Tuberculous Meningitis


Article Author:
Valori Slane


Article Editor:
Chandrashekhar Unakal


Editors In Chief:
Jessica Snowden
Asif Noor
H Davies


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
5/8/2019 5:18:27 PM

Introduction

Tuberculous meningitis (TBM) is a manifestation of 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, there is a high degree of bacteremia that 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 the symptoms of meningitis.  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. All of these immune responses can lead to the development of complications associated with tuberculous meningitis and chronic sequela seen in patients who recover from TBM.[1][2]

Etiology

Predicting which patients with TB infection will develop TBM is difficult. Children with MTB, especially those aged 0 to-4, have a higher incidence of TBM.  This infection is more prevalent in the developing world where there is an overall higher incidence of MTB in children.  By contrast in the developed world, TBM is more often seen in adults who experience reactivation TB. Other immunocompromised states like chronic steroid use, diabetes mellitus, and chronic alcoholism carry the same risk of developing TBM.[3][4] The highest correlation remains with HIV co-infection with reports that these patients being five to ten times more likely to develop CNS disease.[5]

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. The number of persons infected with tuberculosis continues to increase despite advances in treatment and worldwide efforts to provide accessibility to the medications and universal standard protocoled treatment programs. Tuberculous meningitis carried a fatal prognosis before the development of anti-tuberculous medications. Despite the treatment availability, 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.[2]

Tuberculous meningitis presents 1% of all causes 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.[6]

History and Physical

The clinical presentation of tuberculous meningitis is similar to other forms of chronic meningitis, which can make the diagnosis difficult to make and the differential broad. The clinical presentation is associated with fever, headache, altered sensorium, and focal neurologic deficits.  Typical neurologic deficits include facial palsy.[5] The additional diagnostic difficulty is that the symptoms can be present anywhere from a few days and up to six months. The clinical presentation of TBM is similar regardless of HIV status.[4]

Evaluation

Tuberculous meningitis assessment is by obtaining cerebrospinal fluid (CSF) for analysis. Typically, the CSF reveals low glucose, elevated protein, and modestly elevated WBC count with lymphocytic predominance. The CSF analysis most closely resembles the CSF analysis of viral meningitis.[6]

Confirming the diagnosis of TB is a difficult diagnostic dilemma; this is especially true in resource-poor areas. Definitive diagnosis results from positive 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%.[5] CSF mycobacterium cultures are variable in their yield and are only positive 40 to 83% of the time and can take from 6 to 8 weeks to grow.[6]   Daily large volume spinal taps, over a series of several days, sent for microbiological analysis can improve the culture sensitivity greater than 85%.[7] 

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 tests results.  The choice of diagnostic in most cases is going to depend on the resources available. Despite advances in the development of improved and accurate diagnostic modalities MTB, confirmation by culture in the CSF remains the gold standard globally.[5][6][7] Culture allows for assessment of drug sensitivity results. Drug-resistant MTB carries up to twice the mortality.[7]

These diagnostic difficulties lead to decreased recognition of tuberculous meningitis and have led to the development of clinical algorithms to aid in the diagnosis of TBM and differentiation 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.[8][9]

Neuroimaging can further aid in the diagnosis of TBM. Magnetic resonance imaging (MRI) has demonstrated superiority to computed tomography (CT), as it is higher quality for assessment of the brainstem and spine in the detection of 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.  CT imaging can also show basal exudates.[7]

Treatment / Management

It is imperative that anti-tuberculous treatment starts in a timely fashion 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 daily isoniazid (INH), rifampin (RIF), pyrazinamide (PZD) and either streptomycin (SM) or ethambutol (EMB). This regimen is then followed by 7 to 10 months of INH and RIF. This treatment plan is based on the assumption that the MTB is not a resistant strain. Drug sensitivities, however, can take months to result, at which time, treatment can be tailored to the identification of the drug sensitivities.[7]

Adjunctive therapy with corticosteroids has been used in the treatment of TBM. The goal of steroid treatment is to dampen the over exaggerated response of the immune system 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 that 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, mainstay treatment has been daily intravenous dexamethasone for up to four weeks followed by a four-week oral taper.[7] 

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 (CVA)

  • Sympathomimetic syndrome due to drug abuse

  • Delirium associated with urinary tract infection

Prognosis

Tuberculous meningitis is considered the deadliest form of MTB infection.[3] TBM carries a mortality rate between 20 and 67% with anti-tuberculous treatment and is fatal without treatment.[6] Patients at both ends of extremes of age and patients with HIV co-infection carry the highest mortality.[3][10] Prognosis of TBM depends on the patients’ neurologic status at the time of initial presentation and timeliness of the initiation of anti-tuberculous agents.[5] Patient who develop hydrocephalus secondary to MTB also has a poor prognosis even with neurosurgical intervention.[7][10]  

Complications

Tuberculous meningitis can cause a myriad of neurologic sequela that can be present at the time from the initial presentation and can produce residual effects even after successful treatment.[2]

Some significant complications to remember include:

  • Hydrocephalus due to obstruction of CSF outflow causing raised intracranial pressure
  • Hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion, this is seen in 40 to 50% of patients with TBM
  • 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 patient with TBM depending on which diagnostic modalities is used in diagnosis with MRI being superior in diagnosis than CT.  

Deterrence and Patient Education

The primary goal in TB treatment of all forms involves medication regimen adherence. The treatment of all varieties of TB are 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. Health care 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 greatly improve the outcomes in these efforts. Public and private sector contributions are imperative to the advancements in diagnostic modalities and treatments in MTB.[11]

Tuberculous meningitis is a serious condition that requires a multidisciplinary, interprofessional team that includes physicians, with an emphasis on an infectious disease specialist, specialty infection control nurses, and pharmacy. By working together and maintaining open communication, the patient can receive apporriate care in a timely fashion. [Level V]


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Tuberculous Meningitis - Questions

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A 7-year-old male presents with seven days of fever and lethargy. On physical exam is he is febrile, tachycardic, mildly tachypneic with normal blood pressure. He appears generally ill with nuchal rigidity. Non-contrast CT of the brain shows no mass and no midline shift. A lumbar puncture was performed due to the physical findings. Lumbar puncture showed cerebrospinal fluid with 100 WBC/microL with 100 percent lymphocytes, protein 160 mg/dL, glucose 20 mg/dL, and negative gram stain. Tuberculous meningitis (TBM) is considered the most likely diagnosis and standard four-drug therapy was initiated with Isoniazid (INH), rifampin (RIF), pyrazinamide (PZD) and either streptomycin (SM) or ethambutol (EMB). Which other class of drug should be used in addition to the 4-drug regimen?



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Which of the following forms of Mycobacterium tuberculosis infection should be treated with corticosteroids along with antitubercular drugs?



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Which population has the highest mortality associated with tuberculous meningitis?



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Which central nervous system infection is typically associated with the lowest cerebrospinal fluid glucose levels?



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A 47-year-old male with a past medical history of HIV with known low CD4 count presents to the emergency department with fever and headache. He states he recently started taking antiretroviral therapy in the last few weeks. He states he has been sick for the last week. On exam, the patient appears uncomfortable but not toxic. He is currently afebrile, he has mild nuchal rigidity and has no rash. Non-contrast CT of the brain shows no acute process and no midline shift or mass. Lumbar puncture is performed. The WBC count in the cerebrospinal fluid is mildly elevated with lymphocyte predominance, the protein is elevated, and the glucose is low. Tuberculous meningitis (TBM) is suspected, and appropriate therapy is initiated. What is the most likely reason this patient presented with TBM?



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Mycobacterium tuberculosis (MTB) can invade and seed every organ in the body. MTB can even penetrate the blood-brain barrier and affect the neurologic system. What is the most common neurologic manifestation of infection with Mycobacterium tuberculosis?



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A 50-year-old male with a history of diabetes mellitus and HIV who is not currently on antiretroviral therapy presents with headache, neck pain and fever for two weeks. On exam, the patient appears unwell, and there is no rash. There is nuchal rigidity, photophobia, and mild tachycardia. Lumbar puncture is performed showing elevated opening pressure, white blood cell count mildly elevated with lymphocyte predominance, elevated protein, and low glucose. The gram stain is negative. All of the following clinical diagnosis present with low cerebrospinal fluid (CSF) glucose. In which would one expect to find the lowest serum to CSF glucose ratio?



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A 7-year-old male presents with seven days of fever and lethargy. On physical exam is he is febrile, tachycardic, mildly tachypneic with normal blood pressure. He appears generally ill with nuchal rigidity. Non-contrast CT of the brain shows enhancement of the basal cisterns after contrast injection but no mass and no midline shift. A lumbar puncture was performed due to the physical findings. Lumbar puncture showed cerebrospinal fluid with 100 WBC/microL with 100 percent lymphocytes, protein 160 mg/dL, glucose 20 mg/dL, and negative gram stain. Which of the following is the most likely diagnosis?



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Tuberculous Meningitis - References

References

Thwaites G,Chau TT,Mai NT,Drobniewski F,McAdam K,Farrar J, Tuberculous meningitis. Journal of neurology, neurosurgery, and psychiatry. 2000 Mar;     [PubMed]
Luo M,Wang W,Zeng Q,Luo Y,Yang H,Yang X, Tuberculous meningitis diagnosis and treatment in adults: A series of 189 suspected cases. Experimental and therapeutic medicine. 2018 Sep;     [PubMed]
Davis A,Meintjes G,Wilkinson RJ, Treatment of Tuberculous Meningitis and Its Complications in Adults. Current treatment options in neurology. 2018 Feb 28;     [PubMed]
Chin JH, Tuberculous meningitis: Diagnostic and therapeutic challenges. Neurology. Clinical practice. 2014 Jun;     [PubMed]
Soria J,Metcalf T,Mori N,Newby RE,Montano SM,Huaroto L,Ticona E,Zunt JR, Mortality in hospitalized patients with tuberculous meningitis. BMC infectious diseases. 2019 Jan 5;     [PubMed]
Lee SA,Kim SW,Chang HH,Jung H,Kim Y,Hwang S,Kim S,Park HK,Lee JM, A New Scoring System for the Differential Diagnosis between Tuberculous Meningitis and Viral Meningitis. Journal of Korean medical science. 2018 Jul 30;     [PubMed]
Marx GE,Chan ED, Tuberculous meningitis: diagnosis and treatment overview. Tuberculosis research and treatment. 2011;     [PubMed]
Jipa R,Olaru ID,Manea E,Merisor S,Hristea A, Rapid Clinical Score for the Diagnosis of Tuberculous Meningitis: A Retrospective Cohort Study. Annals of Indian Academy of Neurology. 2017 Oct-Dec;     [PubMed]
Hristea A,Olaru ID,Baicus C,Moroti R,Arama V,Ion M, Clinical prediction rule for differentiating tuberculous from viral meningitis. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2012 Jun;     [PubMed]
Hsu PC,Yang CC,Ye JJ,Huang PY,Chiang PC,Lee MH, Prognostic factors of tuberculous meningitis in adults: a 6-year retrospective study at a tertiary hospital in northern Taiwan. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi. 2010 Apr;     [PubMed]
Silva DR,Rendon A,Alffenaar JW,Chakaya JM,Sotgiu G,Esposito S,Migliori GB, Global TB Network: working together to eliminate tuberculosis. Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia. 2018 Set-Oct;     [PubMed]

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