Original Article Ind I Tub., 1991, 38, 149

INVOLVEMENT OF HYPOTHALAMUS IN TUBERCULOUS MENINGITIS: PATHOLOGICAL CHANGES AT AUTOPSY

K.R. Vani1, S.K. Shankar2, Sarala Das3, T. Asha4 and T. Vasudev Rao5

(Original received 19.6.1990; Accepted 16.4.1991)

Introduction

Tuberculous meningitis (TBM) continues to be one of the common causes of morbidity and mortality in our country. Approximately 2.5% of all paediatric patients admitted to hospitals in India suffer from tuberculous meningitis.1 One of the important factors contributing to high mortality and morbidity is failure to recognise the condition in its early stages. Medical aid is usually sought late i.e., after the patient has become unconscious, resulting in mortality ranging from 17-71%.2

In tuberculous meningitis, the exudate is predominantly basal in location, being centred at the interpeduncular fossa and involving the cisterna ambiens and cisterna pontis.3 These lesions are close to the pituitary gland and the hypothalamus, the nuclei of which may be affected either directly or secondary to ischemic changes or to variable degrees of obstructive hydrocephalus.4 As a sequel to tuberculous meningitis, endocrinopathies are known to

become evident months or years after recovery from the disease, secondary to progressive scarring of the hypothalamus and hypothalamohypophyseal pathway.5 Obesity, hypogonadism, Frolich's syndrome, sexual precocity, growth retardation,5'6'7'8 diabetes insipidus4 and inappropriate secretion of ADH1 have all been reported as post TBM sequelae.

Occasionally, in some cases of TBM, sudden death has been attributed to adrenal failure, especially if the patient manifests irreversible peripheral circulatory failure and shock, even though pathological evidence for primary adrenal involvement in these cases is lacking. It has not been established whether this terminal event is due to primary adrenal involvement or secondary to disruption of the hypothalamo-pituitary-adrenal axis.

The earlier pathological studies of tuberculosis of the nervous system have either not paid attention to or made only a passing reference to the hypothalamic involvement.13 To the best of our knowledge, there is no pathological study elucidating adequately the hypothalamic involvement in TBM. Hypothalamus is the area in the brain involved in stress and endocrine modulation. Information regarding morphological changes in the neurons of this zone, and the response to inflammatory stress is totally lacking.

The aim of the present study was to document the type and extent of pathological changes in the hypothalamus found in autopsied cases of TBM. Further, attempt has been made for the first time to immunochemically demonstrate the presence "stress protein" in the hypothalamic neurons. In a variety of stressful states, like elevated body temperature, respiratory inhibition, exposure to

Summary : A systematic study of 39 autopsied cases of tuberculous meningitis (TBM), from 1982 to 1989 revealed frequent involvement of the hypothalamic nuclei, especially those involved in homeostasis in stress. Sudden death in some cases of TBM is attributed to adrenal failure but in the true sense, this could be due to the sub-optimal reaction of the hypothalamus to stress de to infective pathology. Further, it is probable that administration of steroids in combination with anti-tuberculosis drugs masks the physiological expression of hypothalamic failure which, thus, escapes clinical recognition.

1. Senior Resident; 2. Additional Professor; 3. Professor and Head of the Department; 4. Assistant Professor; 5. Associate Professor, Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bangalore 560 029. Correspondence: Dr. S.K. Shankar, Additional Professor, Department of Neuropathology, National Institute of

Mental Health and Neuro Sciences, Hosur Road, Bangalore 560 029.

150 KRVANI ETAL

toxins and metals, there is an enhanced synthesis of a limited set of proteins, called 'heat-shock' or 'stress proteins', in all living organisms.10'11 These proteins are phylogenetically highly conserved and are considered to protect cells from the stress induced damage as well as play a vital role in intracellular assembly and transport of protein complexes. One well characterised member of the family of such proteins has molecular weight of 65 KD, which is widely present, and monoclonal antibodies for its detection are available. Material and Methods

Thirty-nine cases of tuberculous meningitis autopsied over a period of 7 years (1982-1989) were systematically analysed. Only those cases where coronal section of the hypothalamus at the optic chiasma, infundibulum and mamillary bodies was available were included in the study. The supraoptic, paraventricular and tuberal nuclei of hypothalamus were examined critically since these nuclei are the ones primarily involved in the hypothalamo-pituitary-adrenal axis. Other nuclei were also examined.

The important clinical features noted were age, duration of illness and endocrinal disturbances. The gross pathological changes looked for included the presence of chronic/ acute inflammatory exudate, hydrocephalus, parenchymal tuberculoma and ischemic changes. The histological features recorded were diffuse lesion involving the whole brain and specific involvement of the hypothalamus. Pituitary gland could be studied in 21 of the 39 cases. Since a majority of the autopsies were limited to the brain, information on adrenal glands was available only in two cases.

The representative brain sections were processed routinely and stained with haematoxylin-eosin, Luxol fast blue for myelin, PTAH for gliosis and Bodian silver for the evaluation of neuronal and axonal pathology.

Immuno-histochemical localisation of 65 KD "stress protein" in the hypothalamic neurons was attempted, using 'ML-30' clone of monoclonal antibodies (Courtesy J. Ivany, MRC, London) by the Sterbergers PAP techniques/The necessary controls were incorporated in the study.

Observations

Age of the patients ranged from 7 months to 60 years. The duration of illness varied from 15

days to 6 months, but in children below 10 years of age, it was 15 days to 3 months. The diagnosis of TBM, for inclusion in the study was based on clinical and radiological features, laboratory results and pathological features found at autopsy. Only in four cases could tubercle bacilli be cultured from the cerebrospinal fluid. In two cases, endocrinal disturbances, indicative of adrenal failure and a hypothyroid state respectively, had been noted antemortem. Death in the majority of these cases was relatively sudden.

Examination of the brain revealed basal and/ or superolateral surface meningeal exudate of varying degree in 37 cases. Presence of parenchymal tuberculoma away from the hypothalamus was noted in 10 cases. The histological lesions found were the following (a) arteritis: 35 cases; (b) only border zone reaction due to contiguous spread of meningeal inflammation to the border brain parenchyma : 29 cases; (c) arteritis with border zone reaction : 29 cases; (d) infarcts in varying stages of evolution (all with associated arteritis) : 26 cases; (e) arteritis without infarcts : 9 cases and (f) hydrocephalus of varying degree : 28 cases.

The study of hypothalamic nucleus involvement revealed paraventricular nucleus involvement in maximum number of cases (37/39 cases) followed by the supraoptic (25/39 cases) and tuberal nuclei (14/39 cases). Other parts of the hypothalamus had variable degree of affection, either due to discrete or contiguous spread. The various pathological changes observed in the principle nuclei are detailed in Table 1. No definite correlation was found between duration of illness and the pathological lesion, indicating a variable temporal progression, mostly by contiguous spread of the lesions. The sub-ependymal granulomas, located along the third ventricle were seen to break into the paraventricular nuclei parenchyma with caseous necrosis, vasculitis and microglial reaction. The supraoptic nuclear involvement was common in those cases who had florid basal exudate. In an occasional case, healing infarcts and axonal spheroids were also seen, in this area, suggesting chronicity and disruption of the axonal pathways interconnecting different nuclei. Gliosis, though seen in all the three zones, was more prominent in the tuberal and infundibular nuclei.

Where adrenal failure had been clinically suspected in one case, pathological examination

HYPOTHALAMUS IN TB MENINGITIS 151

Table 1. Spectrum of pathological lesions met with in hypothalamus in 39 autopsies

Location

Lesion Supra-Optic Nucleus

Tuberal Nucleus

Paraventricular Nucleus

Arteritis with infarcts 9 4 14

Arteritis without infarcts 1 1 3 Lymphocytic infiltration 10 3 14 Microglial proliferation 6 1 12 Sub-ependymal granuloma - - 26 Border zone reaction 10 4 4 Gliosis 8 10 10

Fig.l A. Whole mount preparation showing dense basal exudate at the level of infundibulum. The optic tract and the supra-optic area is involved by ischemia on the side marked by the arrow. H.E. x 3

Fig.2. A sub-ependymal granuloma rupturing the lining and projecting into the ventricle. Note extension of the inflammation into paraven- tricular hypothalamic nucleus. H.E x 90

Fig.lB. Whole mount preparation showing dense*

basal exudate around the optic chiasma. Arrow shows hemorrhages and ischemia of the paraventricular nucleus. H.E. x 90

Fig3. Involvement of the supra-optic nucleus by the

extension of the basal inflammation. Neurons show chromatolysis and other degenerative changes. H.E. x 90

152 K.R.VANIE7ML

revealed minimal basal exudate with no arteritis or ischemic lesions. However, the supraoptic and paraventricular nuclei were involved, showing neuronal degeneration, microglial proliferation and inflammatory infiltration into the nuclei. Examination of the adrenal glands and pituitary, in this case, failed to reveal any evidence of tuberculous pathology or ischemia. In a 45 year old case with antemortem clinical features of hypothyroidism, significant basal exudates with vasculitis were found at autopsy. The paraventricular and tuberal nuclei showed ischemic lesions, focal hemorrhages and gliosis, suggesting disruption of the hypothalamo-hypophyseal axis.

Histological changes in the pituitary were studied in 21 cases. The stalk and hypothalamo-hypophyseal axis were involved in the inflammatory infiltration in four cases. The parenchymal involvement of either or both adeno and neurohypophysis was variable but was noted in a few cases. Infarction of the whole gland was seen in one case and focal infarction in two cases along with hypothalamic involvement. Mild lymphocytic infiltration and focal scarring was seen in five cases.

Immuno-histochemical study in six cases revealed expression of "stress protein" in neurons of paraventricular and supraoptic nuclei in addition to glial cells and macrophage system. Some of these neurons were located away from the exudate and ischemic lesions, suggesting indirect response of the hypothalamic neurons to the inflammatory pathology.

Discussion'

Following stressful stimuli, cortisol secretion by the adrenal cortex is directly under the control of hypothalamus, which in turn controls ACTH secretion.12 In any type of physical stress, it is believed that the stimulus is transmitted to the parafornicial area of the hypothalamus which transmits the signals to other areas of the hypothalamus and eventually to the median eminence where CRF (corticotropin releasing factor) is secreted into the hypophyseal portal system. Within minutes, the entire control sequence leads to the release of large quantities of glucocorticoids into the blood via the ACTH pathway. Therefore, destruction of the

hypothalamus by the inflammatory, process hi TBM, particularly the nuclei modulating hypothalamo-adrenal axis can lead to dysfunction and secondary adrenal failure.

The present study has shown how frequent is the involvement of the hypothalamic nuclei in TBM, especially those involved in protection against stress. Specific hypothalamic syndromes, with corresponding confirmed lesion in the hypothalamus, however, do not occur frequently due to the diffuse nature of TBM. Though sudden death in some cases of TBM is attributed to adrenal failure, in the true sense this could be secondary in nature with the primary pathology located in the hypothalamus. The sub-optimal reaction of the hypothalamus to stress, due to infective pathology, could really be the cause of sudden death, a possibility hitherto neglected. Further, i t could be postulated that administration of steroids in combination with anti-tuberculosis drugs probably masks the physiological hypothalamic failure.

Non-availability of a detailed clinical evaluation of the cases, for getting better insight into the relationship between clinical syndromes and observed hypothalamic pathology is a limitation of this retrospective study. However, the objective of a structural assessment and the pathological involvement of the hypothalamic nuclei is fulfilled. In the cases observed, it acquires a great significance when related to the earlier clinical studies, in India as well abroad, which report on endocrinal abnormalities of hypothalamic origin following recovery from TBM. Further, the immunochemical component of the study has shown the response of the relatively well preserved hypothalamic neurons to the inflammatory process by the expression of stress protein which is considered as a protective response.

Similar prospective pathological studies in conjunction with a more detailed clinico-pathological correlation in tuberculosis of the nervous system and hypothalamic endocrino-pathies is necessary for better understanding and to evolve better management strategies. It is further suggested that children who have recovered from TBM should be followed up with appropriate endocrine function tests to facilitate timely supportive hormonal therapy as well as to provide functional correlation to hypothalamic physiology.

HYPOTHALAMUS IN TB MENINGITIS 153

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Material and Methods