CNS Tuberculosis

Prof R Shukla(DM,Neurology)KGMU

Case history

20 yrs old female patient presented with c/o

• Fever mild to moderate grade since 1 ½ months

• Headache with vomiting since 1 ½ months

• Decreased vision both eyes since 1 month

ExaminationGeneral examination including vitals – Normal CNS examination

• GCS- 15/15

• Neck rigidity/ Kernigs sign – Absent.

• Optic nerves- Visual acuity- PL/PR absent both eyes. Fundus- Bilateral primary optic atrophy.

• Bilateral 3rd 4th 6th cranial nerves palsy present.• Right LMN facial nerve palsy present.

• Rest of the neurological examination - normal

Looking down Looking up

Looking to right Looking to left

Oculomotor examination

Investigations Routine hematological & biochemical investigations - NormalCSF examination • TLC – 440 cells Lymphocytes – 95% Polymorphs – 5%• Proteins – 111 mg%• Sugar – 21 mg%• Corresponding blood sugar 171 mg%.• AFB, Gram’s stain & India ink staining normal• TB PCR report awaited.

Axial Sagittal

MRI brain with Gd contrast

Introduction• Tuberculosis is a major cause of death worldwide.

• India has the highest TB burden, accounting for 1/5 of the global incidence and 2/3 of cases in SE Asia.

• Nearly 40% of population in India is affected.

• CNS tuberculosis occurs in up to 10% and has protean clinical manifestations.

• The burden of CNS tuberculosis is directly proportional to the prevalence of tuberculous infection.

• Tuberculous meningitis is the most devastating form of extra-pulmonary tuberculosis with 30% mortality and disabling neurological sequelae in > 25% survivors.

Classification of neurotuberculosis

• Tuberculous meningitis- Basal and spinal

• Tuberculoma- Intracranial (parenchymal & extraparenchymal)- Spinal (parenchymal & extraparenchymal)

• Tuberculous abscess• Tuberculous encephalopathy

- With or without meningitis• Spinal cord involvement secondary to skeletal

tuberculosis

Contd…

Classification of neurotuberculosis Contd…

• Intracranial

- Tuberculous meningitis

- Tuberculoma

- Tuberculous abscess

- Tuberculous encephalopathy

- Tuberculous vasculopathy

• Spinal

- Pott’s spine and Pott’s paraplegia

- Tuberculous arachnoiditis

- Spinal tuberculoma

- Spinal meningitis

Causative organism

• CNS tuberculosis is caused by the human strain of Myobacterium tuberculosis.

• However in immunocompromised patients, atypical mycobacteria are an important cause of infection.

• They are now called non-tuberculous mycobacteria which include:

Mycobacterium avium

Mycobacterium intracellulare

Pathophysiology

• CNS tuberculosis is secondary to disease elsewhere in the body.

• Mycobacteria reach the brain by hematogenous route.

• Initial small tuberculous lesions (Rich foci) develop in meninges, subpial or subependymal surface of the brain or the spinal cord, and may remain dormant for years.

• Reactivation may be due to endogenous factors:

Innate immunological and non immunological defenses

Level of function of cell mediated immunity.

• Tumour necrosis factor ά may have a role.

Pathology

• Release of M tuberculosis results in a T lymphocyte dependent necrotising granulomatous inflammatory response.

• Thick gelatinous exudate around the sylvian fissures, basal cisterns, brainstem and cerebellum.

• Three processes cause most of the neurological deficits:

HydrocephalousAdhesive arachnoiditis Obliterative vasculitis

Tuberculous brain abscess

• Distinct from CNS tuberculoma. • 4 to 7.5% of patients with CNS

tuberculosis. • Usually solitary, uniloculated or

multiloculated of variable size • Progresses much more rapidly

than tuberculomas. • Clinical features include partial

seizures, focal neurological deficit and raised intracranial tension.

• CT and MRI show a large size lesion with marked surrounding oedema.

Tuberculous encephalopathy

• Seen in infants and children.

• Characterized by convulsions, stupor and coma with signs of meningeal irritation or focal neurological deficit.

• CSF is largely normal.

• Responsive to corticosteroids.

Tuberculoma

• Firm avascular spherical granulomatous mass.

• Usually 2-8cm in diameter.

• Symptoms related to their size and location.

• Low grade fever, headache, vomiting, seizures, focal neurological deficit, and papilloedema are the characteristic.

• Target sign is characteristic.

Spinal tuberculosis

• < 1% of patients. • Infection starts in cancellous bone

usually adjacent to an inter-vertebral disc or anteriorly under the periosteum.

• Thoracic (65%) lumbar (20%), cervical (10%), thoraco-lumbar (5%), and atlanto-axial region (< 1%).

• Two (<90%), Three (50%) vertebrae• Paraspinal abscess 55-90%. • Local pain, tenderness over the

affected spine or a gibbus associated with paravertebral muscle spasm or a palpable paravertebral abscess.

• Neurological deficit results from multiple causes.

Potts spine

Myelitis

Non-osseous spinal cord tuberculosis

• Can occur in the form of tuberculomas.

• Extradural tuberculomas are the most common.

• Intramedullary tuberculomas are rare.

Tuberculous arachnoiditis

• Features of spinal cord or nerve involvement may predominate, but most often there is a mixed picture.

• Subacute paraparesis, radicular pain and bladder dysfunction.

• The hallmark of diagnosis is the characteristic myelographic picture, showing poor flow of contrast material with multiple irregular filling defects, cyst formation and sometimes spinal block.

Spinal form of tuberculous meningitis

• May result from rupture of Rich foci in the spinal arachnoid space.

• The acute form presents with fever, headache, and root pains accompanied by myelopathy.

• The chronic form presents with spinal cord compression.

• Spinal forms of tuberculous meningitis may be associated with syrinx formation.

Tuberculous meningitis (TBM)

• Commonest form of neurotuberculosis (70 to 80%) .

• TBM is also the commonest form of chronic meningitis.

• Clinical features include h/o vague ill health for 2-8 weeks prior to development of meningeal irritation.

• Non specific symptoms include malaise, anorexia, fatigue, low grade fever, myalgia and headache.

• Prodromal symptoms in infants and children include irritability, drowsiness, poor feeling, and abdominal pain..

Contd…

Tuberculous meningitis (TBM) Contd…

• Meningeal irritation - neck stiffness, Kernig’s sign, Bickelle’s sign and Brudzinski’s sign.

• Cranial nerve palsies (20-30%), fundus - papilloedema or rarely choroid tubercles, seizures, focal neurological deficits secondary to infarction.

• Visual loss may be due to optic nerve involvement, optochiasmatic arachnoiditis, third ventricular compression of optic chiasma, ethambutol toxicity and occipital lobe infarction.

• Increasing lethargy, confusion, stupor, deep coma, decerebrate or decorticate rigidity.

Clinical presentation of TBM

History Tuberculosis 55 8-12Symptoms Headache 20-50 50-60 Nausea/vomiting 50-75 8-40 Apathy/behavioural changes 30-70 30-70 Seizures 10-20 0-15Signs Fever 50-100 60-100 Meningismus 70-100 60-70 Cranial nerve palsy 15-30 15-40 Coma 30-45 20-30

Clinical Features Children (%) Adults (%)

Zuger A. Tuberculosis. In: Scheld WN, Whitley RJ, Marra CM, editors. Infections of Central Nervous System. Philadelphia: Lippincott, 2004. pp. 441-9.

Staging of TBM

TBM is classified into 3 stages according to the British Medical Research Council (MRC) criteria

Stage I: Prodromal phase with no definite neurologic

symptoms.

Stage II: Signs of meningeal irritation with slight or no

clouding of sensorium and minor (cranial nerve

palsy) or no neurological deficit.

Stage III: Severe clouding of sensorium, convulsions, focal

neurological deficit and involuntary movements.

Modified MRC criteria

Grade I: Alert and oriented (GCS 15) without focal

neurological deficit.

Grade II: GCS 14-10 with or without focal neurological

deficit or GCS 15 with focal neurological deficit.

Grade III: GCS less than 10 with or without focal

neurological deficit.

Diagnostic rule for TBM

4

0≥ 90

< 90

CSF neutrophil %

3

0

≥ 750

< 750

CSF WBC count (103 / ml)

-5

0> 6

≤ 6

History of illness (days)

4

0

>15000

≤15000

Blood WBC count (103/ ml)

0<36

2>36Age (years)

Score Variable

Score : < 4 –TBM; > 4 - Non TBM

Differential diagnosis of TBM  

• Fungal meningitis (cryptococcosis, histoplasmosis, blastomycosis, coccidioidal mycosis)

• Viral meningoencephalitis (herpes simplex, mumps)

• Partially treated bacterial meningitis

• Neurosyphills

• Focal parameningeal infection

• CNS toxoplasmosis

• Neoplastic meningitis (lymphoma, carcinoma)

• Neurosarcoidosis

Investigations

• CSF examination• CSF Smear examination: Zeihl Nelson’s, Gram’s

and India Ink stain.• CSF culture on solid media: Egg or agar based

BACTEC systems.• Adjunctive tests CSF tuberculostearic acid,

adenosine deaminase, radiolabelled bromide partition test.

• Molecular diagnosis : Nucleic acid amplification, DNA finger printing, PCR.

Cerebrospinal fluid examination

• Predominantly lymphocytic pleocytosis, with increased proteins and low CSF/ blood glucose ratio.

• WBC count can be normal in presence of depressed CMI (elderly and HIV positive individuals).

• CSF protein (> 150 mg/dl) should always raise the suspicion of tuberculosis or fungal infection, rarely seen in viral meningitis.

• Smear is +ve in 10%, can be increased by examining large volume of CSF.

• Culture is +ve in 25-70%.

Cerebrospinal fluid examination

• Repeat CSF frequently shows a falling glucose level, a rising protein concentration and a shift to mononuclear predominance.

• CSF cell counts decrease by 50% during the first month but may not become normal for a year.

• CSF glucose becomes normal in 1 to 2 months and protein becomes normal by 12 months or longer.

• CSF cultures should be sterile by the first month, but PCR results may remain positive for a month.

Investigations

• CSF examination:• CSF Smear examination: Zeihl Nelson’s, Gram’s

and India Ink stain.• CSF culture on solid media: Egg or agar based

BACTEC systems.• Adjunctive tests : CSF tuberculostearic acid,

adenosine deaminase, radiolabelled bromide partition test.

• Molecular diagnosis : Nucleic acid amplification, DNA finger printing, PCR.

Sensitivity and specificity of adjunctive tests for the diagnosis of TBM

BiochemicalRadiolabelled bromide partition ratio 90-94 88-96 48CSF adenosine deaminase level 73-100 71-99 <24CSF tuberculostearic acid level 95 99 <24

Immunologic test (ELISA)Antigen ELISA 38-94 95-100 <24Antibody ELISA 52-93 38-94

Tests Sensitivity (%) Specificity (%) Time Required (h)

Kalita J, Misra UK. Tuberculosis Meningitis. In Misra UK, Kalita J (Eds) Diagnosis and Management of Neurological Disorders. Wolter Kluwers Health New Delhi 2011; pp. 145-66.

Sensitivity & specificity of various diagnostic tests for TBM

Menzies et al, Ann Int Med. 2007; 146: 340-354.

Diagnostic test Sensitivity Specificity

ZN staining 10-20% 100%

LJ Culture 15% (25-80) 100%

BACTEC Culture 55% 100%

ELISA 52.3% 91.6%

TB PCR 56% 98%

TST 73% 56%

QTF-GOLD 76% 98%

ELISPOT 87% 92%

Diagnostic criteria for TBM

Patients with at least four of the following:i. History of tuberculosis.ii. Predominance of lymphoytes in the cerebrospinal fluid.iii. A duration of illness of more than six days.iv. A ratio of CSF glucose to plasma glucose of less than 0.5.v. Altered consciousnessvi. Turbid cerebrospinal fluid.vii. Focal neurologic signs.

Possible

Patients with one or more of the following:i. Suspected active pulmonary TB on chest radiography.ii. AFB found in any specimen other than the CSF.iii. Clinical evidence of extrapulmonary tuberculosis.

Probable

Acid-fast bacilli seen in the cerebrospinal fluid.Definite

DefinitionClass

Thwaites GE et al. Diagnosis of adult tuberculosis meningitis by use of clinical and laboratory features. Lancet 2002; 360: 1287-92.

Imaging in TBM• CT/ MRI confirm the presence and extent of basal arachnoiditis, cerebral

oedema, infarction, ventriculitis and hydrocephalus.

• Abnormalities depend upon stage of disease:

I (normal in 30%), II (Normal in 10%), III (Abnormal in all).

• Hydrocephalus (70-85%), basal meningeal enhancement (40%), infarction (15-30%), tuberculoma (5-10%).

• Meningeal enhancement, tuberculoma or both have a sensitivity of 89% and specificity of 100%.

• Precontrast hyperdensity in basal cisterns is the most specific radiological sign.

• Radiological findings also help in prognostication.

Imaging abnormalities in TBM

Search for extra CNS TB

• An extra-neural focus should be sought clinically and radiologically in all patients of CNS TB as it may indicate safer and more accessible sites for diagnostic sampling e.g. X-ray chest, FNAC of the enlarged lymphnodes, abdominal USG, CT scan .

• 77% of HIV +ve TBM patients have extra-meningeal TB compared to only 9% with HIV –ve patients.

Thwaites G, et al. J Neurol Neurosurg Psychiatry 2000;68:289-99.

Principles of treatment of TBM• Treatment should be started early in suspected TBM. • Multiple antimicrobial drugs are required.

• Drugs must adequately cross the blood-CSF barrier to achieve therapeutic concentrations in CSF.

• Drugs should be taken on a regular basis for a sufficient period to eradicate the CNS infection.

• Intrathecal therapy is not required.

• No general consensus regarding the choice of drug, doses and duration of treatment.

List of antitubercular drugs

INH CycloserineRifampicin EthionamideRifapentine Levofloxacin*Rifabutin* Moxifloxacin*Ethambutol Gatifloxacin*Pyrazinamide p-aminosalicylic acid**

Streptomycin**Amikacin/Kanamycin*Capreomycin

First-Line Drugs Second-Line Drugs

* Not approved by U.S. FDA** Included in second-line drugs due to toxicity, limited efficacy or difficulty in administration.

Treatment• CNS tuberculosis is categorised under TB treatment

category I by WHO.

• Initial phase therapy ( 2 mths) with isoniazid, rifampicin, pyrazinamide and streptomycin or ethambutol followed by continuation phase (7 mths) with isoniazid and rifampicin.

• The BTS and IDSA/ATS recommend 9-12 months of ATT. Therapy should be extended to 18 months in patients who do not tolerate pyrazinamide.

• Short duration therapy (6 mths) might be sufficient if the likelihood of drug resistance is low.

• However as the emergence of neurological deficit has been seen in some of the studies so a minimum of 12 months treatment would be worthwhile.

What is the best anti-tuberculous drug regimen?

• Isonaizid, rifampicin and pyrazinamide are considered mandatory at the beginning of TBM treatment.

• 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 TBM has confirmed its central role in the treatment of CNS disease.

• There is no conclusive evidence to demonstrate that pyrazinamide improves outcome of CNS tuberculosis, although it is well absorbed orally and achieves high concentration in the CSF. Thwaites GE et al. J Neurol Neurosurg Psychiatry 2000; 68: 289-99; Lancet Neurol 2005; 4: 160-70.

Choice of the fourth drug

• No data from controlled trials.

• Most authorities recommend either streptomycin or ethambutol, although neither penetrates the CSF well in the absence of inflammation.

• Streptomycin should not be given to those who are pregnant or have renal impairment.

• Ethambutol should be avoided where optic neuropathy is a concern.

• The fluoroquinolones may represent an effective fourth agent, although data concerning their CSF pharamacokinetics and safety during prolonged therapy are limited.

• Others-Ethionamide, prothionamide.

Adjunctive steroid therapy

• The use of corticosteroids as adjunctive therapy in the treatment of CNS tuberculosis began as early as the 1950s.

• The rationale behind the use of steroids includes the reduction of inflammation within the subarachnoid space.

• The largest RCT in TBM recommends dexamethasone treatment in patient with TBM for 6-8 weeks.

Thwaites GE et al. N Engl J Med 2004; 351: 1741-51; Lancet Neurol 2007; 6: 280-6.

Adjunctive steroid therapy

• A recent Cochrane review and meta-analysis of 7 randomised controlled trials involving 1140 participants (with 411 deaths) concluded that corticosteroids improved outcome in HIV-negative children and adults with TBM, but the benefit in HIV infected individuals remains uncertain.

Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008;(1):CD002244.

Role of surgery in CNS tuberculosis

• Hydrocephalus, tuberculous cerebral abscess and vertebral tuberculosis with paraparesis are all indications for neurosurgical referral (A,II).

• Early ventriculo-peritoneal shunting should be considered in those with non-communicating hydrocephalus (A,II) and in those with communicating hydrocephalus falling medical management (B,II).

• Communicating hydrocephalus may be treated initially with frusemide (40 mg/24 h adults, 1 mg/kg children) and acetazolamide (10-20 mg/kg adults, 30-50 mg/kg children) (B,II) or repeated lumbar punctures (B,III).

• Urgent surgical decompression should be considered in all those with extra-dural lesions causing paraparesis (A,II).

TBM in HIV positive patients • The optimal regimens have not been clearly established,

should be same as in HIV –ve individuals.

• Four drug regimen including pyrazinamide is recommended.

• Initiation of HAART depends upon CD 4 counts.

• Infection with NTM (M avium/M intracellulare). Current recommendations include using

azithromycin (500-100mg/day) and clarithromycin (500- 1000mg/day) in combination with ethambutol (15mg/kg/day) or clofazimine (100 mg/day).

Alternative regimens include the use of ciprofloxacin and rifampicin. Rifabutin is recommended in place of rifampicin for those taking protease inhibitors.

Treatment of multi-drug resistant TBM

• The treatment of multi drug resistant TBM should abide by the principles of treatment of multi drug resistant pulmonary tuberculosis.

• Never add a single drug to a failing regimen.

• Use at least three previously unused drugs, one of which should be a fluoroquinolone.

• Streptomycin resistance does not confer resistance to other aminoglycosides, therefore amikacin or kanamycin can be used.

• Treatment should be given for at least 18 months.

Prognosis

• Virtually all patients with no focal deficits and only minor lethargy recover, most-without sequelae.

• Comatose patients have a mortality of 50% and a high incidence of residual disability.

• The incidence of residual neurological deficits after recovery from TBM varies from 10-30%.

• Late sequelae include cranial nerve deficits, gait disturbance, hemiplegia, blindness, deafness, learning disability, dementia and various syndromes of hypothalamic or pituitary dysfunction.

Poor prognostic factors

• Stage of disease.

• Presence of miliary disease

• Severe disease on admission

• Delay in initiation of treatment

• Extremes of age, preexistence of a debilitating condition

• Very abnormal CSF (very low glucose or elevated protein)

Conclusion

• CNS tuberculosis is a common, eminently treatable disorder with protean manifestations.

• Early diagnosis requires a high index of suspicion.

• Careful bacteriology of CSF is as good as or better than molecular method before starting treatment.

• CT or MRI showing basal meningeal enhancement with any degree of hydrocephalus is strongly suggestive of TBM.

• Clinical outcome depends greatly on the stage of disease at which therapy is initiated.

1. Spinal tuberculosis is classically thought to begin in which portion of the vertebral body:

– Antero inferior

– Antero superior

– Postero superior

– Postero inferior

1. Spinal tuberculosis is classically thought to begin in which portion of the vertebral body:

– Antero inferior

– Antero superior

– Postero superior

– Postero inferior

2. A decreased CSF glucose concentration is not seen in

– Tuberculous meningitis

– Fungal meningitis

– Viral meningitis

– Neuro-Sarcoidosis

2. A decreased CSF glucose concentration is not seen in

– Tuberculous meningitis

– Fungal meningitis

– Viral meningitis

– Neuro-Sarcoidosis

3. For a positive smear on Zeihl-Neelsen staining, the bacterial load (in AFB/ml) required is

– 10×10

– 10×102

– 10×103

– 10×104

3. For a positive smear on Zeihl-Neelsen staining, the bacterial load (in AFB/ml) required is

– 10×10

– 10×102

– 10×103

– 10×104

4. Which of the following adjunctive tests has the highest sensitivity and specificity for the diagnosis of TBM

– Radiolabelled bromide partition test

– CSF adenosine deaminase level

– CSF tuberculostearic acid level

– CSF antigen ELISA

4. Which of the following adjunctive tests has the highest sensitivity and specificity for the diagnosis of TBM

– Radiolabelled bromide partition test

– CSF adenosine deaminase level

– CSF tuberculostearic acid level

– CSF antigen ELISA

5. Maximum CSF concentration occurs with:

– INH

– Rifampicin

– Pyrazinamide

– Ethambutol

5. Maximum CSF concentration occurs with:

– INH

– Rifampicin

– Pyrazinamide

– Ethambutol

6. In a patient with antitubercular therapy, if the primary elevation is in bilirubin and alkaline phosphatase, the most likely offending drug is,

– Isoniazid

– Rifampicin

– Ethambutol

– Pyrazinamide

6. In a patient with antitubercular therapy, if the primary elevation is in bilirubin and alkaline phosphatase, the most likely offending drug is,

– Isoniazid

– Rifampicin

– Ethambutol

– Pyrazinamide

7. Which of the following quinolone antibiotics has highest CSF penetration

– Levofloxacin

– Moxyfloxacillin

– Gatifloxacin

– Ofloxacin

7. Which of the following quinolone antibiotics has highest CSF penetration

– Levofloxacin

– Moxyfloxacillin

– Gatifloxacin

– Ofloxacin

8. Chemoprophylaxis for tuberculosis is indicated in persons with high risk medical conditions, if the tuberculin reaction size (in mm) is,

– <5

– ≥5

– ≥10

– ≥15

8. Chemoprophylaxis for tuberculosis is indicated in persons with high risk medical conditions, if the tuberculin reaction size (in mm) is,

– <5

– ≥5

– ≥10

– ≥15