This presentation was part of the annual Clinico pathologic case conference of the Bengaluru Neurological Society for the year 2019. The case was provided by the Department of Neurology and pathology, NIMHANS, Bengaluru and i was the discussant. The clinical, radiological and investigation aspects of the case are discussed in detail and the final diagnosis based on histopathology was revealed in the end.

1. Clinico pathologic conference
Bengaluru Neurological Society
Presenter: Dr Pramod Krishnan
Consultant Neurologist
Manipal Hospital, Bengaluru

2. May 2017
Initial presentation

3. Chief complaints
• 48yr/ male, farmer from West Bengal.
• Apparently normal till January 2017. Since then:
1. Holocranial throbbing headache
2. Mild intermittent fever
3. Bilateral painless impairment in vision (April 2017)

4. History of presenting illness: fever
• First seen at NIMHANS on 13.05.17.
• Fever from January 2017, mild, intermittent, and usually in the
form of an evening rise of temperature.
• The fever used to subside with anti-pyretics with mild sweating.
There were no chills or rigors.

5. Headache
• Headache was holocranial, worse in the occipital and neck region.
• It was intermittent and throbbing in nature.
• It was not associated with vomiting.
• There was no specific diurnal or postural change.

6. Impairment of vision
• From April 2017, developed bilateral painless impairment in vision.
• It was worse in the right as compared to the left eye.
• The onset was not clear, but there was no progression from the
time it was noted.
• There was intermittent redness of the eyes (? no pain).
• There was no excessive lacrimation or diplopia.

7. History of presenting illness
• No symptoms referable to other cranial nerves or limbs.
• No band-like sensation, inco-ordination of limbs, involuntary
movements, cognitive decline, seizures or altered sensorium.
• No history of skin rash, pain or swelling of joints, photosensitivity,
muco-cutaneous ulcers, diabetes mellitus or hypertension.
• No significant past medical history.

8. Personal and family history
• Mixed diet
• No change in appetite or weight loss.
• No substance use.
• He had contact with cattle, but denied handling placental products
or raw milk.
• No family history of tuberculosis.

9. Treatment history
• He was diagnosed as TBM at another centre and was on treatment
from 6th May 2017 (HRZE and 20mg/d prednisolone).

10. Analysis

11. Fever
• Fever, low grade, lasting 5 months is most likely due to
inflammatory conditions (infectious, non-infectious) but may
occur with non-inflammatory conditions like neoplasms.
• No significant systemic symptoms or weight loss.

12. Headache
• Headache since 5 months is diffuse, poorly localised, persistent,
and consistent with a secondary headache.
• To consider an intracranial pathology in view of the poorly
localised deep seated pain.
• Cause could be inflammation, raised ICP or lesions causing
stretch, compression, or infiltration of pain-sensitive structures.

13. Headache
• No history to suggest raised ICP as the cause of headache, such as
pain worse on awakening, coughing/straining, activity, or
associated vomiting, tinnitus, dizziness, TVO.
• Headache is worse in the occipital and neck region, indicating
involvement of posterior fossa structures, meninges.
• Meningeal pathology causes non-localising headache, with or
without raised ICP features.

14. Visual impairment
• Bilateral (asymmetric) painless loss of vision (non-progressive):
1. Bilateral optic neuropathies: inflammatory, ischemic, toxic.
2. Papilledema
3. Lesions of optic chiasma, less often, optic tracts.
4. Occipital stroke, bilateral
5. Pituitary apoplexy.
6. Trauma
7. Functional visual loss.

15. Causes of Red eye Remarks
Corneal abrasions Trauma, Vth or VIIth nerve palsy.
Subconjunctival hemorrhage Spontaneous, trauma, coughing, bleeding diathesis.
Pingueculitis Inflammation of pinguecula, a small, raised nodule at the temporal or nasal
limbus.
Dacryocystitis Obstruction of the lacrimal system.
Conjunctivitis Infectious (viral, allergic).
Keratitis Trachoma, HSV, VZV, other bacterial and fungal infection, Vit A def.
Keratoconjunctivits sicca Drugs, Sarcoidosis, Sjogren, radiation, VIIth nerve palsy.
Episcleritis Idiopathic > autoimmune.
Scleritis Usually autoimmune: RA, SLE, PAN, Wegeners, relapsing polychondritis.
Anterior uveitis (iridocyclitis) Sarcoidosis, AS, JRA, IBD, psoriasis, Reiter’s, Behcets, TB, leprosy,
Lymes, syphilis, herpes, onchocerciasis.
Posterior uveitis Sarcoidosis, Behcets, VGH, IBD, bacterial, fungal, spirochetal and
mycobacterial infections.
Endophthalmitis Bacterial, fungal, viral, parasitic infections.
Acute angle closure glaucoma

16. Provisional diagnosis
1. Chronic infectious meningitis: TB, Brucella, fungal
2. Chronic non-infectious meningeal inflammation: vasculitis
3. Slowly progressive diffuse intracranial neoplasm.
• Raised ICP due to either of these pathologies to be considered.
• Wide range of infectious etiology to be considered as patient could
be immunocompromised.

17. Clinical examination
• He was conscious, alert, and oriented.
• General physical examination was normal.
• Visual acuity was 6/9 and 6/12 in the right and left eyes
respectively.
• Optic fundi were normal. Other cranial nerves were normal.
• Motor system, sensory system, DTRs, were normal.
• Plantar response was flexor bilaterally.
• There were no meningeal signs.

18. Analysis
• No papilledema, therefore headache and visual impairment is
unlikely due to raised ICP.
• Bilateral visual impairment with normal fundi and EOMS
indicates inflammatory, infiltrative or ischemic pathology involving
optic chiasma/ optic nerves.

19. Provisional diagnosis
• Structures involved:
1. Meninges
2. Optic chiasma and adjoining posterior portions of both the optic
nerves/ tracts.
3. ?Uveitis/ keratoconjnctivitis
• Pathology:
1. Chronic infectious meningitis
2. Chronic non-infectious meningeal inflammation
3. Slowly progressive diffuse intracranial neoplasm.

20. Uveo-meningitis
Sarcoidosis Primary angiitis of CNS.
Vogt-Koyanagi-Harada syndrome Syphilis
Primary CNS lymphoma Lyme disease
Behcets syndrome HTLV type 1 infection
SLE Acute multifocal placoid pigmentary epitheliopathy

21. Course of his illness

22. CSF analysis (done elsewhere)
• Confirms meningeal pathology,
most likely inflammation.
• 5 months into his illness,
protein elevation is mild
(unusual for TB and other
infections), with lymphocytic
pleocytosis.
• Primary leptomeningeal
neoplasm can mimic
tuberculosis.
Parameter May 17*
Appearance
Cell count (/cu mm) 102
Cell type L- 70%
P- 30%
CSF protein (mg/dl) 74
CSF glucose (mg/dl) 42
CSF Chloride (mmol/L) NA
CSF Lactate (mg/dl) NA
Gram stain
India Ink NA
Cryptococcal Ag
Bacterial culture
AFB culture

23. Course of his illness
• In view of visual impairment, ATT was modified.
• Ethambutol was stopped and streptomycin (750 mg/ day, IM) and
ofloxacin (800 mg/ day) were introduced.
• The dose of oral prednisolone was increased to 60 mg/ day.

24. July 2017

25. Course of his illness
• Fever subsided from June 2017.
• Headache reduced partially. There was minimal change in vision.
• Developed impaired hearing in the left ear from June 2017.
• There was no local pain, swelling or ear discharge.
• AC > BC in the right ear, and Weber’s test showed lateralisation to
the right ear; the patient could not perceive the sound of the
tuning fork by air or bone conduction in the left ear (left SNHL).
• There were no other new neurological deficits.

26. Comment
• Improvement in headache and fever could be due to ATT, or more
likely due to steroids.
• Inspite of therapy, vision did not improve and he developed left
sided sensori neural deafness, suggesting left VIIIth nerve
involvement.

27. August 2017

28. Parameter May 17* Aug 2017
Appearance Clear
Cell count (/cu mm) 102 115
Cell type L- 70%
P- 30%
L- 70%
P- 29%
Degenerative
cells 1%
CSF protein (mg/dl) 74 47
CSF glucose (mg/dl) 42 47
CSF Chloride
(mmol/L)
NA NA
CSF Lactate (mg/dl) NA NA
Gram stain
India Ink NA Negative
Cryptococcal Ag
Bacterial culture
AFB culture No growth
Parameter May 17 Aug 2017
Gene Xpert
Cytospin Transformed
lymphocytes,
admixed with
reactive
monocytes and
RBCs. Few
PMN cells are
also seen
VDRL Non-reactive
Xcyton panel
CSF Analysis
No significant improvement except
for drop in protein levels.

29. Course of his illness
• Streptomycin and pyrazinamide were discontinued in August 2017.
Isoniazid, rifampicin and ofloxacin were continued along with oral
prednisolone (60 mg/day).
• He also developed cushingoid facies by August 2017.

30. November 2017

31. Course of the illness
• Recurrence of fever from November 2017, which was mild,
intermittent and usually in the morning. This was not associated
with night sweats, loss of appetite or weight loss.
• Headache increased in frequency and intensity, was frontal in
location and used to resolve spontaneously in 5 to 10 minutes.
• He also developed diabetes mellitus which was treated.

32. 2018

33. Course of his illness
• Isoniazid, rifampicin and ofloxacin were continued.
• Prednisolone was tapered from January 2018 by 5 mg every 15 days
to 5 mg/ day by July 2018.
• The patient developed neck pain from mid-July 2018 along with left
hemicranial headache.
• Isoniazid and rifampicin were continued. Ofloxacin was
discontinued in November 2018.

34. 2019

35. Course of his illness
• Ethambutol (800 mg/ day) and Moxifloxacin (400 mg/ day) were
added.
• Oral prednisolone was increased to 60 mg/ day.
• However, there was progressive increase in headache, mainly in
the neck and vertex region.
• Hence he underwent biopsy of meninges on 14th March 2019.
• Based on the biopsy he was initiated on treatment. He was
discharged on 20th March 2019. There is no further follow up.

36. Test 27/July/17 12/Nov/18 28/Feb/19 13/Mar/19 14/Mar/19 16/Mar/19
Hb (ref: 13-17 gm/dl) 15.4 16.0 14.1
Haematocrit (ref: 40-50%) 45.2%
MCH (ref: 27-32 pg) 30.5
MCHC (31.5-34.5 g/dl) 34.0
MCV (ref: 83-101 fl) 89.7
TLC (ref: 4-11K/ µl) 10.5 13.4 11.4
Differential count N=52.2%,
L=36.3%, M=6.3%,
E=4.8%, B=0.4%
N=75.2%,
L=14.1%,
M=9.4%,
E=0.4%,
B=0.9%
Platelets (ref: 150-450K/µl) 82 207 207
ESR (ref: 0-10 mm/hr) 9 20 20 80
Peripheral smear Normal except for
several large
platelets seen. No
hemoparasites.
Hematology

37. Tests 27/July/17 30/ Jan/ 18 5/ Nov/ 18 28/ Feb/ 19 13/ Mar/ 19 14/ Mar/ 19
RBS (mg/dl) (ref: 70-140 mg/ dL) 90 324 70
FBS (mg/dl) (ref: 70-100 mg/ dL) 161
PPBS (mg/dl) (ref: 100-140 mg/dl) 322
Urea (mg/dl) 15 16 18.0 20.0
Creatinine (mg/dl) 0.91 0.78 0.8 0.8
T Protein (g/dL) (ref: 5.7-8.0 g/ dL) 6.6 6.20 6.60
Albumin (g/dL) (ref: 3.5-5.2 g/ dL) 3.86 4.00 3.90
Globulin (g/dL) (ref: 2.5-5.6 g/ dL) 2.7 2.20 2.70
A:G Ratio (ref: 1.2-2.5) 1.4 1.80 1.40
Total Bilirubin (mg/dl) 0.90 0.34 0.75
ALP (U/L) (ref: 52-171 U/ L) 106 102 70
SGOT (U/L) (ref: 8-50 U/ L) 92 14.0 33.0
SGPT (U/L) (ref: 7-50 U/ L) 240 30.0 36.0
Sodium (mEq/L) 139.4 141.00 140.0 137.2
Potassium (mEq/L) 4.21 3.92 4.18 3.82
Chloride (mEq/L) 100.2 98 104.2 107.2
Homocysteine (ref:<15micromol/L) 12.9
Vitamin B12 (ref: 197-771 pg/ml) 257
Biochemistry

38. Parameter May 17* Aug 2017 Sept 2018 Nov 18 Jan 2019 Mar 2019
Appearance Clear Clear Hazy Slightly hazy
Cell count (/cu mm) 102 115 350 140 1000 120
Cell type L- 70%
P- 30%
L- 70%
P- 29%
Degenerative
cells 1%
L- 80%
Degenerated cells-
20%
Occasional RBCs
L- 70%
P- 30%
L- 20%
P- 80%
Occasional
RBCs
L- 20%
P- 75%
Degenerative cells
5%
CSF protein (mg/dl) 74 47 155 105 338 177
CSF glucose (mg/dl) 42 47 73 175 297 216
CSF Chloride
(mmol/L)
NA NA 120 119 114 119
CSF Lactate (mg/dl) NA NA NA 28 NA NA
Gram stain Pus cells. No
bacteria
Pus cells. No
bacteria
India Ink NA Negative Negative NA Negative Negative
Cryptococcal Ag Negative
Bacterial culture No growth
AFB culture No growth No growth No growth
CSF analysis
* reported from another centre.

39. Parameter May 17 Aug 2017 Sept 2018 Nov 18 Jan 2019 Mar 2019
Gene Xpert Insufficient sample Negative Negative
Cytospin Transformed
lymphocytes,
admixed with
reactive
monocytes and
RBCs. Few
PMN cells are
also seen
Transformed
lymphocytes, few
reactive monocytes,
PMN cells &
RBC's.
Predominantly
PMN cells, few
lymphocytes,
occasional
reactive
monocytes,
eosinophils &
plasmacytoid
cells.
Numerous
degenerating
PMN cells, few
intermixed
reactive
lymphocytes and
monocytoid cells.
VDRL Non-reactive Non-reactive
Xcyton panel Positive for
cysticercal
antibody
CSF analysis

40. Chronic meningitis with neutrophilis in CSF
Infections Non-infectious
Tuberculosis SLE
Brucella Chemical meningitis: craniopharyngioma
Nocardia asteroides Adult Stills disease
Actinomyces israeli Primary CNS angiitis.
Cysticercal meningitis
Fungi: Blastomyces dermatitidis, Candida albicans, Histoplasma capsulatum,
Aspergillus spp, Pseudallescheria boydii, Cladophialophora bantiana.

41. Cysti-CheX test for cysticercosis (Xcyton)
• Semi-quantitative ELISA for detecting antibodies to cysticercal E-
S antigens.
• It uses Secretory and Excretory antigens of cysticerci (E-S
antigen).
• These antigens are very specific and immunogenic.
• Sensitivity and specificity of the test is close to 100% (Neurological
practice: an Indian perspective. 2015. Ed Noshir H Wadia, Satish V Khadilkar)

42. Other investigations Results
TFT Normal
ANA, ANA profile, ANCA, RA Negative
ACE level Normal
PT, APTT Normal
HIV, S. VDRL Non reactive
Blood culture No growth
HbA1c 8.8% (Jan 2018), 15.6% (March 2019)
Serum paraneoplastic antibody panel GAD65 positive (1+)
Brucella Standard Agglutination Test Negative
Absolute CD4 count 1856 /ul

43. Anti GAD 65 positivity
Stiff person syndrome Hashimotos thyroiditis
Autoimmune encephalitis Pernicious anemia
Brain stem encephalitis Type 1 diabetes.
Cerebellar ataxia syndromes Myelitis
Myasthenia gravis Miller Fischer syndrome like presentation
Lambert Eaton syndrome Autoimmune encephalitis
Positive GAD 65 antibody may suggest an autoimmune process in this patient.

44. Audiometry (23/8/17): right ear normal. Left ear shows severe
sensori neural deafness.
July 2017 November 2018
Right eye Inferior altitudinal scotoma Normal
Left eye Normal Normal
Visual field charting:
VEP: P100 latency- 107.7 ms (Rt), 106.5 ms (lt): upper limit of
normal.
SSEP of median and posterior tibial nerves: Normal
BAER I II III IV V I-III III-V I-V
Right ear 1.45 2.76 3.74 4.98 5.96 2.29 2.22 4.51 Normal
Left ear 2.39 5.57 7.13 4.74 Delayed.

45. Radiology
September 2018

46. MRI brain 3D post-contrast T1W axial sequence shows few enhancing nodules along tentorium and
meninges.

47. MRI brain post contrast T1W axial sequence shows dural enhancement along prepontine cistern and
seventh nerve in left IAC (left) and focal enhancing nodule along pial surface of medulla (right).

48. MRI upper cervical cord post contrast T1W sequence axial (left) and sagittal (right) showing tiny
enhancing foci along surface of cervical cord.

49. MRI brain post contrast T2flair axial sequences show lepto-meningeal enhancement in the basal
cisterns.

50. March 2019

51. MRI cervical spine coronal and axial post contrast of cervical spine shows nodular dural
enhancement in upper cervical cord on right side .There is also enhancement along left cervical
nerve roots.

52. MRI brain post contrast T1W axial sequence shows Persistence of dural enhancement along pre-
pontine cistern and left seventh nerve.

53. MRI brain post contrast T1W axial sequence shows leptomeningeal enhancement along lateral and
posterior surface of brainstem.

54. MRI brain post contrast flair shows increased leptomeningeal enhancement in basal cisterns and
interval appearance of leptomeningeal enhancement in right posterior Sylvian fissure.

55. MRI brain fiesta images shows right half of chiasm, optic tract showing increased signal. There
is also absent CSF plane with adjacent structures ? Septations. No post contrast enhancement.

56. Summary of MRI images
• Leptomeningeal nodular patchy enhancement involving basal
cisterns, optic chaisma and around the cervical cord and roots,
with adhesions.
• No parenchymal involvement at the end of 2 years.
• Small areas of dural involvement noted in the cervico medullary
junction.
• Definite increase in lesions while on treatment.
• Possibilities are granulomatous leptomeningeal disease > primary
leptomeningeal neoplasm.

57. Other radiological investigations
• CT thorax (twice): unremarkable.
• CT brain: unremarkable. No calcification.
• X ray chest: unremarkable.
• X ray cervical spine: unremarkable.
• USG abdomen: normal.

58. The Last Lap!!

59. Summary
• Chronic meningeal disease of > 2 years duration, with fever.
• No response to ATT, clinically or based on CSF, MRI.
• Partial benefit with steroids, with worsening on steroid reduction,
but some worsening occurred while on 60 mg/d prednisolone.
• Nodular patchy leptomeningeal enhancement on MRI involving
basal cisterns, surface of medulla and cervical cord, roots, sylvian
fissure, with dural involvement and adhesions and without
parenchymal involvement.
• CSF shows lymphocytic pleocytosis with mild elevation of proteins
and later shows predominance of PMNs and counts >1000 cells.

60. Bacterial and parasitic infections
Disease Points in favour Points against
Tuberculosis Neutrophilic CSF pleocytosis can occur,
(but usually early in the disease).
Leptomeningeal disease of 2 years with
fever and headache can occur.
?MDR TB.
No parenchymal involvement.
No systemic symptoms.
No response to ATT
Gene X pert repeatedly negative
Only mild elevation of CSF
protein
Cysticercal
meningitis
Xcyton cysticercal test positive in CSF.
Partial response to steroids.
Involvement of basal cisterns, adhesions.
Neutrophils in CSF and cell count of >1000
are described in this condition.
No cysts seen in the basal
cisterns.
No CSF pathway obstruction
seen.

61. • 138/336 pts (41%) had parasites in the subarachnoid space at the base of the brain.
• Group A had a mean ± SD disease duration of 36.33 ± 13.4 months, and Group B had a
mean ± SD disease duration of 15.6 ± 1.91 months.
• Group A had increased neutrophils with a mean ± SD of 2,158 ± 475.78 cells/cumm.

62. 14 patients in this series presented as chronic meningitis.

63. Clinical Infectious Diseases 2013;56(10):1407–12
The sensitivity of tube agglutination (TA) in CSF was 0.94, specificity 0.96, positive
predictive value 0.94, and negative predictive value 0.96.
Points in favor Points against
Rifampicin, Streptomycin are effective
treatment for Brucellosis
No musculoskeletal disease or brain
parenchymal disease at the end of 2 years.
Can present as chronic meningitis. Brucella antibody test is negative
h/o contact with cattle. CSF cell count of 1000 is not reported.
Neutrophils in CSF may be seen.

64. Chronic fungal/ Nocardia meningitis
• Some of these organisms are ubiquitous and endemic in parts of
India, but others are very rarely reported.
• CSF neutrophils can be seen.
• However, more common in immunocompromised patients.
• No appropriate exposure history.
• Absence of brain parenchymal lesions, parameningeal focus, sino-
pulmonary disease over 2 years, while on steroids is odd.
• Usually cause complicated meningitis.

65. Wegeners granulomatosis
Points in favour Points against
Nodular leptomeningeal enhancement.
Dural involvement.
Isolated CNS disease is possible.
Intermittent red eye.
CSF can show neutrophils
Poor response to steroids alone is
possible as it requires aggressive
immunosuppression.
No sinus or pulmonary disease.
Usually causes pachymeningitis.
ANCA negative.
CSF cell count of 1000 is rare.

66. Neurosarcoidosis
Points in favour Points against
Isolated neurosarcoidosis is well
known.
Cranial neuropathy (II, VIII).
Partial response to steroids.
Possible uveitis (red eye).
CT thorax normal (twice).
ACE levels normal.
CSF neutrophils not reported.
Steroids are the mainstay of treatment, so
response should have been better.
CSF cell count of 1000 is unlikely.

67. • 10/91 patients with neurosarcoidosis had isolated neuro-sarcoidosis.
• Common clinical manifestations: headache (9), paresthesia (5), and cranial
neuropathies (4).
• No extraneural sarcoidosis developed during a long follow-up period (mean 58 mo).
• Compared with those who also had systemic neurosarcoidosis, isolated
neurosarcoidosis patients had a more common frequency of headache, hemiparesis,
and radiculopathy, leptomeningeal involvement on brain MRI, increased cell count in
cerebrospinal fluid, and a more favorable clinical outcome (P < 0.05).
The Neurologist 2012; 18:373–377)

68. Disease Points in favour Points against
SLE, Sjogrens CSF neutrophils is
reported.
Possible uveitis.
ANA, ANA profile negative.
Very high cell counts is not reported.
Absence of brain parenchymal disease or
systemic disease.
Inadequate response to steroids.
Behcets disease Possible uveitis. Usually a recurrent meningitis.
No oro-genital ulcers.
CSF neutrophils, very high cell counts not
reported.
SLE, Behcets disease, Primary CNS angiitis
Primary CNS angiitis is unlikely as the presentation is usually subacute dementia, multiple
infarcts.
ESR of 20 (on one occasion ESR was 80 mm at 1st hr).
Intermittent red eye, anti GAD 65 antibody positive.

69. Ann Indian Acad Neurol 2006; 9: 240-8
Primary leptomeningeal neoplasm: diffuse leptomeningeal glioneuronal tumor
Points in favor Points against
Pure leptomeningeal disease Usually seen in children and adolescents.
Reported in 4th and 5th decades also No fever.
Indolent course over years. Usually complicated by hydrocephalus.
Very high CSF counts and neutrophils in CSF unlikely.
Patchy meningeal enhancement. Dural involvement.
Protein in CSF is markedly elevated.
Primary leptomeningeal melanoma: in slightly older patients, more rapid course as in
the above case report.

70. Final differential diagnosis
• Wegeners granulomatosis
• Neuro-sarcoidosis
• Cysticercal meningitis.
• ?MDR TB

71. Final diagnosis

72. Final diagnosis based on histopathology
• Chromoblastomycosis !!
• A common fungus found in the soil which can be inoculated into
the body by minor trauma.
• Infection with this fungi is very rare, can occur in
immunocompetent hosts and is usually very indolent.
• This patient responded to therapy with anti-fungal agents.

73. THANK YOU