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• 62 years male, Kham Bahadur Gurung• From Syangja• Dizziness and vomiting for 10 days• Fever for 2 days along with headache and neck
stiffness• He was in delirious state with behavioral changes• Bowel and bladder habits were normal• He was treated outside but did not get better.
• Personal history: alcoholic but non smoker• Past history : PTB 10 yrs back, treated• Surgical history : -Right hydrocele was operated 3 yrs ago -Right eye was operated 1 month back• O/E : General condition: fair, confused,
GCS:14/15, febrile• Other vitals: stable
SYSTEMIC EXAMINATION
• Respiratory: normal vesicular breath sounds in both lungs
decreased air entry in right upper lobe
• Cardiovascular : S1S2M0
• Per abdomen: soft, non tender, no organomegaly
Central Nervous System: • Higher mental function: delirious, not oriented to time,
place and person• Neck rigidity : present• Ophthalmoplegia : present• Slight facial deviation on left side• Power : intact in all the four limbs• Tone : increased in upper limbs• Deep tendon reflexes : exaggerated in all four limbs• Plantar: B/L upgoing
LABS• WBC: 10360/mm3
• Hb: 12.3 mg/dl• Platelets: 458000 cu/mm• PMN: 82%• ESR: 14 mm
• Blood culture : no growth after 72 hours
• Malaria parasite: not seen• B24-negative
• S. creat: 1.4 mg/dl• K+: 5.6 mmol/L• Na+: 136 mmol/L• ALP: 105 U/L• AST: 28 U/L• ALT: 10 U/L• RBS: 183 mg/dl
CSF FLUID ANALYSIS
• WBC: 155 (↑↑)• RBC: 15 (↑↑)• POLYS: 42% • LYMPHS: 58%• GLUCOSE: 48mg/dl (↓)• PROTEIN: 176.0mg/dl (↑↑)• ADA: 17
ETIOLOGY
• Causative organism: Mycobacterium tuberculosis• First description of TBM credited to Robert
Whyte, on the basis of his 1768 monograph, Observations of Dropsy in the Brain.
• Described as a distinct pathological entity in 1836
• Robert Koch demonstrated that TB was caused by M. tuberculosis in 1882.
RISK FACTORS
• HIV coinfection is the strongest risk factor for progression to TBM.
• Unimmunized with BCG Other contributing factors• Malnutrition• Alcoholism• Substance abuse• Diabetes mellitus
EPIDEMIOLOGY
• In populations with a low prevalence of TB, most cases of TBM occur in adults.
• However, TBM is more common in children than in adults, especially in the first 5 years of life.
PATHOPHYSIOLOGY• Following primary infection or late reactivation TB elsewhere in
the body, scattered tubercles are established in the brain, meninges, or adjacent bone.
• Subcortical or meningeal focus from which bacilli gained access to the subarachnoid space is the critical event for development of tuberculous meningitis .
• Due to chronic reactivation bacillemia occurs in older adults due to immune deficiency caused by aging, alcoholism, malnutrition, malignancy, or human immunodeficiency virus (HIV) infection
• Head trauma may also lead to destabilization of an established quiescent focus resulting in meningitis
• The spillage of tubercular protein into the subarachnoid space produces an intense hypersensitivity reaction due to a dense gelatinous exudate, giving rise to inflammatory changes.
• Proliferative arachnoiditis, most marked at the base of the brain, produces a fibrous mass involving cranial nerves and penetrating vessels.
• Vasculitis with resultant thrombosis and infarction involves vessels that traverse the basilar or spinal exudate or are located within the brain substance itself.
• Variety of stroke syndromes may result, involving the basal ganglia, cerebral cortex, pons, and cerebellum.
• Communicating hydrocephalus results from extension of the inflammatory process to the basilar cisterns and impedance of CSF circulation and resorption.
CLINICAL PRESENTATION• TBM is difficult to diagnose and a high index of suspicion
is needed to make an early diagnosis
HISTORY:
• Recent contact with patients of TB• Past history of TB• History of immunosuppresion from a known disease or
from drug therapy• Negative history of BCG vaccination-see for scar
• Choroid tubercles on opthalmoscopy -multiple, ill-defined, raised yellow-white nodules (granulomas) of varying size near
the optic disc
Atypical features:• Meningitic syndrome rapidly progressing-
suggesting acute infection• Dementia over months or years- personality
change, social withdrawal, loss of libido, and memory deficits
• Encephalitic course with stupor, coma, and convulsions without overt signs of meningitis
PHYSICAL EXAMINATION• Look for BCG vaccination scar• Visual findings: papilledema or a small grayish white choroidal
nodule• cranial neuropathies: VI most affected, then III, IV, VII and less commonly II, VIII, X, XI, XII.• Kernig’s sign and Brudzinki’s sign • Tremor is the most common movement disorder seen in the course
of TBM. • In a smaller percentage of patients, abnormal movements,
including choreoathetosis and hemiballismus, have been observed, suggesting of deep vascular lesions.
• Stage I - apathy, irritability, headache, malaise, fever, anorexia, nausea, and vomiting, without any alteration in the level of consciousness.
• Stage II - altered consciousness without coma or delirium but with minor focal neurological signs; symptoms and signs of meningism and meningitis are present, in addition to focal neurological deficits, isolated CN palsies, and abnormal involuntary movements.
• Stage III - advanced state with stupor or coma, dense neurological deficits, seizures, posturing, and/or abnormal movements
CLINICAL STAGING
DIFFERENTIAL DIAGNOSES Based on CSF findings of ↓Glucose, ↑Protein & lymphocytic
pleocytosis
• Subacute or chronic meningitis syndrome caused by Cryptococcosis, Granulomatous fungal infections, Brucellosis, and Neurosyphilis.
• Parameningeal suppurative infection, eg.brain abscess, or spinal epidural space infection.
• Herpes encephalitis
WORK UP
• Electrolyte concentrations: - mild-to-moderate hyponatremia present in roughly 45% of patients - in some cases constituting a true syndrome of inappropriate diuretic hormone secretion (SIADH). • Blood urea nitrogen (BUN) and creatinine level• Urinalysis• Tuberculin skin testing
• CSF Analysis -Cell counts, differential count, cytology
-Glucose level, with a simultaneous blood glucose level
-Protein level
-Acid-fast stain, Gram stain, India ink stain
-Cryptococcal antigen and herpes antigen testing
• Culture: (87% diagnostic) - CSF specimens for M. tuberculosis. - The demonstration of acid-fast bacilli (AFB) in the CSF is the effective means for an early diagnosis. - Minimum of 3 lumbar punctures be performed at daily intervals.
• Polymerase chain reaction: - 60% sensitive in rapid detection of M. tuberculosis in CSF. - Recommended whenever clinical suspicion is sufficiently high for empirical therapy or AFB is negative.
• Neuroimaging: - CT & MRI are helpful in detection. - CT can present the extent of basilar arachnoiditis, cerebral edema and infarction, and the presence and course of hydrocephalus.
• Hydrocephalus combined with marked basilar enhancement is indicative of advanced meningitic disease and carries a poor prognosis.
• Marked basilar enhancement correlates well with vasculitis and, therefore, with a risk for basal ganglia infarction.
• Interferon-gamma release assay (IGRA) using specific tuberculous antigens is a rapid, specific and sensitive method for the detection of tuberculous infection.
OTHERS• Angiography- for narrowing of the arteries
especially the small vessels at the base of the brain
• Electroencephalopathy-abnormal if meninigitis has progressed to advanced stage
• Brainstem Auditory Evoked Response Testing-abnormal in advanced stage of meningitis
TREATMENT
• The mainstay of treatment for TB is clinical suspicion & starting of empirical therapy.
• First line drugs — Isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) are bactericidal, can be administered orally all having good meningeal penetration.
RECOMMENDED REGIMEN
• Intensive phase (Initial 2 months)• A four drug regimen- INH, RIF, PZA, and either EMB or STM
• Continuation phase (9-12 months) • INH and RIF alone if the
patient makes good progress.
DURATION OF THERAPY
• 9 to 12 months in drug-sensitive infections. • If PZA is omitted or cannot be tolerated,
treatment should be extended to 18 months with isoniazid and thiacetazone.
VALUE OF CORTICOSTEROIDS
• has now been established by a controlled trial.• Particularly for young children and severely ill. • Begin with Prednisolone 30 mg twice daily (1mg/kg
twice daily for chidren) for 4-6 weeks then decrease over several weeks as the patient improves.
• For the patients on rifampicin the dose should be increased by half, i.e. 45 mg for adults and 1.5 mg/kg for children. The reason being Rifampicin antagonises the action of Prednisolone.
• Dexamethasone — -A total dose of 8 mg/day for children weighing <25 kg; -12 mg/day for adults and children >25 kg, -for 3 weeks, then tapered off gradually over the following 3 to 4 weeks.
SECOND LINE DRUGS• Aminoglycosides: e.g., amikacin , kanamycin
• Polypeptides: e.g., capreomycin, viomycin, enviomycin;
• Fluoroquinolones: e.g., ciprofloxacin , levofloxacin, moxifloxacin ;
• Thioamides: e.g. ethionamide, prothionamide
• Cycloserine (the only antibiotic in its class);
• p-aminosalicylic acid (PAS or P).
OTHERS• Macrolides: e.g., clarithromycin• Linezolid (LZD)• Thioacetazone (T)
• Immunomodulators- cytokine-based therapy which enhance both the mycobacterial killing activity of effector cells and the restriction of bacterial intracellular multiplication
• BCG vaccination offers a protective effect (approximately 64%) against TBM.
SURGICAL INTERVENTION
• In patients with evidence of obstructive hydrocephalus and neurological deterioration who are undergoing treatment for TBM, placement of a ventricular drain or ventriculoperitoneal or ventriculoatrial shunt should not be delayed.
COMPLICATIONS
• Hydrocephalus• Infarctions• Coma/stupor• Motor deficits- CN palsies, hemiparesis• Seizures• Mental impairment• Abnormal behavior• Brain damage• High morbidity and mortality
PROGNOSIS• Very critical disease in terms of fatal outcome and
permanent sequelae, requiring rapid diagnosis and treatment.
• Prognosis is directly related to the clinical stage at diagnosis.
• Kumar et al reported that children with TBM who have been vaccinated with BCG appear to maintain better mentation and have superior outcomes.
• Coexisting HIV encephalopathy and diminished immune competence contribute to the more severe clinical and neuroradiological features.
TAKE HOME MESSAGE
• Start ATT empirically when suspicion of TB• See for the BCG scar in suspected case• Counsel the patient for medication/side
effects• Complete the course• Follow up
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