TB Meningitis

Case PresentationBy:Dr. Fabha Naveed ButtDr. M. Wasiq Paracha

CaseA 22 year old male, unmarried, k/c of non-compliant Koch’s disease (pulmonary TB), presented in ER with the following complains

• Fever for 15 days• ALOC for 2 day• Fits for 1 day

According to the attendant (brother) the patient was in his usual state of health 15 days back when he developed fever, gradual in onset, low grade, documented once at 101F, relieved on taking anti-pyretics, associated with cough. Not associated with nausea or vomiting. Not associated with morning headaches.

History of altered level of consciousness for 2 days, initially the patient being lethargic and then lost consciousness.

History of fits, multiple episodes, lasting 10-15 seconds, for one day, simple focal in nature (head jerks), without frothing from mouth. No hx of fecal or urinary incontinence.

Past history of Pulmonary TB diagnosed on CXR/Sputum test 1 year ago and took ATT for one week only. Hx of chronic productive cough. Sputum was white in color, not foul smelling or blood stinged. No documentation of TB confirmation available.

Social history - contact hx of TB negative

Family history - not significant. Parents and siblings alive, healthy.

Personal history – k/c of heroine addict. Left 1 year back.Sleep – NormalAppetite – decreasedUndocumented weight loss (approx 20 kg).

Systemic review

CVS; no history of chest pain, breathlessness, palpitations, syncope/dizziness or edema

CNS; past episodes of headaches: dull in nature and developing on the entire head, not associated with diplopia or any sensory/motor deficit.

RS; history of chronic cough, more at night, productive in nature.

GI; decreased appetite. No history of recurrent episodes of diarrhea, malabsorption, no history of UGI and LGI bleed.

GUS; no history of difficult voidance, burning micturation, hematuria or incontinence. No history of flank pain.

MSS; no history of muscle or joint pain, chronic fatigue and loss of cordination.

ES; no history of abnormal weight gain/weight loss prior to illness, hot flashes, abnormal sweating or increased urinary frequency.

General Examination

Young, thin, emancipated patient of average height, orientated and responsive.

Vitals;Pulse 68 BP 110/80Respiratory rate 24 Temperature 101FGCS 15/15 (M6, V5, E4)

Subvitals;J -ve, A -ve, Cl –ve. Cy –ve, Ky –ve, LN –ve, Edema –ve, Thyr –ve.

Multiple dental cavities with dry, ulcerated mucosa. No glossitis, cuts or leukoplakia.

BCG scar not present.

Hands have guttering and thenar wasting. No signs of clubbing or cyanosis.

CNS Examination

GCS 15/15 (M6, V5, E4)

Motor and sensory exam

Right Left

UL UR LL LR

Bulk Decreased Decreased Decreased Decreased

Power +1 +1 +1 +1

Tone Increased Increased Increased Increased

Light Touch NA NA NA NA

Position Intact Intact Intact Intact

Coordination NA NA NA NA

Cranial NervesI intactII Normal vision, PBERL.III, IV, VI Normal eye movementsV light touch intact, wasting of muscles of mastication, cornel reflex present, jaw jerk not performed.VII symmetrical face with no drooping of eye lids or angle of mouth. Decreased power of facial muscles.VIII Not performedIX, X Gag reflex intact. Normal movement of palate.XI No performed.

Reflexes Knees Ankle Biceps Triceps Supinator Plantar

Right + + + + + Up going

Left + + + + + Up going

Fundoscopy not performed.

Kernigg’s sign negative

Neck rigidity negative

No history of photophobia.

Fundoscopy not performed.

Abdominal examination

Inspection; symmetrical, scaphoid abdomen. No scars, pigmentation or visible pulsation. Moving with breathing

Palpation; Soft, non-tender. No visceromegaly.

Percussion, tympanic all over.

Auscultation; guts sounds audible, 2-3/min.

CVS Examination

Normal shape of chestApex beat in 4th ICS, MCL.S1 + S2 + O

Peripheral pulses palpable, regularly regular. Normal volume.

JVP not raised

Respiratory System

No chest deformityTrachea deviated to rightB/L equal and symmetrical expansion of chest

On percussion;

On auscultation;B/L equal air entryB/L coarse crepts

Vocal resonance; patient comatose.

Musculoskeletal System

Gait; NA

No signs of local inflammation of joints or deformity of limbs. Complete passive ROM.

Impression

1. TB Meningitis2. Bacterial Meningitis3. Encephalitis4. Metabolic encephalotpathy

InvestigationsComplete blood count

Hb 12.5MCV 40.5MCH 67.5TLC 11.5Neutros 90.6%Lymhos 3.7%Monos 5.5%Plts 498

Biochemistry

BUN 14Cre 0.4Na+ 118K+ 4.9Cl- 74Ca++ 8.2Mg++ 1.9P 4.2

Liver Function Tests

Total Bilirubin 0.62SGPT 22Alk-phos 144

Viral Markers

HBsAg N/RAnti-HCV N/RHIV Ag/Ab N/R

Sputum positive for AFB smear.

Gene Xpert/RIF result awaited.

Radiology

CXR 10/01/2017

Infiltrates, consolidations and cavities seen in the upper lungs B/L with hilarlymphadenopathy

Plain CT scan showed ventricular dilatation

Contd..

CSF studies

Test Result RangesGlucose 34 mg/dl (40-70)Chloride 93 mEq/l (122-132)Protein 259 mg/dl (15-40)WBC 20/cu mm (0-5)Polymorph 05% (0-5)Lymphocytes 95%RBC 04/cu mm (0-0)Pus Cells RareNO Organism Nil

Gene xpert/MTB-RIF

Mycobacterium Tuberculosis complex not detectedAFB Culture to follow in 6 weeks*Detection of MTB-C: smear positive (sens 100%, spec 100%). Smear negative (sens 70-78%, spec 99%

TB Meningitis

TBM complicates approximately 1 of every 300 untreated primary TB infections.

Risk factors

• HIV co-infection• Malnutrition• Alcoholism• substance abuse• diabetes mellitus• corticosteroid use• Malignancy• head trauma• Homeless persons, people in correctional facilities, and

residents of long-term care facilities also have a higher risk of developing active TB compared with the general population.

Pathogenesis

Many of the symptoms, signs, and sequelae of tuberculous meningitis (TBM) are the result of an immunologically directed inflammatory reaction to the infection.

TBM develops in 2 steps. Mycobacterium tuberculosis bacilli enter the host by droplet inhalation, the initial point of infection being the alveolar macrophages. Localized infection escalates within the lungs, with dissemination to the regional lymph nodes to produce the primary complex. During this stage, a short but significant bacteremia is present that can seed tubercle bacilli to other organs.

In persons who develop TBM, bacilli seed to the meninges or brain parenchyma, resulting in the formation of small subpial or subependymal foci of metastatic caseous lesions. These are termed Rich foci, after the original pathologic studies of Rich and McCordick. Tuberculous pneumonia develops with heavier and more prolonged tuberculous bacteremia. Dissemination to the central nervous system (CNS) is more likely, particularly if miliary tuberculosis (TB) develops.

Contd..

The second step in the development of TBM is an increase in size of a Rich focus until it ruptures into the subarachnoid space. The location of the expanding tubercle (ie, Rich focus) determines the type of CNS involvement. Tubercles rupturing into the subarachnoid space cause meningitis. Those deeper in the brain or spinal cord parenchyma cause tuberculomas or abscesses. While an abscess or hematoma can rupture into the ventricle, a Rich focus does not.

A thick exudate infiltrates the cortical or meningeal blood vessels, producing inflammation, obstruction, or infarction. Basal meningitis accounts for the frequent dysfunction of cranial nerves (CNs) III, VI, and VII, eventually leading to obstructive hydrocephalus from obstruction of basilar cisterns. Subsequent neurological pathology is produced by 3 general processes: adhesion formation, obliterative vasculitis, and encephalitis or myelopathy.

Contd..c

Clinical features

Principle presentation is subacute febrile illness that progresses through three discernible phases:

The prodromal phase malaise, lassitude, headache, low-grade fever, and personality change.

The meningitic phase neurologic features, such as meningism, protracted headache, vomiting, lethargy, confusion, and varying degrees of cranial nerve and long-tract signs.

The paralytic phase, confusion, stupor and coma, seizures, and often hemiparesis. Death may occur.

Choroid tubercles on opthalmoscopy - multiple, ill-defined, raised yellow-white nodules (granulomas) of varying size near the optic disk

Clinical stages

It is useful for prognosis and therapy

• Stage I patients are lucid with no focal neurologic signs or evidence of hydrocephalus.

• Stage II patients exhibit lethargy, confusion; may have mild focal signs, such as cranial nerve palsy or hemiparesis.

• Stage III represents advanced illness with delirium, stupor, coma, seizures, multiple cranial nerve palsies, and/or dense hemiplegia.

Ventricular dilatation may be present (asterisks), along with as inflammatory exudate in the ambient cistern (black arrows) and multiple foci of vasculitis-associated subacute, ischemic necrosis (white arrows)

Electrolyte concentrations should be assessed. Mild-to-moderate hyponatremia is present in roughly 45% of patients, in some cases constituting a true syndrome of inappropriate diuretic hormone secretion (SIADH).

Diagnosis

Cerebrospinal fluid examination:• Protein 100-500mg/dl • Glucose <45 mg/dL (80%)• Initial stages PMN predominance later changed to

lymphocytic dominance.

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: nucleic acid-based amplification test (NAAT) relies upon the polymerase chain reaction (PCR) is 60% sensitive in rapid detection of M. tuberculosis in CSF. Recommended whenever clinical suspicion is sufficiently high for empirical therapy or AFB is negative.

Neuroradiology: 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. To assess the extent of brain parechyma and meningial involvement, MRI (brain) with contrast is the studyy of choice.

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. The high interferon-gamma concentration in the CSF increases further after the antigen stimulation, suggesting theoretically the presence of tuberculous antigen-specific T cells.

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.

Drug Dose Side-effects

INH (Isoniazid) 5-10 mg/kg per day Hepatitis, hypersensitivity

Rifampin (RIF) 10 mg/kg per day (600 mg in adults)

Hepatic toxicity, red-orange staining, Drug interactions.

Pyrazinamide (PZA) 15 to 30 mg/kg per day(max 2g)

Peripheral neuropathy, abdominal pain

Streptomycin 15 mg/kg per day IM-1g in adults20 to 40 mg/kg per day in children)

Deafness, dizziness

Ethambutol 25 mg/kg/day single dose

optic neuritis

Pyridoxine (VitB6) 50mg daily

First line drugs

Recommended regimen

Intensive phase (Initial 2months) — A four drug regimen that includes INH, RIF, PZA, and either EMB or STM Continuation phase (7-10m) — INH and RIF alone if the isolate is fully susceptible,

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.

Glucocorticoid regimen

The use of corticosteroids in adults is controversial; they may be indicated in the presence of increased intracranial pressure (ICP), altered consciousness, focal neurological findings, spinal block, and tuberculous encephalopathy. Treatment of tuberculoma consists of high-dose steroids and continuation of antituberculous therapy, often for a prolonged course.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. Prednisone — A dose of 2 to 4 mg/kg per day for children; 60 mg/day for adults, for 3 weeks, then tapered off gradually over the following 3 weeks.

Second line drugs

• Aminoglycosides: e.g., amikacin (AMK), kanamycin (KM);• Polypeptides: e.g., capreomycin, viomycin, enviomycin;• Fluoroquinolones:

e.g. ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF);• Thioamides: e.g. ethionamide, prothionamide• Cycloserine (the only antibiotic in its class);• p-aminosalicylic acid (PAS or P).

Others

• Macrolides: e.g., clarithromycin (CLR);• Linezolid (LZD);• Thioacetazone (T);• Immunomodulators- cytokine-based therapy but more research

needed for other cytokines and chemokines that may enhance both the mycobacterial killing activity of effector cells and the restriction of bacterial intracellular multiplication

Complications

HydrocephalusInfarctionsComa/stuporMotor deficits-CN palsies, hemiparesis , Seizures, Mental impairmentAbnormal behaviorBrain damageHigh morbidity and mortality

Take home message

Start ATT empirically when suspicion of TBCounsel the patient for medication/side effectsComplete the courseFollow up

Thank you!