice the mortality.[9]

Other tests that can be utilized are antigen testing in the urine and adenosine deaminase.[10]

These diagnostic difficulties lead to decreased recognition of tuberculous meningitis. They have led to the development of clinical algorithms to help diagnose TBM and differentiate it from other forms of meningitis. The diagnostic algorithm bases its results on CSF values and patient clinical presentation. The criteria consist of the duration of symptoms greater than or equal to 5 days, neurologic impairment, CSF to serum blood glucose level ratio less than 0.5, and CSF protein level greater than 100 mg/dl. These algorithms have been tested in several trials; however, these have been retrospective trials and have not received validation through prospective trials. Therefore, high clinical suspicion must remain based on patient risk factors to diagnose TBM.[11][12]

Neuroimaging can further aid in the diagnosis of TBM. Magnetic resonance imaging (MRI) has demonstrated superiority to computed tomography (CT), as it is of higher quality for assessing the brainstem and spine in detecting TBM. Imaging can assess cerebral infarcts, cerebral edema, and meningeal enhancement. CT imaging is best used to rule out the emergent complication of TBM-related hydrocephalus that could result in the need for immediate neurosurgical intervention. T imaging can also show basal exudates.[9]

Treatment / Management

Anti-tuberculous treatment must start promptly to reduce morbidity and mortality in tuberculous meningitis. First-line anti-tuberculous treatments have excellent CSF penetration. Treatment for TBM consists of two months of an intensive phase of daily isoniazid (INH), rifampin (RIF), pyrazinamide (PZD), and either streptomycin (SM) or ethambutol (EMB). This regimen is followed by the continuation phase of 7 to 10 months of INH and RIF. This treatment plan is based on the assumption that the MTB is not a resistant strain. However, drug sensitivity results can take months to receive, and treatment can be tailored to identify the drug sensitivities.[9] In children, ethambutol (EMB) Is replaced by either an aminoglycoside or ethionamide because of difficulty monitoring for ethambutol-associated optic neuritis.

Treatment with daily rifampin, ethambutol, pyrazinamide, and fluoroquinolone is advised with isoniazid-resistant CNS TB. Moreover, the duration of therapy should be extended to 18 to 24 months, depending on the clinical response to treatment, the severity of the illness, and the patient's immune status.

Adjunctive therapy with corticosteroids has been used in the treatment of TBM. The goal of steroid treatment is to dampen the immune system's exaggerated response, which causes most of the neurologic complications seen with TBM, including tissue damage and brain edema. There has been concern that steroids would reduce the penetration in the CSF of the anti-tuberculous medication, but to date, studies have not shown this to occur. Studies have demonstrated improved clinical outcomes and reduced mortality with the administration of steroids. While there are no trials comparing which steroid is superior, the mainstay treatment has been daily intravenous dexamethasone for up to four weeks, followed by a four-week oral taper.[9]

Differential Diagnosis

  • Bacterial meningitis

  • Viral meningitis

  • Encephalitis of all causes

  • Intracranial space-occupying lesions of various etiologies, including infectious and non-infectious

  • Non-specific viral syndromes

  • Sepsis

  • Acute cerebral vascular accident

  • A sympathomimetic syndrome due to drug abuse

  • Delirium associated with urinary tract infection

Treatment Planning

Drug Preparations Daily dose (adults) Notes
Isoniazid
  • Tablets (50 mg, 100 mg, 300 mg)
  • Elixir (50 mg/5 mL)
  • Aqueous solution (100 mg/mL) for intravenous or intramuscular injection
  • 5 mg/kg (maximum dose 300 mg)
 Pyridoxine (vitamin B6; 25 to 50 mg daily) is given to prevent neuropathy. 100 mg/day is recommended for patients with peripheral neuropathy. 
Ethambutol
  • Tablets (100 mg, 400 mg)

Based on estimated lean body weight

  • Patient weight 40 to 55 kg: 800 mg (14.5 to 20 mg/kg)
  • Patient weight 56 to 75 kg: 1200 mg (16 to 21.4 mg/kg)
  • Patient weight 76 to 90 kg: 1600 mg (17.8 to 21.1 mg/kg) 

Renal dysfunction with creatinine clearance <30 mL/min (by Cockroft-Gault equation) or requiring intermittent hemodialysis, dosing consists of 20 to 25 mg/kg (ideal body weight) per dose orally 3 times a week.

1600 mg is the maximum dose regardless of weight.
Rifampin (rifampicin)
  • Capsules (150 mg, 300 mg)
  • Aqueous solution for intravenous injection
  • 10 mg/kg (maximum dose 600 mg)
 Reduce plasma estrogen concentrations and efficacy of oral contraceptives.
Rifabutin
  • Capsule (150 mg)
  • 5 mg/kg (maximum dose 300 mg)
 The dose may need adjustment with the concomitant use of nonnucleoside reverse transcriptase inhibitors or protease inhibitors.
Pyrazinamide
  • Tablet (500 mg)

Based on estimated lean body weight

  • Patient weight 40 to 55 kg: 1000 mg (18.2 to 25 mg/kg)
  • Patient weight 56 to 75 kg: 1500 mg (20 to 26.8 mg/kg)
  • Patient weight 76 to 90 kg: 2000 mg (22.2 to 26.3 mg/kg)

Renal dysfunction with creatinine clearance <30 mL/min (by Cockroft-Gault equation) or requiring intermittent hemodialysis, dosing consists of 25 to 35 mg/kg (ideal body weight) per dose orally 3 times a week.

Patients weighing more than 90 kg should have serum concentration monitoring.

Weight-based dosing is likely best based on measurements of ideal (versus total) body weight in obese patients.

Table 1. First-line drugs for the treatment of CNS tuberculosis[13]

Drug Adult dose with normal renal function Main adverse effects CSF penetration Pregnancy Notes
Imipenem-cilastatin 1000 mg IV every 6 to 8 hours; each dose must be given with clavulanate 125 mg orally GI toxicity, seizures. Poor-Low Can be used when there are no suitable alternatives  
Meropenem 1000 mg IV every 8 hours; each dose must be given with clavulanate 125 mg orally GI toxicity, seizures. Moderate Can be used when there are no suitable alternatives  
Amoxicillin-clavulanate 2000 mg amoxicillin/125 mg clavulanate orally every 8 to 12 hours GI toxicity. Poor May be used Coadministered with imipenem-cilastatin or meropenem
Ethambutol 15 mg/kg once a day (when used as a companion drug), or 25 mg/kg (for use as a bacteriostatic agent to complete a fully active regimen) Visual disturbance (optic neuropathy, decreased visual acuity, or red-green colorblindness) observed at higher doses. Poor-Low May be used  
Amikacin

15 mg/kg IM or IV once daily (maximum dose 1 g) adjusted according to serum concentrations.

Alternative: 25 mg/kg IM or IV three times per week.

 Ototoxicity, vestibular toxicity, nephrotoxicity, electrolyte disturbances, and local pain with IM injection. Low-Moderate Avoid

Target trough <1 mcg/mL and target peak of 56 to 64 mcg/mL for once-a-day administration.

5 to 7 days a week, depending on disease severity

The initial duration of therapy is at least 2 to 3 months. After documentation of culture conversion, 3-days-per-week dosing can be used for the remaining duration of injectable use (normally through at least six months beyond culture conversion).
Bedaquiline 400 mg orally once a day for 2 weeks, followed by 200 mg 3 times weekly for 24 weeks (total duration 26 weeks) QT prolongation, GI toxicity, and hepatitis High May be used  
Capreomycin 15 mg/kg IM or IV once a day (maximum 1 g) adjusted according to serum concentrations Electrolyte disturbances, ototoxicity, vestibular toxicity, nephrotoxicity, and local pain with IM injections. Insufficient data Avoid  
 Levofloxacin 750 to 1000 mg orally or IV once a day  CNS effects, QT prolongation, GI toxicity, dysglycemia, rash, tendonitis, tendon rupture  Good Can be used when there are no suitable alternatives  
Moxifloxacin 400 mg orally or IV once a day (doses up to 800 mg once daily have been used, but need more safety data) CNS effects, QT prolongation, GI toxicity, dysglycemia, rash, tendonitis, tendon rupture, hepatotoxicity. Moderate Can be used when there are no suitable alternatives  
Linezolid 600 mg orally or IV once a day Myelosuppression, GI toxicity, neuropathy (optic and peripheral) Good and fast, following IV administration Avoid Pyridoxine (100 mg orally once daily) may be used to prevent or reduce peripheral neuropathy.
 Cycloserine 10 to 15 mg/kg (250 to 750 mg/day) orally in 2 divided doses (maximum dose 500 mg twice a day) adjusted according to serum concentrations  CNS toxicity (psychiatric symptoms, seizures usually occur at peak concentrations >35 mcg/mL but may occur in the normal therapeutic range), peripheral neuropathy, and dermatologic effects include serious cutaneous hypersensitivity reactions.   Good Can be used when there are no suitable alternatives  Pyridoxine (100 mg orally once daily) may be used to prevent or reduce peripheral neuropathy. 
Ethionamide 15 to 20 mg/kg orally (usually 500 mg per day) as a single daily dose or 2 divided doses (maximum dose 1 g per day) GI toxicity (may need antiemetic premedication), hepatic toxicity, metallic taste, neurotoxicity including optic neuritis, endocrine effects including hypothyroidism (treat with thyroid replacement therapy).  Excellent Can be used when there are no suitable alternatives  

Pyridoxine (100 mg orally once daily) may be used to prevent or reduce peripheral neuropathy. 

Start with 250 mg once daily and increase gradually as tolerated is recommended.
Delamanid 100 mg orally twice daily with food (maximum duration studied 26 weeks) GI toxicity, QT prolongation. No data Avoid  
Ethambutol 15 mg/kg once daily (used as a companion drug) or 25 mg/kg (for use as a bacteriostatic agent to complete a fully active drug regimen) Visual disturbance (optic neuropathy, manifested as decreased visual acuity or red-green colorblindness) at higher doses. Poor-Low May be used  
Para-aminosalicylic acid 4 g orally twice or thrice daily Hepatotoxicity, GI toxicity, hypothyroidism (treat with thyroid replacement therapy). More data is needed, poor Can be used when there are no suitable alternatives    
Isoniazid, high dose 15 mg/kg orally, IM, or IV once a day Hypersensitivity, hepatitis, peripheral neuropathy Excellent May be used Pyridoxine (100 mg orally once daily) may be used to prevent or reduce peripheral neuropathy.  
Kanamycin 15 mg/kg IM or IV once a day (maximum dose 1 g) adjusted according to serum concentrations Ototoxicity, electrolyte disturbances, vestibular toxicity, nephrotoxicity. Low Avoid  

 Table 2. Second-line antituberculosis drugs in adults[14][15]

Prognosis

Tuberculous meningitis is considered the deadliest form of MTB infection.[16] TBM carries a mortality rate between 20 and 67% with anti-tuberculous treatment and is fatal without treatment.[3] Patients at both ends of extremes of age and patients with HIV co-infection carry the highest mortality.[16][17] The prognosis of TBM depends on the patient's neurologic status at the time of initial presentation and the timeliness of the initiation of anti-tuberculous agents.[2] Patients who develop hydrocephalus secondary to MTB also have a poor prognosis, even with neurosurgical intervention.[9][17]

Complications

Tuberculous meningitis can cause a myriad of neurologic sequela that can be present at initial presentation and can produce residual effects even after successful treatment.[18]

Some significant complications to remember include the following:

  • Hydrocephalus due to obstruction of CSF outflow causing raised intracranial pressure
  • Hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion is seen in 40 to 50% of patients with TBM.[19]
  • Tuberculomas can occur independently of TBM and have not been shown to be affected by adjunctive steroid treatment.
  • Vasculitis and stroke occur in 15 to 57% of patients with TBM depending on which diagnostic modalities are used in diagnosis, with MRI being diagnostically superior in diagnosis to CT.
  • Seizures, generally focal, result from hyponatremia, infarction, and meningeal irritation[20]
  • Loss of vision that could be permanent due to compression of the optic chiasma by the dilated third ventricle as the optic chiasma and optic nerve are encased by thick tuberculous exudates[21]
  • Transverse myelitis manifests as paraparesis or quadriparesis, sensory symptoms, and urinary retention in the lower limbs.[22]

Consultations

Patients with TBM usually present in the emergency, where the first medical contact is emergency or medicine practitioners. Consultation with neurologists and infectious disease specialists is almost always needed.

Deterrence and Patient Education

The primary goal in TB treatment of all forms involves medication regimen adherence. The treatment of all varieties of TB is lengthy, and without strict adherence, resistance develops, which creates a considerable public health risk.

Enhancing Healthcare Team Outcomes

MTB eradication is a top priority in global health. Healthcare professionals across all disciplines are vital to the continued progress of this global effort. Globally, eradication efforts have involved every aspect of society. Collaboration between frontline clinicians, infectious disease nurses, pharmacists, and all government health entities will significantly improve the outcomes of these efforts. Public and private sector contributions are imperative to the advancements in diagnostic modalities and treatments in MTB.[23]

Tuberculous meningitis is a serious condition that requires an interprofessional team that includes clinicians, emphasizing an infectious disease specialist, specialty infection control nurses, and infectious disease specialized pharmacists. When these interprofessional team members work together and maintain open communication, the patient can receive prompt, appropriate care. [Level 5]

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Valori H. Slane

Editor:

Chandrashekhar G. Unakal

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