1. ACUTE AND SUBACUTE MENINGO-ENCEPHALITIS
CLINICAL, ETIOLOGICAL AND PROGNOSTIC
FEATURES
Dr. Ankit Raiyani

2. Background
• 25 year male presents with 6 days history of
fever, 3 days headache and altered sensorium
• Clinically— GCS -10, neck stiffness +, no focal CNS
signs, spleen +, chest clear
• Diagnosis- Acute onset febrile
meningoencephalitis syndrome
– ? Bacterial/ viral /tuberculous meningitis
– ? CNS msnifestation of Malaria/ leptospirosis/ dengue
– ? Undiagnosed viral illness

3. What are the clinical criteria for etiological
diagnosis of meningoencephalitis?
Tuberculous Pyogenic Viral encephalitis Cryptococcus
Cerebral malaria 2 Leptospirosis 1
meningitis 1 meningitis 1 1 meningitis 1
•Fever with •acute •fever with •acute •acute •subacute
subacute presentation •behavioural presentation presentation presentation,
presentation, •high grade fever, changes, with with high grade •altered mental
•prominent signs •signs of •seizures, •high grade fever with chills, status and
of meningism, meningism, and •focal intermittent •severe myalgia, •prominent signs
•altered mental •altered mental neurological fever with chills, •other system of raised
status, and status deficits •seizures, involvement, intracranial
•signs of raised •impaired •headache, pressure at the
intracranial sensorium, •impaired time of
pressure at the •other system sensorium. presentation
time of involvement
admission
1.InfectionsOf The Nervous System (Bacterial, Fungal, Spirochetal, Parasitic) And Sarcoidosis. In: .Ropper Samuels.
Adams and Victor’s principles of neurology.
2NJ White, JG Breman. Malaria. In: Longo, Fauci, Kasper, Hauser, Jameson, Loscalzo. Harrison’s principles of
internal medicine 18th ed. Page 1688-1706

4. Are the investigation criteria part of diagnostic
criteria?
Tuberculous Pyogenic Viral Cerebral Leptospirosis
meningitis1 meningitis encephalitis malaria
Imaging Required Not required Required Not required Not required
(CT/ MRI)
CSF studies Required Required Required Not required Not required
Other peripheral Serological
investigations blood smear tests

5. Are the investigation criteria part of diagnostic
criteria?
Tuberculous Pyogenic Viral Cerebral Leptospirosis
meningitis meningitis encephalitis malaria
Imaging * Basal Basal exudates, MRI-hyper Cerebral edema Cerebral edema
(CT/ MRI) exudates, intensity in the Infarcts in
*infarctions, fronto- watershed
*hydrocephalus temporal, areas
*tuberculoma cingulate, or
-- in various insular regions
combinations of the brain on
T2W, FLAIR, or
DWI
CSF studies Lymphocytic Neutrophillic CSF PCR for viral Not required Not required
pleocytosis, pleocytosis, nucleic acid
protein ≥2 g/L, CSF staining &
ADA levels, culture
CSF PCR,
Other Not required Not required Not required asexual form of Serological
investigations P. falciparum in tests for
peripheral leptospirosis
smear

6. Background
• Early etiological diagnosis of meningoencephalitis
definitely makes a difference in each etiology
• Studies showing positive relation between early
treatment and prognosis in different etiologies
– Pyogenic meningitis- Vincent et al1
– Viral encephalitis- Panagaria et al2
– Cerebral malaria- Kochar et al3
– Leptospirosis- Panicker et al4
– Tuberculous meningitis- Kalita et al5
1Vincent J. Quagliarello, M.D., and W. Michael Scheld, M.D. Review Article Treatment of Bacterial Meningitis. N Engl J Med 1997; 336:708
2Panagariya A, Jain RS, Gupta S, Garg A, Sureka RK, Mathur V. Herpes simplex encephalitis in North West India. Neurol India. 2001Dec;49:360
3Kochar DK, Shubhakaran, Kumawat BL, et al. Cerebral malaria in Indian adults: a prospective study of 441 patients from Bikaner, north-west
India. J Assoc Physicians India 2002; 50: 234–41.
4J N Panicker, R Mammachan, R V Jayakumar. Original article. Primary neuroleptospirosis. Postgrad Med J 2001;77:589-590
5Kalita J, Misra UK, Ranjan P. Predictors of long-term neurological sequelae of tuberculous meningitis: a multivariate analysis. Eur J Neurol
2007; 14: 33–37

7. Aims and Objectives
To study serial cases of febrile meningoencephalitis over 18 months so as to
determine-
1. How many cases are diagnosed with a view to etiology by –
a) Clinical criteria alone
b) By addition of CSF studies, specialized serological
investigations, imaging
2. How many cases of acute/subacute meningoencephalitis, in our
setting, do not satisfy current criteria (clinical and investigational) for
diagnosis, but have some features of specific etiology, and therefore, end
up as being treated for that specific etiology
3. Does HIV positivity influence the formulation of an etiological diagnosis ?

8. Aims and Objectives
4. What is the role of following in the differential diagnosis of
meningoencephalitis
a) Clinical features alone
b) Specialized serological investigations
c) CSF study
d) Neuroimaging
5. What percentage of patients remain ‘unclassified’ ?
a) How many patients do not fit diagnostic criteria, but clinically fit into
some etiology?
b) How many patients neither fit diagnostic criteria, nor can be put
into some etiology on basis of clinical features?
6. What is the outcome in patients of febrile meningoencephalitis ?

9. Methodology
• Prospective, serial recruitment of patients with acute or subacute
meningoencephalitis
Inclusion criteria
• Patients of age ≥ 12 years with fever with
– signs of meningism (Nuchal rigidity, Headache, Vomiting).
OR
– signs of encephalitis (Altered sensorium, Seizures, Focal neurological deficits).
OR
– combination of the 2 features detailed above.
Exclusion criteria
• Once above inclusion criteria were satisfied there were no applications of
any exclusion criteria.

10. Schema of methodology
Final diagnosis based on set
History taking and clinical Neuroimaging (CT/MRI) when
criteria and re-allotment to
examination required
etiological group
Daily follow up during hospital
Clinical diagnosis. Start CSF PCR study as and when
stay. Monthly follow up after
treatment required
discharge
CSF
Hematological and biochemical
cytological, microbiological, and Analysis and results
investigations
biochemical studies

11. Statistics
• IBM SPSS Statistics 20 was used in statistical
analysis

12. Results
• 112 patients with acute and subacute
meningoencephalitis (mean age 34.14
year, range 13 to 71 years) were evaluated.
AGE DISTRIBUTION
AGE 12-20 21-40 41-60 >60 TOTAL
MALE 12 37 16 4 69
FEMALE 8 23 10 2 43
TOTAL 20 60 26 6 112

13. Distribution of cases as per clinical and
final diagnosis
DIAGNOSIS
ETIOLOGY CLINICAL FINAL
TUBERCULOUS MENINGITIS (TBM) 42 35
PYOGENIC MENINGITIS (PM) 14 11
CRYPTOCOCCAL MENINGITIS (CrM) 2 3
VIRAL ENCEPHALITIS (VE) 11 6
CEREBRAL MALARIA (CM) 42 31
LEPTOSPIROSIS (NL) 1 7
DENGUE 0 1
SSPE 0 1
UNCLASSIFIED 0 17

14. STRATIFICATION OF CLINICAL NEUROLOGICAL SIGNS AS
PER ETIOLOGY
STRATIFICATION OF CLINICAL NEUROLOGICAL SIGNS AS PER ETIOLOGY
ETIOLOGY
TUBERCULOUS PYOGENIC VIRAL CEREBRAL
LEPTOSPIROSIS UNCLASSIFIED
MENINGITIS MENINGITIS ENCEPHALITIS MALARIA
TOTAL 35 11 6 31 7 17
LEVEL OF
CONSCIOUSNESS 17 7 5 6 2 6
(GCS <12)
MENINGEAL SIGNS 34 8 2 13 4 11
SEIZURES 16 1 6 2 0 4
FOCAL DEFICITS 12 2 4 2 0 6
INVOLUNTARY
MOVEMENTS
0 0 3 0 0 2
SIGNS OF RAISED ICT 22 4 1 1 0 3

15. Other system involvement in
meningoencephalitis
OTHER SYSTEMS INVOLVEMENT
ETIOLOGY RENAL RESPIRATORY CARDIAC HEPATOBILIARY
TUBERCULOUS
MENINGITIS (35) 6 9 0 3
PYOGENIC MENINGITIS
(11) 6 5 0 5
CRYPTOCOCCAL
MENINGITIS (3) 0 0 0 3
VIRAL ENCEPHALITIS (11) 1 0 0 2
CEREBRAL MALARIA (31) 14 1 1 16
LEPTOSPIROSIS (7) 5 1 2 7
UNCLASSIFIED (17) 2 1 1 2

16. HIV positivity in meningoencephalitis
cases
HIV POSITIVITY
TOTAL HIV POSITIVE PERCENTAGE
TUBERCULOUS MENINGITIS 35 11 31
PYOGENIC MENINGITIS 11 1 9
CRYPTOCOCCAL
MENINGITIS 3 3 100
VIRAL ENCEPHALITIS 6 1 17
CEREBRAL MALARIA 31 1 3
LEPTOSPIROSIS 7 0 0
DENGUE 1 0 0
UNCLASSIFIED 22 1 5

17. Radiological features in meningo-
encephalitis cases.
RADIOLOGICAL FEATURES
TUBERCULOUS PYOGENIC VIRAL CEREBRAL
MENINGITIS MENINGITIS ENCEPHALITIS MALARIA UNCLASS-
(35) (11) (6) (31) IFIED (17)
CEREBRAL EDEMA 2 1 1 21 4
FOCAL CT BRAIN 5 1 4 2 6
INVOLV
EMENTS MRI BRAIN 0 0 6 0 9
BASAL EXUDATES 31 6 0 0 4
HYDROCEPHAUS 6 0 0 0 1
TUBERCULOMA 1 0 0 0 2
OTHER 0 0 0 0 0

18. T2W MRI image in herpes simplex
encephalitis patient

19. T2W & FLAIR MRI image in Japanese B
encephalitis patient

20. CT Brain in a case of TBM

21. Tuberculous meningitis
34 patients with
final diagnosis of
TBM
1 patient diagnosed
42 patients clinically
as cryptococcal
diagnosed as TBM
meningitis
7 patients remained
unclassified

22. • Comparison of the 2 groups-- 35 patients with
final diagnosis of TBM (Group 1) versus 7 patients
in unclassified group with clinical diagnosis of
TBM (Group 2), showed the following—
Group 1 Group 2
Mean duration of 19.65 19.14
fever (in days)
Focal neurological 25.71% 14.28%
deficits
CSF cells/cmm 172/cmm 71
CSF proteins/cmm 186/cmm 126
Mean CSF ADA 14 11
Imaging findings 80% 100%

23. Details of 7 patients in unclassified group with
clinical diagnosis of tuberculous meningitis
TB of
Fever Predomin CSF
Sr, No, other CSF cells CSF ADA Imaging Outcome
duration ant cells proteins
systems
Basal
1 18 - 79 P 164 13 Improved
exudates
Exudates
Improved
2 18 - 71 P 164 8 tuberculom
a
Exudates, Improved
3 28 - 73 L 93 10
Hydroeph.
Improved
4 31 - 67 L 115 11 Exudates
Improved
5 15 - 2 L 164 6
Improved
6 13 - 81 L 103 16 Exudates
Improved
7 20 + 72 P 133 9

24. Cerebral malaria (CM)
31 patients with
final diagnosis of
CM
6 patients
diagnosed as
leptospirosis
42 patients clinically
diagnosed as CM
1 patient diagnosed
as dengue
encephalitis
4 patients remained
unclassified
• All the 31 patients with final diagnosis of CM were from initial 42
patients with clinical diagnosis of CM, thus giving 100% sensitivity
to clinical criteria of CM

25. Patients with clinical diagnosis of
cerebral malaria (42)
Patients with CM (31) Patients with other
diagnosis (11)
Mean duration of fever 5.5 days 6.88 days
Signs of meningism 28.35% 54.76%
Headache 26.19% 72%
Focal deficits 4% 0%
Seizures 36.44% 9%
Altered sensorium (GCS) 12.41 12.09
Mean platelet count /cmm 29903 67545
CSF cells (/cmm) 9.29/cmm 57.27/cmm
Neuroimaging (cerebral 44.3% 27.68%
edema)

26. Neuroleptospirosis
• Total 7 patients with final diagnosis of
neuroleptospirosis.
• Only one of them was clinically suspected as
leptospirosis on the basis of
jaundice, myalgia, headache in addition to
acute presentation with fever
• Other 6 patients were clinically diagnosed as
CM due to lack of characteristic features of
neuroleptospirosis.

27. Neuroleptospirosis
• In a large series of neuroleptospirosis, by Thomas Mathew
et al1, conjunctival congestion with or without
haemorrhage was seen in 38.7% patients, icterus in 45%
and mild hepatosplenomegaly in 35.5% patients only
• Panicker et al2 have delineated the various neurological
presentations in 40 patients with leptospirosis, presenting
with acute neurological disease. These included Aseptic
meningitis (13 patients), Myeloradiculopathy (13
patients), Myelopathy (7 patients), Guillain-Barré syndrome
(7 patients), Meningo-encephalitis (3 patients), and
Intracerebral bleed (2 patients).
1 Thomas Mathew, P. Satishchandra, A. Mahadevan, S. Nagarathna, T. C. Yasha, A. Chandramukhi, D.K.
Subbakrishna, S.K. Shankar. Neuroleptospirosis - revisited: experience from a tertiary care neurological
centre from south India. Indian J Med Res 124, August 2006, pp 155-162
2J N Panicker, R Mammachan, R V Jayakumar. Original article. Primary neuroleptospirosis. Postgrad Med J
2001;77:589-590

28. Comparison between Neuroleptospirosis and
Dengue encephalitis patients
Leptospirosis (7) Dengue encephalitis (1)
Mean duration of fever 5.28 days 5 days
Signs of meningism 57.14% Absent
Headache Present in all Present
Mean GCS 12.29 11
Other systems involvement 71.42% Absent
Mean CSF cells (/cmm) 44.71 /cmm acellular
Neuroimaging (cerebral absent absent
edema)

29. Did CSF help/ confound in diagnosis of
CM/ leptospirosis ??
CSF PICTURE IN CEREBRAL MALARIA, AND
LEPTOSPIROSIS
CEREBRAL
CSF MALARIA LEPTOSPIROSIS
TOTAL 31 7
CELLULARITY <20 26 2
(CELLS/CMM) >20 5 5
LYMPHOCYTE 23 6
PREDOMINANCE POLYMORPH 8 1
>50 16 5
PROTEINS in mg/dl <50 15 2
>0.6 17 3
SUGAR (CSF/PLASMA)
RATIO <0.6 14 4

30. Pyogenic meningitis (PM)
11 patients with
final diagnosis of
PM
1 patient
diagnosed as
14 patients TBM
clinically
diagnosed as PM 1 patient
diagnosed as HSV
encephalitis
1 patient
remained
unclassified

31. Viral encephalitis
• Total 11 patients were clinically diagnosed with
viral encephalitis.
• Out of 6 (HSVE-4, Jap B-2) patients with final
diagnosis of viral encephalitis, on the basis of CSF
PCR positivity, 5 were from above 11 patients,
while one was from pyogenic meningitis.
• Out of 6 patients put in unclassified group, 4
patients showed clinical and investigation
features compatible with a diagnosis of VE, but
had PCR negative.

32. Comparison of investigational features
in viral encephalitis
Proven Viral
Probable VE True unclassified
encephalitis (VE)
Total 6 4 2
Mean CSF
32.5/cmm 40.5/cmm 62/cmm
(cells/cmm)
CSF proteins
60 38.5 88.2
(mg/dl)
MRI findings
6 4 0
consistent with VE
CSF PCR positivity 6 0 0

33. Unclassified patients (17)
Likely TBM (5) Likely VE (4) True unclassified
(8)
Duration of fever 17.25 days 8.25 days 12.50 days
Signs of meningism 80% 25% 37.5%
Headache 60% 25% 62.5%
Focal deficits 20% 100% 2
Seizures 2 75% 3
Mean GCS 12 10.25 12.12
Other systems 0 2 2
involvement
CSF cells 71/cmm 40.5/cmm 56/cmm
Serology Negative Negative Negative
Imaging 80% 100% 37.5%

34. Flow-chart depicting the clinical and final diagnosis in 112 patients

35. OUTCOME
SATISFACTORY
TOTAL AVG. MORTALITY
IMPROVEMENT*
CASES HOSPIT
AL STAY
No. PERCENTAGE ON DISCHARGE 90 DAYS
ETIOLOGY IN DAYS
TUBERCULOUS
35 12 9 26% 18 20
MENINGITIS
PYOGENIC
11 7 2 22% 5 6
MENINGITIS
CRYPTOCOCCAL
3 16 3 100% 0 0
MENINGITIS
VIRAL ENCEPHALITIS 6 15 4 67% 1 1
CEREBRAL MALARIA 31 4 1 4% 27 27
LEPTOSPIROSIS 7 5 0 0% 7 7
DENGUE 1 7 0 0% 1 1
SSPE 1 17 1 100% 0 0
UNCLASSIFIED 17 13 5 26% 10 12
*satisfactory improvement for tuberculous meningitis, pyogenic meningitis, cryptococcal
meningitis, and viral encephalitis was modified Rankin’s scale < 3. For cerebral malaria,
leptospirosis, and dengue, satisfactory improvement was modified Rankin’s scale of 0.

36. Conclusions

37. Clinical diagnosis
112 patients
Crypto.
TBM (42) CM (42) PM (14) VE (11) Lepto (1)
Meningitis (2)
Final diagnosis
112 patients
TBM (35) CM (31) PM (11) Lepto (1) Dengue (1) SSPE 1
Crypto.
VE (6)
Meningitis (3)
Final diagnosis was made (mean) 3.78 days after admission.

38. Accuracy of clinical criteria
Clinical
Sensitivity Specificity PPV NPV
criteria
Tuberculous
meningitis
97.14% 89.61% 0.80 0.98
Pyogenic
meningitis
100% 97.02% 0.78 1
Cerebral
malaria
100% 87.91% 0.73 1
Viral
encephalitis
83.33% 94.33% 0.45 0.99

39. Conclusions
• Clinical criterion for prolonged fever was not satisfied
in 3/40 patients with definite + probable TBM.
• Failure of investigations towards final diagnosis of TBM
– Of 35 patients with final diagnosis of TBM, 5 had not
satisfied CSF criteria, 7 had not CT/MRI features of TBM, 25
did not have evidence of extra CNS tuberculosis
• Contribution of investigations towards diagnosis of
possible TBM
– Of 5 patients with possible TBM, 3 had satisfied CSF
criteria, 3 had CT/MRI features of TBM, 1 had evidence of
extra CNS tuberculosis

40. Conclusions
• Contribution of investigations towards
diagnosis of VE
– Of 11 patients with clinical diagnosis of VE, 9 had
CT/MRI features of VE, 5 had CSF PCR positive for
either HSV-1 or Jap B.

41. Conclusions
• Outcome:
– In hospital mortality was high in patients with VE
(67%), TBM (26%), Crypto. Meningitis (100%), and
in Unclassified cases (26%).
– CM, Leptospirosis, dengue patients had more
favorable outcome.
– Satisfactory improvement, at 90 days follow up,
was 57% in TBM , 81% in PM, 87% in CM, 100% in
leptospirosis.

42. Limitations
• Statistical significance could not be achieved
due to paucity of numbers, in each
subcategory, as the etiological categories were
multiple.
• CSF TB-PCR was not done for definitive
diagnosis of TBM.
• Inability to perform specialised CSF virological
studies for undiagnosed patients.

43. Recommendations
• A larger cohort of acute meningoencephalitis
patients would need to be studied to
statistically validate present criteria for early
diagnosis of TBM and VE, along with complete
virological studies to see if the undiagnosed
cases are truly aseptic meningitis, or early
TBM not satisfying clinical and lab criteria.

44. Thank you
I thank my patients, guide, head of dept. of medicine, dean of the institute.