Tropical Neurology - part 1 pptx

Misra, M.D., D.M., F.A.M.S.Professor and Head Department of Neurology Sanjay Gandhi Post-Graduate Institute of Medical Sciences Lucknow, India J.. Associate Professor Department of Neuro

9 Human Rabies: Pathogenesis,

Clinical Aspects and Current

Recommendations

for Prophylaxis

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10 Subacute SclerosingPanencephalitis

11 HTLV-I-Associated Myelopathy

12 Neurological Manifestations ofHIV

13 Parainfectious DemyelinatingDiseases of the Nervous System

14 Fungal Infections of the CentralNervous System

U K Misra, M.D., D.M., F.A.M.S.

Professor and Head Department of Neurology Sanjay Gandhi Post-Graduate Institute

of Medical Sciences Lucknow, India

J Kalita, M.D., D.M.

Associate Professor Department of Neurology Sanjay Gandhi Post-Graduate Institute

of Medical Sciences Lucknow, India

R A Shakir, F.R.C.P.

Consultant Neurologist Charing Cross Hospital

VADEMECUMTropical NeurologyLANDES BIOSCIENCEGeorgetown, Texas U.S.A.

Copyright ©2003 Landes Bioscience

All rights reserved

No part of this book may be reproduced or transmitted in any form or by anymeans, electronic or mechanical, including photocopy, recording, or anyinformation storage and retrieval system, without permission in writing from thepublisher

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ISBN: 1-57059-637-9

Library of Congress Cataloging-in-Publication Data

Tropical neurology/[edited by] U K Misra, J Kalita, R A Shakir

p ; cm (Vademecum)

Includes bibliographical references and index

ISBN 1-57059-637-9

1 Nervous system Diseases 2 Tropical medicine 3 Nervous

system Infections 4 Neurological manifestations of general

diseases I Misra, U K II Series

[DNLM: 1 Nervous System Diseases 2 Tropical Medicine WL

Dedication

We dedicate this book

to our parents and teachers.

Satyajit B Naique and V J Laheri

3 Pyogenic Infections of the Central Nervous System 50

Kameshwar Prasad, Sumit Singh, Shailesh Gaekwad and Chitra Sarkar

7 Acute Viral Encephalitis 115

J Kalita and U K Misra

8 Poliomyelitis 139

P M Jeena

9 Human Rabies: Pathogenesis, Clinical Aspects

and Current Recommendations for Prophylaxis 154

Terapong Tantawichien and Visith Sitprija

10 Subacute Sclerosing Panencephalitis 175

U K Misra and J Kalita

11 HTLV-I-Associated Myelopathy 185

Masanori Nakagawa and Mitsuhiro Osame

12 Neurological Manifestations of HIV 200

Shri Kant Mishra, J Kalita and Indu Subramanian

13 Parainfectious Demyelinating Diseases

of the Nervous System 217

J Kalita and U K Misra

14 Fungal Infections of the Central Nervous System 238

David Saffer and Raymond A Smego, Jr.

Oscar H Del Brutto

16 Cerebral Malaria 284

J E Touze, L Fourcade, P Heno, P Riviere and P Paule

17 Neuroschistosomiasis 300

José Eymard Homem Pittella

18 Human African Trypanosomiasis,

Sleeping Sickness 325

Bernard Bouteille and Michel Dumas

19 Environmental Neurotoxins in the Tropics 344

U K Misra and J Kalita

20 Insecticides and Industrial Poisons 370

Basim A Yaqub and Saleh M Al Deeb

23 Epilepsy in the Tropics 422

J M K Murthy

24 Stroke in the Tropics 434

D Nagaraja and M Veerendrakumar

25 Mental Retardation 456

Veena Kalra and K S Rana

26 Nutritional Deficiency Disorders

of the Nervous System 470

N H Wadia, U K Misra and J Kalita

27 Neuroepidemiology in the Tropics 491

K Radhakrishnan and P N Sylaja

28 Craniovertebral Anomalies 512

R Shukla

Index 533

U K Misra

Professor and Head Department of Neurology Sanjay Gandhi Post-Graduate Institute of Medical Sciences

Lucknow, India

Chapters 1, 7, 10, 13, 19, 26

J Kalita

Associate Professor Department of Neurology Sanjay Gandhi Post-Graduate Institute of Medical Sciences

Lucknow, India

Chapters 1, 7, 10, 12, 13, 19, 26

R A Shakir

Consultant Neurologist Charing Cross Hospital London, U.K.

Chapter 4

Saleh M Al Deeb

Department of Neurosciences

Riyadh Armed Forces Hospital

Riyadh, Saudi Arabia

of Medical SciencesSevagram, India

Chapter 6

M DumasInstitute of Tropical NeurologyUniversity of LimogesLimoges, France

Chapter 18

L FourcadeTropical Medical Institutefor French ArmyMarseille, France

Chapter 16

S GaekwadDepartment of NeuroradiologyAll India Institute of Medical SciencesNew Delhi, India

Chapter 3

Contributors

Tropical Medical Institute

for the French Army

All India Institute of Medical Sciences

New Delhi, India

Chapter 25

V J Laheri

Department of Orthopedics

The Seth G S Medical College

& King Edward VII Memorial Hospital

The Seth G S Medical College

and King Edward VII

Chapter 11

S de A NishiokaCentro de Ciências BiomédicasUniversidade Federal

de Uberlândia,Uberlândia, Brazil

Chapter 21

M OsameThird Department of Internal MedicineKagoshima University School

of MedicineKagoshima, Japan

Chapter 11

P PauleTropical Medical Institutefor the French ArmyMarseille, France

Chapter 16

J E H PittellaDepartment of Pathology and LegalMedicine

School of MedicineFederal University of Minas GeraiBelo Horizonte, Brazil

Chapter 17

S PrabhakarDepartment of NeurologyPostgraduate Institute of MedicalEducation and ResearchChandigarh, India

Chapter 5

K PrasadDepartment of NeurologyAll India Institute of Medical SciencesNew Delhi, India

Chapter 3

K Radhakrishnan

Department of Neurology

Sree Chitra Tirunal Institute

for Medical Sciences

All India Institute of Medical Sciences

New Delhi, India

Chapter 25

P Riviere

Tropical Medical Institute

for the French Army

Marseille, France

Chapter 16

David Saffer

Department of Neurology

Chris Hani Baragwanath Hospital

University of the Witwatersrand

Johannesburg, South Africa

Chapter 14

Chitra Sarkar

Department of Pathology

All India Institute of Medical Sciences

New Delhi, India

P Paulo Victor Silveira

Centro de Ciências Biomédicas

Chapter 3

Visith SitprijaQueen Saovabha Memorial InstituteBangkok, Thailand

Chapter 9

R A Smego, Jr

Department of Infectious Diseasesand Clinical MicrobiologyUniversity of WitwatersrandSouth African Institute for MedicalResearch

Johannesburg, South Africa

Chapter 12

Indu SubramanianDepartment of NeurologyUCLA School of MedicineLos Angeles, California, U.S.A

Chapter 14

P SyalDepartment of NeurologyPostgraduate Institute of MedicalEducation and ResearchChandigarh, India

Chapter 5

P N SylajaDepartment of NeurologySree Chitra Tirunal Institutefor Medical Sciencesand TechnologyThiruvananthapuram, India

Chapter 27

Terapong TantawichienDivision of Infectious DiseasesDepartment of MedicineChulalongkorn Universityand Queen SaovabhaMemorial InstituteBangkok, Thailand

Chapter 9

Tropical Medical Institute

for the French Army

Chapter 26

Basim A YaqubDepartment of NeurosciencesRiyadh Armed Forces HospitalRiyadh, Saudi Arabia

Chapter 22

Tropical neurology refers to those diseases of the nervous system which prevail betweenthe Tropics of Cancer and Capricorn Warm and humid tropical climates are ideal forgrowth and multiplication The diversity and density of flora and fauna, including thehuman population, is not surprising in this region Initially the tropical diseases includedmainly the infectious and parasitic diseases Today the world population is close to 5.6billion and by 2050, is likely to exceed 10 billion; much of this growth is likely to occur inthe tropical region To this are added the problems of environmental changes and globalwarming The common neurological diseases like stroke and epilepsy also have markedlydistinct etiological, clinical and prognostic features in tropical countries.

Tropical medicine was initiated by the colonial masters to look after the health of theirpersonnel both in their colonies and following return to their own countries The special-ity of Tropical Neurology has come a long way in many western countries and severaltropical countries Developments in the speed and ease of travel and globalization of theeconomy have resulted in large scale migration, rendering the boundaries of the tropicalregion less distinct Wars, famines, natural disasters and economic sanctions have added

to the problem of infection and aggravated pre-existing nutritional deficiency disorders inmany tropical countries

A major portion of this book is devoted to various bacterial, viral and fungal infectionsand parasitic diseases of the nervous system There are four chapters devoted to environ-mental effects on the nervous system: environmental neurotoxins, industrial toxins, ani-mal toxins and heat stroke A chapter each on nutritional deficiency syndromes and men-tal retardation has been included because of their significance in tropical regions Lack ofepidemiological data is one of the most important limitations and is central to any plan-ning and intervention strategy; therefore, a chapter on epidemiology has been included Achapter on craniovertebral anomalies has also been included because of its common oc-currence on the Indian subcontinent and serious consequences following delayed diagnosis

or misdiagnosis of these disorders

Each chapter is written by an established authority who has made significant tions in his or her respective field and has first-hand experience with the problem A largenumber of photographs, tables and illustrations have been used to highlight the impor-tant points Each chapter is followed by a few important references, which are recom-mended for further reading This book is aimed at residents, practicing physicians, healthworkers and physicians from western countries who are visiting the tropical countries Wehope that this book will be useful to the readers and put the subject of tropical neurology

contribu-in correct perspective and contribu-initiate further studies and research contribu-in tropical neurology

U K Misra

J Kalita

R A Shakir

Preface

A chance meeting with Mr Ron Landes on the net resulted in the idea of

putting together this handbook, Tropical Neurology Editing a book is only

possible through the active support of a number of colleagues and friends.

We thank all the contributors who not only have given the essence of their knowledge and experience in their chapters but have also respected the limi- tations of format and deadlines We thank the Council of Science and Tech- nology for financially supporting Mr Rakesh Kumar Nigam who has shown exceptional zeal and efficiency in typing the manuscripts We acknowledge the help of Dr Prasen Ranjan in compiling the chapters We also appreciate the support and encouragement which we received from our parents and family members during preparation of this book U K Misra especially thanks

Mr M H Rizvi for his guidance and encouragement from time to time.

U K Misra

J Kalita

R A Shakir

U K Misra and J Kalita

Tuberculosis (TB) affects one third of world’s population and is a leading cause

of human mortality and morbidity Among those aged 5 years or more, tuberculosiskills more people than AIDS, malaria, diarrhea, leprosy and all of the tropical diseasescombined Treating tuberculosis is the most efficient and cost effective of all healthinterventions With the emergence of the AIDS pandemic, there has been a resurgence

of tuberculosis in those regions of the world where it had declined earlier to a negligiblelevel Other factors contributing to increased occurrence of tuberculosis are poverty,unhygenic living conditions, malnutrition, drug abuse and immigration It has beenestimated by WHO that the global incidence of tuberculosis in 1990 was about 7.5million cases which will increase to about 12 million by 2005.1 It is estimated thatmost of these new cases will be in Southeast Asia due to AIDS Tuberculosis of thecentral nervous system constitutes about 5% of extrapulmonary cases In AIDSpatients having tuberculosis, however, 50% or more develop extra-pulmonaryinvolvement, the CNS being a common site In the population with lower TBprevalence tuberculous meningitis (TBM) occurs mostly in adults, whereas inpopulations with a higher TB prevalence the peak incidence is 0-4 years Certain

ethnic groups are more susceptible to M tuberculosis, such as blacks Certain

polymorphisms in the human NRAMPI gene may affect susceptibility to pulmonarytuberculosis in West Africans but the relevance of these factors is not known intuberculous meningitis

Etiopathogenesis

Nearly all the CNS tuberculosis is due to human tubercle bacillus M tuberculosis

which is a nonmotile, rod-shaped, nonspore forming bacterium, measuring 0.5 µm

by 3 µm It does not stain on Gram’s staining; however, once stained the bacilluscan-not be decolorized by acid or alcohol, therefore, it is known as acid fast bacillus

(AFB) M tuberculosis grows slowly Its generation time is 15-20 hours as opposed

to less than 1 hour for pyogenic bacteria and it takes weeks after incubation forvisible mycobacterial colonies The mycobacterial cell wall has complex proteins,peptides, lipids and glycolipids with specific immunologic properties Other antigensare present in the cytoplasm These molecules to a great extent determine thecharacteristic immune response to tubercular infection and resultant pathology

In immunocompetent individuals, M tuberculosis infection develops overt

tu-berculosis in only 10% of people indicating a good immune response to this

infec-tion CNS infection by M tuberculosis begins with inhalation of droplet infectious

particles from a pulmonary tuberculosis patient Airborne droplet nuclei containing

a small number of organisms reach the alveoli and multiply within the alveolarspaces, alveolar macrophages and macrophages derived from circulation For 2-4

weeks following infection, there is virtually no immune response During this riod, hematogenous dissemination occurs throughout the body Lungs, liver, spleenand bone marrow filter many organisms from the blood, whereas the organs notbelonging to the reticuloendothelial system, such as the brain and meninges, traprelatively few organisms Two to four weeks following the infection, cell-mediatedimmunity to mycobacteria develops T lymphocytes are stimulated by bacterial an-tigens to produce lymphokines which in turn attract and activate mononuclear ph-agocytes from the blood stream The immune response in tuberculosis is not poor,but is disregulated The protective immune response in tuberculosis is mediated byTh1 cells, whereas the Th2 or mixed Th1-Th2 response renders cells sensitive tokilling (Fig 1.2) Organisms may be killed within activated macrophages while many

pe-of the macrophages are also killed by the organism or by their toxic antigenic ucts A tubercle is thus formed which consists of macrophages, lymphocytes andother cells surrounding a necrotic caseous center The fate of these tubercles andsubsequent course of the infection depends on immunogenic capacity of the hostand other genetic factors In the presence of good immune status, the minute caseousfoci are completely eliminated and there is a positive tuberculin test Less effectivebut still efficient host immune response results in large caseous foci with a fibrousencapsulation harboring mycobacteria This may later cause reactivation of tubercu-losis if host immune vigilance decreases, such as in old age and immune compro-mised states In the presence of profoundly impaired host immunity, the primarytubercular infection continues to proliferate and the tubercle ultimately rupturesdischarging the organisms into the surrounding tissue Most often rupture of a ‘rich’foci which are subependymal or subpial foci, or an intracerebral tubercle which is

prod-formed during initial silent hematogenous dissemination of M tuberculosis, result

Fig 1.1 The spread of M tuberculosis in the body.

3Tuberculous Meningitis

1

in tuberculous meningitis (Fig 1.2) Rarely the source of TBM is adjacent extraneuralinfection such as vertebrae, ear, mastoid sinuses, etc In a relativelyimmunoincompetent host, especially infants or children below five years of age, the

‘richs’ focus may rupture during primary infection resulting in concomittentmeningeal and pulmonary or meningeal and miliary infection

Pathology

There are a number of pathological changes in TBM which include exudate,vasculitis, hydrocephalus, borderzone encephalitis, tubercular encephalopathy andtuberculoma and tubercular abscess

In TBM, besides the meninges, brain parenchyma and blood vessels are alsoaffected; therefore, it is more appropriately called as meningoencephalitis The mainpathology is formation of thick gelatinous or nodular exudate within the subarach-noid space (Fig 1.3) The exudate is more prominent at the base of the brain aroundinterpeduncular fossa, enveloping optic nerves at the chiasma and extending overthe pons and cerebellum, often into the sylvian fissure, and sometimes extending on

to the cerebral hemispheres In the lateral ventricle, the exudate often covers thechoroid plexus Occasionally the exudate is localized close to the ruptured tubercle.Microscopically, the tubercular exudate contains polymorphonuclear leukocytes, redblood cells, macrophages and lymphocytes within a fibrin network with variablenumber of mycobacteria As the disease progresses, lymphocytes predominate alongwith the appearance of fibroblasts and connective tissue Typical tubercles may de-velop into the exudate and areas of caseation necrosis are formed

The blood vessels traversing tubercular exudate reveal characteristic tion Small and medium sized arteries are most often involved, although capillariesand veins may also be affected The adventitial layer shows changes that are identical

inflamma-to those of adjacent tubercular exudate Intima may also be similarly affected and

Fig 1.2 Schematic diagram showing immune response in tuberculosis.

may be eroded by fibrinoid hyaline degeneration A reactive subendothelial cellularproliferation follows which may completely occlude the vessels Ischemic arterialinfarction resulting from tubercular arteritis is a common sequelae Infarctions aremost commonly present in the distribution of middle cerebral arteries and deepperforating vessels

Hydrocephalus is a characteristic pathological feature of TBM and is more mon in children In a study with 60 patients with TBM, 87% were children and12% adults Nearly all the children with TBM exceeding six weeks have some de-gree of hydrocephalus In TBM hydrocephalus is generally of communicating typeand is attributed to the blockade of basal cisterns and arachnoid villi by exudate thusimpeding CSF absorption Obstruction in the ventricular system, i.e., foramen ofMonro or aqueduct, is responsible for obstructive hydrocephalus in a small percent-age of TBM patients

com-Borderzone encephalitis is a tissue reaction adjacent to thick adherent exudate.The brain tissue is softened with astrocytic, microglial and diffuse inflammatory

Fig 1.3a Tuberculous meningitis with chronic basal arachnoiditis showing dense date covering the infundibulum as nodule, medial aspect of temporal lobe and ventral aspect of pons (Courtesy Prof S K Shankar).

exu-5Tuberculous Meningitis

1

reaction Thrombosed vessels in the exudate may result in zones of hemorrhage andinfarction Chronic untreated hydrocephalus may result in atrophy of both grey andwhite matter Tubercular encephalopathy is another type of encephalopathy inde-pendent of other pathologies in TBM and is probably due to allergic phenomenon

It consists of cerebral edema with perivascular demyelination or hemorrhagic koencephalopathy Usually it affects young children with progressive primary TB.Tubercular abscesses rarely may be associated with TBM These can be single ormultiple and are more commonly found in old or immunocompromised patients.Tubercular abscesses may be indistinguishable from pyogenic abscesses It ismultiloculated, has a thin smooth regular wall, shows contrast enhancement and isassociated with moderate to marked edema Histopathologically, pus contains nu-merous AFB and the wall does not show evidence of granuloma formation

leu-The effect of therapy on the pathology of TBM is also of clinical interest leu-Thesefindings are best described in relation to streptomycin In TBM patients, dying afterstreptomycin treatment, marked organization and fibrosis of the basilar exudate isseen Much of the exudate is replaced by hyalinized connective tissue if the duration

of treatment exceeds two years A concomitant fibrosis of intima of the involvedvessels is also present Hydrocephalus invariably accompanies these changes Thesefindings confirmed the observation that the tissue damage initiated by the infectionpersists despite bacterial eradication

2 Extension of inflammation to brain parenchyma resulting in alteration ofsensorium, seizure, hypothalamic and brainstem signs

3 Vasculitis is responsible for focal neurological deficits

4 Allergic and hypersensitivity responses result in massive brain edema andraised intracranial pressure in the absence of hydrocephalus

The clinical feature of TBM has been divided in to prodrome, stage of meningealirritation and stage of diffuse or focal cerebral involvement

Prodrome The prodrome generally lasts for 2-3 weeks, and occasionally 2-3

months In children, it manifests with vaguely ill health, apathy, lack of appetite,vomiting and pain in abdomen Unless there is history of contact with tuberculosis,the prodromal symptoms seldom arouse suspicion of TBM Certain unusual mani-festations of tuberculous meningitis in children are shown in Table 1.1

Stage of meningeal irritation With the onset of meningeal symptoms, headache,

vomiting and fever become more prominent Fever is generally 101-102° F (39° C).Apathy, irritability, photophobia and varying degrees of neck stiffness set in andmay progress to opisthotonus in young children (Fig 1.4), although it is not asprominent as in pyogenic meningitis In infants, a tense fontanelle and vomiting aremore frequent than headaches and neck stiffness A comparison of clinical features

of TBM in adults and children is shown in Table 1.2 Focal neurological signs such

as seizures, cranial nerve palsy and hemiparesis may precede, accompany or followthe meningeal signs and symptoms Symptoms and signs of raised intracranial ten-sion may precede or follow the classical signs of meningeal irritation SometimesTBM is diagnosed in a patient being investigated for hydrocephalus or brain tumor

Stage of focal or diffuse cerebral involvement As disease progresses, increasing

evi-dence of cerebral dysfunction become apparent Stupor and coma replace apathyand irritability Signs and symptoms of raised intracranial tension become obvious;enlarging head, tense fontanelle in young children and sutural diastesis in olderchildren Papilloedema in adults is seen frequently In children optic disc pallor mayprogress to optic atrophy and blindness due to involvement of the optic nerve orchiasma by basal exudates In older patients, papilloedema may progress to second-ary optic atrophy Fundus changes were reported in 61% of patients with TBM.These changes were present in 73% of patients above 10 years and only in 37%below one year of age

Facial, oculomotor and abducence nerves are commonly affected Often the pupilsare dilated due to an obscure toxic factor.2 Seizures are common in all the stages ofTBM and may be partial or generalized The clinical course may be punctuated bysudden onset of focal neurological deficits Monoplegia, hemiplegia and aphasiamay develop at any time during the illness following seizure or ischemic stroke.Sometimes rapid improvement in focal deficit occurs following relief of intracranial

Table 1.1 Unusual manifestations of neurotuberculosis in children

• Atypical febrile fits.

• Unexplained fever, positive PPD following measles, head injury or pertussis.

• Chronic ear discharge not responding to treatment

• Headache, vomiting, ptosis, squint, facial palsy.

• Child in contact, presenting with fever, headache, vomiting and bulging fontanelle.

• Hypothalamic pituitary syndrome.

7Tuberculous Meningitis

During the course of illness, spread of inflammation and exudate to spinalmeninges results in radiculomyelopathy There may be progressive paraparesis orless commonly tetraparesis due to development of spinal block In some cases, rap-idly developing or even sudden onset of paraparesis may occur due to tubercularvasculitis or tubercular myelitis The clinical picture of TBM is rarely dominated byspinal involvement from the very beginning Intracranial spread may take place sec-ondarily in these patients

The terminal illness in TBM is characterized by deep coma, decerebration ordecortication, extensor rigidity and convulsions Pupils are dilated and fixed Respi-ration becomes irregular Cheyne-Stoke’s or Biot’s type The features of brain hernia-tion and infarctions may contribute to the clinical picture Direct infiltration of thediencephalon may be responsible for irreversible coma

The severity of TBM has been classified into three stages

Stage I : only meningitis

Stage II : meningeal signs with cranial nerve palsy and clouding

of consciousness

Stage III : meningitis, neurological signs and severe clouding

of consciousness

Diagnostic Tests

Laboratory tests are important in the diagnosis of CNS tuberculosis

Fig 1.4 A child with TBM showing neck retraction and opisthotonus.

Cerebrospinal Fluid Analysis (CSF)

CSF shows high leukocyte count with lymphocytic predominance but there may

be neutrophilic predominance in the early stage Characteristic CSF findings inTBM are protein more than 1 g/ml and cells 0.2 x 109/ml, mostly lymphocytic.CSF is rarely normal A wide variety of CSF changes have been reported whichinclude: serous, pseudopyogenic, encephalitic or block patterns.3 CSF openingpressure is significantly elevated in 49-75% of patients CSF is typically clear,infrequently opalescent and rarely xanthochromic A cobweb coagulum forms onthe surface of the CSF if it is allowed to stand for some time which is suggestive butnot pathognomonic of TBM Cobweb coagulum is attributed to high fibrinogencontent along with the presence of inflammatory exudate in the CSF Tubercularbacilli may get entangled in the coagulum thus facilitating their detection in smear

or culture Acid fast bacilli in CSF are seen in only 10-20% of patients For smearpositivity, a bacterial load of 10x104 AFB/ml is required and conventional culturesare positive at a concentration of 10-100 AFB/ml In most patients with CNStuberculosis, the bacterial load of such magnitude is uncommon A number ofmeasures have been suggested to improve the yield of AFB in CSF: staining thecobweb coagulum, examining the centrifuge deposit of a large volume of CSF andrepeated CSF examination; testing second, third or even fourth sample

For a culture of AFB, CSF is inoculated in an egg or agar based medium (LowenStein-Jensen or Middle brook 7 H 10) and incubated at 37° C under 5% CO2 Ittakes up to eight weeks for detectable colonies to appear In modern laboratories,use of liquid media with radiometric growth detection such as BECTAC-460 andthe identification of isolates by nucleic acid probes have replaced the traditionalmethods of isolation on solid media and identification by biochemical tests Thesenew methods have reduced the time required for isolation and speciation to 2-3weeks, however the decision to treat the patient should not wait for culture results

Tuberculin Test

The tuberculin test involves a subcutaneous injection of 0.1 ml of 5 T4 of

PPD-5 (Purified protein derivative) or 1 unit of PPD-RT23 into the volar aspect of the

Table 1.2 Clinical presentation of tuberculous meningitis 15

9Tuberculous Meningitis

1

forearm The response is read after 48-72 hours and the maximum diameter ofinduration measured by palpation is interpreted as >15 mm or ulceration—stronglypositive, >10 mm—positive; 5-9 mm—intermediate, and <5 mm—negative Thistest is of limited value because of low sensitivity and specificity False negative reac-tions are common in immunosupressed patients and those with overwhelming tu-

berculosis False positive results are obtained in subjects exposed to M tuberculosis

without active disease, or in those with sensitization by non-tubercular ria or BCG vaccination In the absence of a history of BCG vaccination, a positiveskin test however may provide additional support for the diagnosis of tuberculosis

mycobacte-Radiological Investigations

CT scan reveals several characteristic changes in patients with CNS tuberculosis.4

Basal exudates In TBM CT scan usually demonstrates isodense or hyperdense

basal cisterns on plain CT scan which homogeneously enhance on contrast istration (Fig 1.5) Meningeal enhancement can extend over the surface of cerebraland cerebellar hemispheres

admin-Hydrocephalus Communicating hydrocephalus is evidenced by dilated ventricles,

including the fourth ventricle with periventricular lucency (Fig 1.6) Sometimethere may be obstructive hydrocephalus In that situation only the lateral and thirdventricles, or only one lateral ventricle may be dilated due to a block in the aqueduct

or foramen of Monro, respectively CT scan is useful to monitor the hydrocephalus

in TBM

Fig 1.5 CT scan, axial section of a patient with TBM showing dense basal exudate, dilatation of temporal horns of lateral ventricles and fourth ventricle.

Infarction In TBM infarctions are small, multiple and are commonly located in

the basal ganglionic region (Fig 1.6) and reported in 20.5-38% of patients Theseare rarely hemorrhagic

Ependymitis Ependymitis is seen as a linear enhancement along the margin of the

ventricles

Tuberculoma The tuberculoma may be solitary or multiple; round, oval or

lobu-lar shaped and iso- or hyperdense on CT scan These are located commonly in thefrontal and parietal regions; however, tuberculoma may also be seen in theinfratentorial region (Fig 1.7) On contrast administration immature tuberculomaenhance as small ring or discs with massive edema and mature tuberculoma as alarge ring or lobulated mass The margin of ring is irregular, unlike cysticercosis.Enplaque meningeal tuberculoma are demonstrated as lenticular enhancing lesions

Calvarial tuberculosis Tuberculosis of the skull is rarely associated with TBM

which may be a circumscribed, single calvarial defect with or without sclerosis orexpanding lytic lesions with well defined margins that may be surrounded by a faintzone of osteoporosis These lesions can spread across the suture line

Tuberculous otomastoiditis Tubercular otomastoiditis may be responsible for TBM

in children In the early stage, CT scan reveals soft tissue in the tympanic cavity andlater destruction of middle ear structures, signs of mastoiditis and retroauricular orepidural abscess

Fig 1.6 Cranial CT scan, axial section of a patient with tuberculous meningitis showing dilatation of lateral and third ventricles with periventricular lucency Small infarctions are also seen in the basal ganglia, thalamus and internal capsule There is also bilateral basal ganglia calcification.

11Tuberculous Meningitis

1

Magnetic Resonance Imaging (MRI)

The MRI changes in CNS tuberculosis depend upon the stage of the disease Inthe early stage conventional spin echo MR acquisitions without use of contrast maynot show any changes Later, distension of subarachnoid space occurs which results

in mild shortening of T1 and T2 relaxation time as compared to CSF T1 weightedimage following gadolinium injection (0.1 mmol/kg IV) shows abnormal enhance-ment which is most prominent in the basal region, but some degree of enhancement

is also seen over the cerebral convexities, sylvian fissure and cerebellum In additionabnormal enhancement of the choroid plexus and lining of the ventricular systemmay also be seen (Fig 1.8)

Ischemic infarctions are common in TBM and the autopsy study by Dastur andhis colleagues reported cerebral infarction in 41% of specimens.5 The reported fre-quency of infarction on CT scan has ranged between 20.5% and 38% On MRI,however, a higher frequency of infarctions has been reported The majority ofinfarctions are in the basal ganglionic and capsular regions

The MRI features of tuberculoma depend on whether the granuloma isnoncaseating with a solid center or caseating with a liquid center The distinguish-ing MRI features of different types of tuberculoma on T1 and T2 and contrast ad-ministration are shown in Table 1.3 Miliary tubercules are less than 2 mm and areeither not visible on conventional spin echo MR or show tiny foci of hyperintensity

on T2 weighted acquisition or on contrast (Fig 1.9a and b) Non-enhancing sidual encephalomalacia with or without calcification is also a sign of healing

re-Fig 1.7 Contrast CT scan axial section of a patient with tubercular meningitis showing multiple enhancing granuloma in cerebellopontine angle and pons with edema This patient had obstructive hydrocephalus.

Calcium deposition, when present, typically appears hypointense in T1 and T2

weighted images Rarely a paradoxical response has been observed in which thelesion increased in size or even first appeared while the patient was on antituberculartherapy These regress on continued treatment

The spinal cord may be involved either as a complication of arachnoiditis ing in infarction or syringomyelia; or it may be complicated with parenchymal tu-bercular myelitis or tuberculoma Syringomyelia is seen as cord cavitation that typicallydemonstrates CSF intensity on both T1 and T2 weighted images that does not en-hance on gadolinium administration (Fig 1.10)

result-MR features of spinal tubercular meningitis include CSF loculation and eration of CSF subarachnoid space with loss of outline of the spinal cord in thecervicothoracic region and walling of nerve roots in the lumbar region Gadoliniumenhanced MR images reveal thick linear intradural enhancement often completelyfilling the subarachnoid space This may be noted when unenhanced images appearnormal In the chronic stage, Gadolinium enhancement may not be present andeven unenhanced images may show signs of arachnoiditis

oblit-Cerebral Angiography

Angiographic triad characteristic of TBM include, evidence of ventricular tion, narrowing of the vessels at the base of brain and narrowing or occluded smalland medium size vessels with scanty collaterals

dilata-The most common sites of abnormality are the supraclinoid portion of the nal carotid artery and the proximal portion of the anterior and middle cerebral

inter-Fig 1.8 Cranial MRI, axial section in MTSE sequence showing hyperintensity of ventricular lining with lesion in the lateral ventricle resulting in asymmetric dilatation of lateral ventricle due to TBM.

13Tuberculous Meningitis

1

arteries The narrowing of vessels is variable It may be a uniform narrowing of alarge segment, small segmental narrowing, irregular beaded appearance or completeocclusion These vascular changes are due to mechanical compression of the vessels

by exudate or arteritis The vascular changes can be non-invasively studied ing MR angiography SPECT studies have confirmed hypoperfusion in the basalganglia, cerebral cortex or both (Fig 1.11)

employ-Newer Diagnostic Tests

The newer adjunctive diagnostic tests are broadly classified

1 biochemical assay measuring feature of AFB or host response to it

2 immunologic test that detects mycobacterial antigen or antibody in theCSF

3 DNA analysis of AFB

The sensitivity and specificity of those tests are given in Table 1.4

Radiolabelled ammonium bromide partition test This test is carried out by oral or

intravenous administration of radiolabelled ammonium bromide and simultaneousestimation of serum and CSF concentration of radio-isotope employing gammacamera after 1-2 days of equilibrium A serum to CSF ratio of 1.6 or less is sugges-

tive of TBM False positive results have been reported in viral encephalitis, Listeria

meningoencephalitis and CNS lymphoma

Adenosine deaminase test Adenosine deaminase enzyme is produced by

lympho-cytes and monolympho-cytes and reflects cell-mediated immunity This enzyme is estimated

by calorimetric method Assessing CSF enzyme concentration in various cal disorders, it has been reported that markedly elevated CSF enzyme concentra-tion is found in TBM

neurologi-Tuberculostearic acid neurologi-Tuberculostearic acid is a component of the cell wall of M tuberculosis, and it can be assessed by employing electron capture gas liquid chroma-

tography Increase in CSF tuberculostearic acid suggests TBM

Immunodiagnostic technique such as enzyme linked immuno sorbent assay (ELISA)

ELISA has some promise for rapid and sensitive diagnosis of TBM Cross reactivityagainst nonpathogenic bacteria as well as bacterial and fungal antigens may compro-mise its specificity All these techniques are still considered investigational and none

is routinely indicated for the diagnosis of TBM

Table 1.3 MRI features of different types of tuberculoma

enhancement

central liquefaction hypointensity hyperintensity, enhancement

peripheral hypointensity (capsule)

* hypointensity depends upon presence of solid caseation, associated regionaledema/gliosis, macrophage infiltration, macrophage biproduct and perilesionalcellular infiltrate

Polymerase chain reaction (PCR) Extraction, amplification and detection of

spe-cific DNA sequences (IS6110) of M tuberculosis utilizing PCR technology was

claimed as a major breakthrough in the diagnosis of tuberculosis, especially in CNStuberculosis where bacterial load is low The advantage of PCR is that it can amplifyminute quantities of DNA to levels that can be readily seen by agarose gel electro-phoresis A disadvantage is that it can amplify contaminating DNA to a level whichcan result in serious errors Use of PCR in the diagnosis of TBM is promising butstill poorly defined The studies suffer from small numbers, different primary tar-gets and differing diagnostic criteria, sensitivities ranging between 33% and 90%and specificity between 88% and 100% In a study in TBM, CSF culture alone hold

a sensitivity and specificity of 39% and 100% respectively whereas PCR had tivity of 48% and specificity of 100% A vietenmers study compared 104 patientstreated for TBM on clinical grounds and results of CSF microscopy, culture andPCR and reported the sensitivity of PCR to be 32%, culture 17% and microscopy1% Of 17 patients with culture positive TBM only 10 were PCR positive It ispossible that the small amount of CSF used in PCR may reduce the quantity ofavailable mycobacterial DNA to undetectable quantities

sensi-The use of PCR to monitor successful treatment of TB meningitis is not yet

defined M tuberculosis can be detected up to six weeks after starting treatment.

Another study reported that of sequential CSF samples from seven patients withTBM, five were negative by day 14, and only one was positive on day 286

A blinded study involving seven different laboratories in six countries revealedsignificant differences in the results.7 At present, because of insufficient reliability,PCR results should neither be used for initiating nor stopping antitubercular therapy

Fig 1.9a Cranial MRI, T 1 sequence showing multiple disc enhancing lesion.

15Tuberculous Meningitis

1

Mere presence of organisms does not indicate the disease Differentiating tion from infections will remain an important challenge With ongoing researchand significant commercial interests, PCR may be established as an important diag-nostic tool in near future

coloniza-Nucleic acid technology employing restriction fragment length polymorphism

(RFLP) has been used to ‘finger print’ strains of M tuberculosis for epidemiological

purposes

Neurophysiological Investigations

Neurophysiological studies such as electroencephalography (EEG), motor andsomatosensory evoked potentials have been used to document respective functionalstates EEG produces nonspecific changes which include diffuse slowing in the theta

to delta range, intermittent rhythmic delta activity in the frontal region, right to leftasymmetry and epileptic discharges EEG changes correlate with the severity ofmeningitis and the degree of coma.8 Motor and somatosensory evoked potentialshave been studied in TB meningitis Motor evoked potential (MEP) is more fre-quently abnormal compared to somatosensory evoked potential (SEP), which may

be due to greater vulnerability to the motor pathway and higher sensitivity of MEPcompared to SEP The MEP and SEP abnormalities include unrecordable or pro-longation of central conduction time The changes are patchy and focal and do notfollow a regular pattern.9

Search for Extra CNS Tuberculosis

In spite of the best efforts, it may not be possible to have a definitive diagnosis ofTBM Every effort therefore should be made to collect evidence of extra CNS

Fig 1.9b Chest radiograph showing miliary tuberculosis.