ACUTE AND SUBACUTE MENINGO-ENCEPHALITIS CLINICAL, ETIOLOGICAL AND PROGNOSTIC FEATURES Dr. Ankit Raiyani
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
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 admission1.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 ofinternal medicine 18th ed. Page 1688-1706
Are the investigation criteria part of diagnostic criteria? Tuberculous Pyogenic Viral Cerebral Leptospirosis meningitis1 meningitis encephalitis malariaImaging Required Not required Required Not required Not required(CT/ MRI)CSF studies Required Required Required Not required Not requiredOther peripheral Serologicalinvestigations blood smear tests
Are the investigation criteria part of diagnosticcriteria? Tuberculous Pyogenic Viral Cerebral Leptospirosis meningitis meningitis encephalitis malariaImaging * 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 DWICSF 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 Serologicalinvestigations P. falciparum in tests for peripheral leptospirosis smear
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 al51Vincent J. Quagliarello, M.D., and W. Michael Scheld, M.D. Review Article Treatment of Bacterial Meningitis. N Engl J Med 1997; 336:7082Panagariya A, Jain RS, Gupta S, Garg A, Sureka RK, Mathur V. Herpes simplex encephalitis in North West India. Neurol India. 2001Dec;49:3603Kochar DK, Shubhakaran, Kumawat BL, et al. Cerebral malaria in Indian adults: a prospective study of 441 patients from Bikaner, north-westIndia. J Assoc Physicians India 2002; 50: 234–41.4J N Panicker, R Mammachan, R V Jayakumar. Original article. Primary neuroleptospirosis. Postgrad Med J 2001;77:589-5905Kalita J, Misra UK, Ranjan P. Predictors of long-term neurological sequelae of tuberculous meningitis: a multivariate analysis. Eur J Neurol2007; 14: 33–37
Aims and ObjectivesTo study serial cases of febrile meningoencephalitis over 18 months so as todetermine-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, imaging2. 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 etiology3. Does HIV positivity influence the formulation of an etiological diagnosis ?
Aims and Objectives4. What is the role of following in the differential diagnosis of meningoencephalitis a) Clinical features alone b) Specialized serological investigations c) CSF study d) Neuroimaging5. 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 ?
Methodology• Prospective, serial recruitment of patients with acute or subacute meningoencephalitisInclusion 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.
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 CSFHematological and biochemical cytological, microbiological, and Analysis and results investigations biochemical studies
Statistics• IBM SPSS Statistics 20 was used in statistical analysis
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
Distribution of cases as per clinical and final diagnosis DIAGNOSIS ETIOLOGY CLINICAL FINALTUBERCULOUS MENINGITIS (TBM) 42 35 PYOGENIC MENINGITIS (PM) 14 11CRYPTOCOCCAL 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
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 2SIGNS OF RAISED ICT 22 4 1 1 0 3
Tuberculous meningitis 34 patients with final diagnosis of TBM 1 patient diagnosed42 patients clinically as cryptococcal diagnosed as TBM meningitis 7 patients remained unclassified
• 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%
Details of 7 patients in unclassified group with clinical diagnosis of tuberculous meningitis TB of Fever Predomin CSFSr, 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
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
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 daysSigns of meningism 28.35% 54.76%Headache 26.19% 72%Focal deficits 4% 0%Seizures 36.44% 9%Altered sensorium (GCS) 12.41 12.09Mean platelet count /cmm 29903 67545CSF cells (/cmm) 9.29/cmm 57.27/cmmNeuroimaging (cerebral 44.3% 27.68%edema)
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.
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 neurologicalcentre from south India. Indian J Med Res 124, August 2006, pp 155-1622J N Panicker, R Mammachan, R V Jayakumar. Original article. Primary neuroleptospirosis. Postgrad Med J2001;77:589-590
Comparison between Neuroleptospirosis and Dengue encephalitis patients Leptospirosis (7) Dengue encephalitis (1)Mean duration of fever 5.28 days 5 daysSigns of meningism 57.14% AbsentHeadache Present in all PresentMean GCS 12.29 11Other systems involvement 71.42% AbsentMean CSF cells (/cmm) 44.71 /cmm acellularNeuroimaging (cerebral absent absentedema)
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 3SUGAR (CSF/PLASMA) RATIO <0.6 14 4
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
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.
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 0consistent with VECSF PCR positivity 6 0 0
Unclassified patients (17) Likely TBM (5) Likely VE (4) True unclassified (8)Duration of fever 17.25 days 8.25 days 12.50 daysSigns of meningism 80% 25% 37.5%Headache 60% 25% 62.5%Focal deficits 20% 100% 2Seizures 2 75% 3Mean GCS 12 10.25 12.12Other systems 0 2 2involvementCSF cells 71/cmm 40.5/cmm 56/cmmSerology Negative Negative NegativeImaging 80% 100% 37.5%
Flow-chart depicting the clinical and final diagnosis in 112 patients
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, cryptococcalmeningitis, and viral encephalitis was modified Rankin’s scale < 3. For cerebral malaria,leptospirosis, and dengue, satisfactory improvement was modified Rankin’s scale of 0.
Clinical diagnosis 112 patients Crypto. TBM (42) CM (42) PM (14) VE (11) Lepto (1) Meningitis (2) Final diagnosis 112 patientsTBM (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.
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
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.
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.
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.
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.
Thank youI thank my patients, guide, head of dept. of medicine, dean of the institute.