Pituitary Hormone Involvement in Tuberculous Meningitis

INTRODUCTION

Tuberculosis (TB) is one of the commonest infectious diseases in developing countries like India.  TB, caused by the bacteria Mycobacterium tuberculosis, is known to affect almost every organ of our body except hair, nail and enamel. Endocrine involvement in TB is a distinct entity with high incidence in the pre-antibiotic era. However, although the incidence has reduced now with usage of anti-mycobacterial drugs, still it remains an important clinical entity with post infection sequelae [1]. Hypopituitarism has been reported in about 20% of patients, even years after recovery from tuberculous meningitis (TBM) in childhood. Tuberculous lesions affect the hypothalamus, pituitary stalk and directly or indirectly, the pituitary itself [2]. The route of spread includes hematogenous and local extension from brain, meninges or sphenoid sinus [1]. Apart from anterior pituitary endocrinal dysfunction, TBM also manifests as diabetes insipidus and syndrome of inappropriate ADH secretion (SIADH). Diabetes insipidus is more common in children as compared to adults. It can occur as part of panhypopituitarism [3]. It is reported that up to 60% of patients with TBM may present with SIADH or hyponatremia at initial presentation and it is usually reversible with treatment of TB in most cases [4]. Thus, pituitary involvement is an important complication of TBM and clinicians should therefore be aware of this entity.

METHODS

The study had a cross-sectional, observational design and was carried out for a period of one year in the inpatient department of a tropical disease institute in India. The study included all cases of 18 to 60 years age of either sex admitted in indoor newly diagnosed as TBM based on Ahuja criteria. Other meningitis due to infective aetiologies were excluded. Those receiving glucocorticoids more than 3 weeks or diagnosed endocrine illnesses or on hormone therapy including oral contraceptives, levothyroxine was excluded. HIV seropositive patients, pregnant or lactating mothers were excluded from the study.

Clinical features of the included cases were noted. Cerebrospinal fluid (CSF) analysis was performed. Pituitary hormone levels were measured using electron chemiluminescent immunoassay. Wherever possible, imaging like Computerized Tomography (CT) scan brain and Magnetic Resonance Imaging (MRI) were done. TBM cases were diagnosed using Ahuja criteria [5] which included Clinical, radiological and laboratory parameters, as follows:

a)    Clinical

Fever and headache lasting for more than 14 days (mandatory). Vomiting, alteration of sensorium or focal deficit (optional).

b)   Cerebrospinal fluid

Pleocytosis with more than 20 cells, predominantly (greater than 60%) lymphocytes, protein greater than 100 mg%, sugars less than 60% of corresponding blood sugars. Negative India ink studies and cytology for malignant cells (in relevant situations).

c)    Radiological

CT studies of the head showing 2 or more of the following:

1. Exudates in basal cisterns or in Sylvian fissures
2. Hydrocephalus
3. Infarcts
4. Gyral enhancement.

d)   Extra neural TB

Active TB of lungs, gastrointestinal tract, urogenital tract, lymph nodes, skeletal system or skin as evidenced by appropriate radiological or microbiological tests or by the presence of caseation necrosis on histopathological examination.

Based on the above criteria, patients are categorized into:

1. Definite tuberculous meningitis

i. Clinical criteria (A)

ii. Bacterial isolation from CSF or diagnosis at autopsy

1. Highly probable tuberculous meningitis

i. Clinical criteria (A)

ii. All 3 of(B) and (C) and (D)

1. Probable tuberculous meningitis

i. Clinical criteria (A)

ii. Any 2 of B, C and D

1. Possible tuberculous meningitis

i. Clinical criteria (A)

ii. Any one of (B) (C) and (D)

SIADH was diagnosed using Schwartz and Bartter Clinical Criterion[6] which includes: 

i. Serum sodium less than 135mEq/L

ii. Serum osmolality less than 275 mOsm/kg

iii. Urine sodium greater than 40 mEq/L (due to ADH-mediated free water absorption from renal collecting tubules)

iv. Urine osmolality greater than 100 mOsm/kg

v. Absence of clinical evidence of volume depletion - normal skin turgor, blood pressure within the reference range

vi. Absence of other causes of hyponatremia - adrenal insufficiency, hypothyroidism, cardiac failure, pituitary insufficiency, renal disease with salt wastage, hepatic disease, drugs that impair renal water excretion.

vii.Correction of hyponatremia by fluid restriction

Tests for SIADH included serum osmolality and serum sodium, urine sodium concentration and osmolality, renal function tests, random blood sugar, thyroid profile, serum cortisol, serum electrolytes, fasting lipid profile and liver function tests.

Data collected was statistically analysed. Descriptive data was represented as mean, standard deviation, frequency or percentages, as applicable. Different levels were expressed at 95% Confidence Interval. All Statistical analysis for various measures was performed using various standard statistical software packages like Microsoft Excel and GraphPad Prism.

RESULTS

Out of the 40 TBM cases, 27 were males and 13 females. Categorizing TBM, 2 were definite cases with CSF CBNAAT being positive. 10 were highly probable cases, i.e., they met clinical criteria, CSF criteria, radiological criteria and had extra neural involvement. Rest 28 cases were probable as per modified Ahuja criteria, i.e., they had clinical features suggestive of TBM along with any 2 of CSF, radiological and extra neural involvement criteria.  Mean age was 31.8 years. All cases were anaemic. (Table 1). Hypotension (BP<100/60 mmHg) was noted in 30% cases; hypoglycaemia (<70mg/dl) in 20% cases and hyponatremia (Serum Na+

All cases presented with fever and headache, while altered sensorium was noted in 80% cases. Vomiting was noted in 8 cases. 3 cases had Focal neurological deficit and 2 had seizures. Lumbar puncture was done in all cases and CSF analysed. CSF analysis showed > 20 cells in 35 cases, where CSF protein was raised - >100mg%, sugar was low (<60% of blood sugar at same time). In 5 cases, CSF was not suggestive.  India ink stains of CSF were negative in all cases. CSF CBNAAT was positive in only 2 cases. CSF for AFB stain was negative in all cases. ADA of CSF was high in 18 cases. 38 TBM cases had suggestive neuroimaging. 38 cases had >=2 of radiological criteria - basal exudates, infarct, hydrocephalus and gyral enhancement. Basal exudates and gyral enhancement were the most common radiological abnormality noticed. (Figure 1)

12 cases had other sites of TB involvement- pulmonary TB in 1 case. 12 had lymphadenopathy – cervical and/ or axillary. 8 had retroperitoneal lymph nodes in USG whole abdomen. CT abdomen for adrenal gland was normal in all patients.

More than one hormone disbalance was noted in 9 cases. Serum cortisol and ACTH was low in 20% cases, while serum prolactin was high in 7.5% cases. SIADH was diagnosed in 15% cases. Testosterone was low in 3.7% males and FSH was low in 15.3% females. TSH and free T4 was low in 15% and 12.5% patients respectively. IGF-1 was low in only 5% patients. (Table 2)

Follow up was done up to after 1year of treatment completion in all cases. More than one year couldn't be done in all cases as some cases were lost to follow up. At 1year follow up, repeat test of hormones revealed reversal to normal levels except for IGF 1, which still remained low, although it's level increased.

Table (1): Characteristics of TBM Cases.

DISCUSSION