- A young lady presented with headache, fever and gradual loss of vision with other neurological symptoms and was diagnosed with tuberculous meningitis based on investigations. She developed drug-induced liver injury during treatment and her anti-tubercular treatment was modified. She also developed seizures and hydrocephalus requiring VP shunt placement. Her condition is being closely monitored during anti-tubercular treatment and management of complications.

1. SATURDAY CLINICAL MEET
Unit-III
SLC Saurabh Mishra
Lt Col Ashutosh Ojha

2. PARTICULARS
• 25 yr/F, married
• Rt handed
• Educated upto 5th std
• Works as daily wage worker in carton factory
• Resident of Jabalpur
• Informant Mother
• Reliability poor

3. HISTORY
• P/C: (04 months ago)
– Fever x 15 days duration
• Moderate grade
• Intermittent
• Associated with chills, no rigors
• No h/o evening rise of temperature/ night
sweats

4. HISTORY
– Headache x 05 days duration
• Insidious onset
• Moderate grade that has increased in severity,
affecting her daily chores
• Dull aching
• Begins over the forehead onwards to involve
the head
• Associated with recurrent episodes of
projectile vomiting, irritability and drowsiness
• Not associated with photophobia
• No Neck pain

5. HISTORY
– Diminution of vision x 04 months
• Insidious onset
• painless
• Describes as ‘blurring of vision’
• Gradually progressive
• Complete loss of vision both eyes x 03 wks
Associated h/o
– dribbling of saliva from Lt side of mouth and
– difficulty in chewing, pushing bolus of food
into mouth
– slurring of speech since then

6. HISTORY
• No h/o loss of consciousness, seizures,
abnormal behaviour, memory disturbance
• No h/o abnormal sense of smell, loss of
sensation over face, gritty sensation in eyes,
facial deviation, hearing loss, tinnitus, vertigo,
nasal twang, regurgitation of food
• No h/o limb weakness, abnormal movement in
limbs

7. HISTORY
• No history s/o
– Sensory system involvement
– Cerebellar involvement
– Bowel & bladder involvement
• No h/o chest pain, palpitations, syncope
• No h/o cough, breathlessness, wheeze
• No h/o pain abdomen, constipation
• No h/o yellowish discoloration of eyes, urine
• No h/o recent travel, blood transfusions

8. HISTORY
• Managed initially as a c/o Enteric Fever with
empirical antibiotics for a period of 07 days
• Showed no response to treatment, though fever
subsided
• Headache persisted

9. Summary

10. Summary
• A young lady presented with headache and
fever with gradual painless loss of vision with
projectile vomiting , unable move food in
mouth.

11. Common Causes of Headache

12. Common Causes of Headache
Primary Headache Secondary Headache
Type Percentage Type Percentage
Tension-type 69 Systemic infection 63
Migraine 16 Head injury 4
Ideopathic stabbing 2 Vascular disorder 1
Emotional 1 Subarachnoid
Hemorrhage
<1
Cluster 0.1 Brain tumor 0.1
HPIM 19 Edn Pages 107

13. Headache Symptoms that Suggest a
Serious Underlying Disorder

14. Headache Symptoms that Suggest a
Serious Underlying Disorder
• "Worst" headache ever
• First severe headache
• Subacute worsening over days or weeks
• Abnormal neurologic examination
• Fever or unexplained systemic signs
• Vomiting that precedes headache
• Pain induced by bending, lifting, cough
• Pain that disturbs sleep or presents immediately upon awakening
• Known systemic illness
• Onset after age 55
• Pain associated with local tenderness, e.g., region of temporal
artery
HPIM 19 Edn Pages 108

15. USMLE –Hard
Facts

16. HISTORY
• MRI Brain revealed
– Diffuse cerebral edema
– Effaced basal cisterns
– Abnormal signal intensity in b/l frontal region
s/o meningo-encephalitis

17. HISTORY
• CSF analysis revealed
S.No Parameter Values
1 Appearance clear
2. Proteins 190 mg/dl
3. Glucose 20 mg/dl
4. Cytology Total cells – 150
Neutrophils – 6%
Lymphocytes – 94%

18. TREATMENT HISTORY
• Diagnosed as a c/o Tubercular Meningitis
• Started on ATT (HRZE) wef 16 Feb 16
• Suboptimal dose of Steroid

19. TREATMENT HISTORY
• H/o
– Nausea
– Vomiting x 01 wk
– Decrease appetite
• Detected to have Transaminitis
• Treatment modified to Levofloxacin,
Streptomycin and Ethambutol

20. Staging of tuberculous meningitis
Stage Clinical Features
Stage 1 Fully conscious, no paresis
Stage 2 Decreased level of consciousness,
localizing pain
Stage 3 Deeply comatose ± gross paresis
British Medical Research Council

21. ATT induced Liver Injury-Causative
Agents

22. ATT induced Liver Injury-Causes
• 1st line TB medications – PZA> INH>Rifampicin
• 2nd line Drugs– Ethionamide, fluoroquinolones, PAS
• ART – Nevirapine most hepatotoxic – Also Efavirenz
and PI’s (especially double dose Lopinavir/ritonavir)
• Several other drugs used in HIV+ patients – Co-
trimoxazole, Fluconazole
• Always consider other causes – Viral hepatitis
• IRIS
• Sepsis
ATS ..position statement 2009

23. ATT induced Liver Injury-Risk factors

24. ATT induced Liver Injury-Risk factors
• Age – Over 35 years
• Females more severe DILI
• Malnutrition – Low albumin
• More extensive TB
• HIV
• Chronic hepatitis B and C
• Genetic polymorphisms – NAT2 slow-
acetylator genotype and INH DILI
ATS ..position statement 2009

25. Reintroduction Regime for ATT

26. Reintroduction Regime for ATT
• No well accepted Guideline
• British Thoracic society
• HRZ
• Minimal dose sequential addition of drugs after 3
days
• American Thoracic society
• Full dose , weekly ,sequential addition of drugs
• European Guidelines as well….

27. Predictors of Drug Induced Hepatotoxicity(DIH)
in Tuberculous Meningitis
• DIH occurs in 43.3%
patients with TBM and
is related to
hypoalbuminemia and
seizure.
• Attention should be
paid to manage under-
nutrition and avoid
enzyme inducing
antiepileptic drugs.

28. Role of Steroid in TB meningitis

29. Role of Dexamethasone in TB
meningitis
This study provides clinical evidence
that early treatment with
dexamethasone and antituberculosis
drugs improves survival among
patients over 14 years of age with
tuberculous meningitis, regardless of
disease severity.
However, dexamethasone probably
does not prevent severe disability in
the survivors.

30. Dexamethasone in TB meningitis
Poor GCS patients Intravenous dexamethasone
for 4 weeks
Week Dose Dexamethasone IV
1 0.4mg/Kg/Day
2 0.3
3 0.2
4 0.1
Taper as oral Dexamethasone 4mg/day, 3mg/day,
2mg/day & 1mg/day each for 1 week

31. Dexamethasone in TB meningitis
Patients with a normal mental status and no
neurological findings receive IV dexamethasone
for 2 weeks (0.2 mg/kg per day in week 1, then 0.1
mg/kg per day in week 2),followed by the same
oral taper as described above
It is recommended that the steroid treatment
should start as soon as possible after initiation of
appropriate first-line anti tuberculosis drugs.

32. PRESENTATION AT CH
• Bedridden x 01 month
– Fever
– Headache
– Blindness
– Drowsiness

33. PAST HISTORY
• No h/o contact with case of TB in neighborhood
• No h/o TB in the past

34. PERSONAL HISTORY
• Poor oral intake since 02 months
• Normal bowel, bladder habits
• Altered sleep pattern
• Does not consume tobacco, alcohol

35. MENSTRUAL & OBSTETRIC HISTORY
• Attained menarche at 14 yrs age
• LMP: 25 Jun 16
• Cycles regular: 3-4/28 days
• Nulligravida

36. FAMILY HISTORY
• No h/o TB in the family

37. BCG
• Not vaccinated for BCG

38. Summary

39. Summary
• A young lady presented with headache, features
of raised intracranial tension, with progressive
loss of vision and cranial nerve involvement
diagnosed as Tuberculous meningitis on CSF
and Neuroimaging, developed Drug induced
Liver Injury and been on Hepatosafe ATT.

40. EXAMINATION
• O/e:
– Pt conscious, disoriented in time, place and
person
– Agitated and restless
– Ht: 160 cms, Wt: 45 kgs, BMI:18 kg/m2
– Thin built
– Temp: 100 oF
– Pulse: 100/min
– BP: 138/100 mm Hg
– RR: 16/min

41. EXAMINATION
• Temporal wasting +
• No pallor, icterus, clubbing, cyanosis,
lymphadenopathy, raised JVP, pedal edema
• No stigmata of TB
• No neurocutaneous markers

42. SYSTEMIC EXAMINATION
• Neurologically, the pt drowsy, irritable and not
co-operative for detailed evaluation
– HMF could not be assessed
– Dysarthria +
– Kernigs sign +ve, Brudzinski sign +ve

43. SYSTEMIC EXAMINATION
• Cranial nerve
– II nerve: absent PL/PR, dilated pupil (b/l) (3
mm), sluggish reaction to light
– III, IV, VI nerve: Lt Lateral rectus palsy
– V nerve: intact sensations over face, absent
corneal and conjunctival reflex (b/l)
– VII nerve: Lt LMN palsy
– IX & X nerve: Gag reflex + Bilat.
– XII nerve: Deviation of tongue to Lt +

44. SYSTEMIC EXAMINATION
• Motor system:
– Bulk normal Tone in all limbs: normal
– Power: Grade 4 in all limbs
– Reflexes:
– Gait unsteady
– Patient was unco-operative for assessment of
cerebellar and sensory system examination
BICEPS SUPINATOR TRICEPS KNEE ANKLE PLANTAR
Rt ++ ++ ++ +++ +++ Extensor
Lt + + + +++ +++ Mute

45. SYSTEMIC EXAMINATION
• Ophthalmology examination:
– Clear fundal media
– Optic disc: normal in size, shape & margins
– Optic disc pallor noted
– Cup/Disc:: 0.5:1
– Optic atrophy (b/l) +
• Other Systems – No abnormality detected

46. INVESTIGATIONS (AT ADMISSION)
Parameters Values
Hb 12.9 g%
TLC/mm3 6900
DLC P64 L25
Platelets 2.79 lac/mm3
ESR 88 mm fall in 01 hr
(Westergren’s)
S.Urea/Creatinine (mg/dl) 21/0.7
Na/K (mEq/L) 132/4

47. INVESTIGATIONS (contd)
Parameters Values
T.Bil/ AST/ALT/ ALP (IU/L) 0.3/21/15/55
HBsAg/ HIV/ anti HCV Ab Negative
Mantoux 24 mm
Blood culture No growth seen
Urine culture No growth seen
CPK 15 IU/dL

48. CXR

49. ECG

50. USG ABDOMEN
• Normal liver size & echo texture
• Normal spleen
• Normal Renal echo texture
• No Ascites/ Lymphadenopathy

51. CSF in TB Meningitis

52. CSF in TB Meningitis
• Opening pressure-150-250mm of H2O
• Proteins -100 to 200mg/dL
• Sugar -<50% of Blood sugar in 75% of cases
• WBCs -25-100/ microlitre
• Cells –Lymphocyte predominant
• AFB stain + ve <25%
• Gram Stain –Occasionally +ve
HPIM 19 Edn Page-766

53. INVESTIGATIONS (contd)
S.No Parameter Values
1. Pressure 18 cms H2O
2. Appearance Straw colored
3. Stains (Gram/Zn) No organisms seen
4. Proteins 250 mg/dl
5. Glucose 60 mg/dl (RBS-80 mg/dl)
6. Cytology RBC – Nil
WBC – 90/cc
Lymphocytes – 70%
7. MTB PCR Negative
8. ADA 3.4 U/L
CSF analysis:

54. Role of Adenosine Deaminase (ADA)

55. Role of Adenosine Deaminase (ADA)
• In conclusion, ADA cannot
distinguish between bacterial
meningitis and TBM, but using
ranges of ADA values could be
important to improve TBM
diagnosis, particularly after
bacterial meningitis has been
ruled out
• The different methods used to
measure ADA and the
heterogeneityof data do not
allow standardization of this
test as a routine

56. INVESTIGATIONS (contd)
• MRI Brain

61. ATT in TB meningitis

62. ATT in TB Meningitis
• Isoniazid (INH), Rifampin (RIF), Pyrazinamide
(PZA), and Streptomycin (SM), all enter
cerebrospinal fluid (CSF) readily in the presence
of meningeal inflammation.
• Ethambutol is less effective in meningeal
disease unless used in high doses.
• The second-line drugs include Ethionamide,
Cycloserine, Ofloxacin, and Para -aminosalicylic
acid (PAS)

63. ATT in TB meningitis
• 4 Drugs for 2 months
• 2 Drugs (7 to 10 months)

64. TREATMENT
• Continued on ATT (LSE regime) + Inj
Dexamethasone 20 mg iv OD
• Reintroduced INH as per American Thoracic
Society Guidelines

65. Anti-Epileptic Drug in TB Meningitis
• New onset seizures occur in about 50% of
children and in 5% of adults.
• Patients with CNS infections, after the first acute
seizure, recurrent seizures are common
• Acute Management – Short acting
Benzodaizapines & Phenytoin
• Long Term Rx with Phenytoin, Valproate-
Hepatotoxic as well as Enzyme inducer
• Levetericetam-Safely given
British Medical Bulletin 2015 :113;1 Pages 117-131

66. COURSE IN HOSPITAL
• Day 3
– Developed 01 episode of GTCS lasting 03-05 mins
– Inj Phenytoin Sodium 1000 mg iv loading dose given
followed by maintenance dose (6mg/kg)
– No recurrence of seizure thereafter
– AED Levetirecetam 1 g BD started
– Rt Medium Pressure VP shunt placed on D5 of
admission

67. Role of Osmotic Agents of tuberculous
meningitis

68. Tuberculous Meningitis with
Hydrocephaly - Grades
Rajshekhar V. Management of hydrocephalus in patients with tuberculous meningitis.
Neurol India 2009;57:368-74
Vellore Grading of Hydrocephaly
Grade Clinical Features
I Headache ,Vomiting, Fever +/_ Neck Stiffness, No neurological
Deficit
Normal sensorium
II Normal Sensorium ,Neurological Deficit present
III Altered sensorium but easily arousable ,Dense neurological
Deficit may or may not present
IV Deeply comatosed ,Decerebrate or decorticate posturing
From Porur et al

69. Role of Osmotic Agents of tuberculous
meningitis
• Short term use of Mannitol, Frusemide and
Acetazolamide in Stage 1 & 2 Disease
• Manitol can be given upto 72 hrs
• Frusemide & Acetazolamide may be used for
weeks
• Only in Open Hydrocephalus
Rajshekhar V. Management of hydrocephalus in patients with tuberculous meningitis.
Neurol India 2009;57:368-74

70. VP-Shunt of tuberculous meningitis..When
Rajshekhar V. Management of hydrocephalus in patients with tuberculous meningitis.
Neurol India 2009;57:368-74

71. Complications of VP shunts

72. Complications of VP shunts
• Infection
• Mal-position
• Occlusion
• Ventricular Collapse

73. POST OPERATIVELY
• Post-operatively, patient was conscious, oriented
and co-operative
• Continued on ATT and Inj Dexamethasone 20
mg iv daily
• Tolerated oral feeds
• Remained afebrile

74. POST OPERATIVELY
• No symptoms of headache
• Persistence of symptoms in the form of
– mild dysarthria
– Difficulty in pushing food bolus into mouth
– Blindness

76. POST OPERATIVELY
• NCCT head revealed functional in-situ shunt
• Re-introduced ATT as per ATS protocol
• Developed asymptomatic Transaminitis on day 14
th.
• Stopped INH & Rifampicin
• Restarted on Hepatosafe ATT(Strepto+
Etham+Levoflox)

77. ATT Plan ..in our case
• Present SGOT/SGPT-178/304 IU/L
• Wait till Transaminases stabilise
• Introduce Rifampicin
• Acetylator Status
• Then INH
• No PZA

78. SUPPORTIVE TREATMENT
• Nutrition and dietary supplements
– Soft high Protein low volume and K+
containing diet and plenty of fluid with liberal
salt
• Supported Ambulation & Limb Physiotherapy

79. Neurological and systemic complications of
tuberculous meningitis

80. Neurological and systemic complications of
tuberculous meningitis
• Mortality and serious long-term sequelae still
occur in about 50% of patients with TBM
• Hyponatremia 49%,
• Hydrocephalus 42%,
• Stroke 33%,
• Cranial nerve palsies 29%,
• Epileptic seizures 28%,
• Diabetes insipidus 6%,
• Tuberculoma 3%,
• Myeloradiculopathy 3%
• Hypothalamic syndrome 3%.

81. Vascular complications of tuberculous
meningitis
• This study showed
extensive damage of
cerebral vessels in TBM,
which was responsible for
the presence of
widespread infarctions.
• Microscopic infarctions in
the brainstem and
cerebellum were much
more common than
reported by radiological
studies.

82. How long AEDs

83. How long AEDs
• Rx on lines of Symptomatic seizure disorder
• We do neuro- imaging and EEG-If normal give
for 2 year seizure free
• If tuberculoma or any other lesion present
may be offered for longer period

84. Prognosis …TB meningitis

85. Prognosis …TB meningitis
• Cranial nerve
involvement occurred in
more than one third of
patients with
tuberculous meningitis.
• The presence of cranial
neuropathy was
associated with poor
outcome.
• Mortality is higher in
extremes of age.

86. No Roles
• Aspirin
• Anti –TNF Alfa Agents

87. PLAN
• Continuation of ATT with gradual and slow re-
introduction of Rifampicin in low dose
• Tapering of steroids
• Physiotherapy
• Follow up

88. AIM
• Approach towards a case of Chronic Meningitis
and TBM
• ATT induced liver injury

89. •Thank You