Stroke in tuberculous meningitis

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Abstract

Stroke in tuberculous meningitis (TBM) occurs in 15–57% of patients especially in advance stage and severe illness. The majority of strokes may be asymptomatic because of being in a silent area, deep coma or associated pathology such as spinal arachnoiditis or tuberculoma. Methods of evaluation also influence the frequency of stroke. MRI is more sensitive in detecting acute (DWI) and chronic (T2, FLAIR) stroke. Most of the strokes in TBM are multiple, bilateral and located in the basal ganglia especially the ‘tubercular zone’ which comprises of the caudate, anterior thalamus, anterior limb and genu of the internal capsule. These are attributed to the involvement of medial striate, thalamotuberal and thalamostriate arteries which are embedded in exudates and likely to be stretched by a coexistent hydrocephalus. Cortical stroke can also occur due to the involvement of proximal portion of the middle, anterior and posterior cerebral arteries as well as the supraclinoid portion of the internal carotid and basilar arteries which are documented in MRI, angiography and autopsy studies. Arteritis is more common than infarction in autopsy study. The role of cytokines especially tumor necrosis factor (TNFα), vascular endothelial growth factor (VEGF) and matrix metaloproteineases (MMPs) in damaging the blood brain barrier, attracting leucocytes and release of vasoactive autocoids have been suggested. The prothrombotic state may also contribute to stroke in TBM. Corticosteroids with antitubercular therapy were thought to reduce mortality and morbidity but their role in reducing strokes has not been proven. Aspirin also reduces mortality and its role in reducing stroke in TBM needs further studies.

Introduction

Tuberculosis is an ancient disease. The skeleton with evidence of spinal tuberculosis dating back to 5000 BC was found in a monolithic cemetery near Heidelberg in 1904 and is the first documented record of human tuberculosis. Anglo-Aryans (1500 BC) were familiar with tuberculosis as it is mentioned in a number of hymns of Rig-Veda [1]. Ancient Chinese books written 2 or 3 millennia BC, describe a condition called ‘Lepoing’ which probably referred to tuberculosis. Writings of Homer (900 BC), Hippocrates (400 BC) and Aristotle (350 BC) support the existence of tuberculosis at that time. In 18th century, the patients with meningitis were referred as phrenitis, cephalitis, brain fever or dropsy of the brain. Whytt in 1768 emphasized on the hydrocephalus (collection of fluid in the ventricles) as the primary manifestation of tuberculosis and for half a century the focus remained on hydrocephalus rather than the underlying etiology [2]. This condition was referred as ‘febris hydrocephalus’. The first reference to the term meningitis was probably by Odier in 1790 under the term ‘hydrocephalic combine ave inflammation des meninges’ [3]. The term meningitis was first used in the thesis of French Army surgeon Herpin in the 1803 [4].

The consistent distribution of tubercules along the pial vessels and occasional restriction of tubercular lesions to one arterial territory along with caseous masses somewhere in the body prompted the conclusion that tuberculous meningitis (TBM) has originated from emboli of an unknown agent in the blood and most likely from older tubercular lesions such as lung, kidney and bone. Rindfleisch found that the large arteries are the seat of a unilateral swelling, while smaller ones presented with spindle shaped thickening which were believed to originate in adventitia [5]. Virchow noted that the ground substance forms the matrix for tubercle in the adventitia of smaller pial arteries [6]. Miliary tubercles in TBM not only develop outside the blood vessels but also from the endothelial linings and the tubercles may perforate from within as well as from without.

Section snippets

Magnitude of the problem

Tuberculosis is a major health problem with a huge and growing worldwide burden. In the year 2007, the worldwide estimate of tuberculosis was 9.27 million new cases and 1.78 million deaths [7]. A link between tuberculosis, atherosclerosis and stroke has been suggested which sometimes correspond with central nervous system (CNS) tuberculosis [8], [9]. In a longitudinal study, 6% of non CNS tuberculosis patients and 3.7% of controls developed stroke. The hazard ratio of ischemic stroke for

Pathology of stroke in tubercular meningitis

The commonest pathology in TBM is caseous meningoencephalitis, typically unevenly distributed dense gelatinous fibrinocellular leptomeningeal exudates located in interpeduncular fossa (Fig. 1). The exudate spreads anteriorly encircling the optic chiasma and anterior cerebral vessels and laterally deep into the Sylvian fissures almost wrapping the carotid, middle cerebral trunks and their penetrating branches. Caudally, the exudate covers the pontomesencephalic, medullary and cerebellar cisterns

Coagulation and fibrinolytic status in tuberculous meningitis

The increased tendency for deep venous thrombosis in patients with pulmonary tuberculosis is well recognized and is attributed to hypercoagulability during the acute stage of disease which generally normalizes during the first month of antitubercular therapy [45], [46]. A hypercoagulable state in TBM has been reported and may increase the risk of infarction [47]. There is a decrease of anticoagulant (Protein S) and an increase of procoagulant factor (Factor VIII). Raised plasminogen activator

Molecular pathogenesis of stroke in tuberculous meningitis

Cytokines are hormone like proteins and act by binding to the specific receptors. Several cytokines are released from astroglia, endothelial cells and especially monocytes by the interaction with bacterial cell wall components. The cytokines amplify and perpetuate inflammation [48]. Within 24 h of cytokine stimulation, it induces rapid and transient expression of cell adhesion molecules. Subsequently neutrophils migrate into CSF through adhesion to endothelial cells via diapedesis and release

Cerebral angiography

The initial information about the vascular involvement in TBM was based on cerebral angiography. The main features in cerebral angiography are marked segmental narrowing and irregular beaded appearance in the supraclinoid portion of the internal carotid artery extending to the anterior and middle cerebral arteries. Partial or total occlusion of vessels may result from subintimal fibrous proliferation. It is not unusual to see beaded areas of narrowing alternating with aneurismal dilation or

Clinical features of stroke in tuberculous meningitis

TBM related stroke most commonly manifests with focal weakness such as monoplegia, hemiplegia or quadriplegia [26], [75]. The other neurological manifestations of stroke such as sensory impairment, ataxia, seizures, movement disorders, cranial nerve palsy, aphasia, apraxia and hypothalamic disturbances depend on the location of infarctions. A large stroke may result in raised intracranial pressure and may lead to decortication or decerebration.

The focal neurological deficit in TBM due to

Outcome

The presence of stroke has been regarded as a poor prognostic predictor of TBM. In a study on 25 children with TBM with infarction, none recovered completely [37]. In another study on 40 patients with TBM, two-thirds of patients complicated by cerebral infarct had poor outcome despite adjunct dexamethasone therapy [21]. Stroke was associated with poor outcome at 3 months of treatment but not at 6. This may be due to the high frequency of basal ganglia lacunar stroke which have better outcome

Treatment of stroke in tuberculous meningitis

There is no specific treatment of stroke in TBM. The patients are managed with standard antitubercular therapy with symptomatic and supportive treatments. Dexamethasone has an anti-inflammatory effect and may favorably affect the outcome of TBM. In an observational study on 43 patients with TBM, the frequency of infarction in the dexamethasone group was 27% compared to 58% in placebo [77].

As per Cochrane review, adjuvant corticosteroids reduce the mortality and sequelae in TBM [81]. In a large

Future directions

The recent developments in the molecular mechanisms of vascular injury may help in understanding the stroke in TBM. The interaction between conventional risk factors including genetic markers needs further studies. New imaging technique such as MRI, MRA, SPECT and PET may help in understanding the structural and functional changes better. There is need to develop the therapeutic and preventive strategies for tubercular vasculitis.

Acknowledgement

We thank Mr. Rakesh Kumar Nigam for secretarial help.

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