Ind I Tub.

, 1991, 38, 149

Original Article

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)
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.

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-pituitaryadrenal 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

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
Arteritis with infarcts
Arteritis without infarcts
Lymphocytic infiltration
Microglial proliferation
Sub-ependymal granuloma
Border zone reaction
Gliosis

Fig.l A.

Fig.lB.

Supra-Optic
Nucleus
9
1
10
6
10
8

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

Tuberal
Nucleus
4

Paraventricular
Nucleus
14

1
3
1
4
10

3
14
12
26
4
10

Fig.2. A sub-ependymal granuloma rupturing the

lining and projecting into the ventricle. Note
extension of the inflammation into paraventricular hypothalamic nucleus.
H.E x 90

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 hypothalamohypophyseal axis.
Histological changes in the pituitary were
studied in 21 cases. The stalk and hypothalamohypophyseal 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, it 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 clinicopathological correlation in tuberculosis of the
nervous system and hypothalamic endocrinopathies 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

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