Hypopituitarism: A rare sequel of cerebral malaria - Presenting as delayed awakening from general anesthesia.

We report a case of delayed emergence from anesthesia in a 37-year-old male who came for emergency laparoscopic appendicectomy. This patient is hailing from one of the endemic zones of Malaria, Orissa State in India. Two months ago he had cerebral malaria and was treated in our intensive care unit. After recovering from cerebral malaria, he presented to us for acute abdomen, and he was taken for emergency laparoscopic appendicectomy. He had delayed emergence of around 2 h to extubate from the time of completion of surgery in spite of termination of anesthetic agents. Further investigations showed to have decreased serum levels of thyroid hormones and cortisol levels in the postoperative period. The Physician promptly diagnosed the condition as hypopituitarism a known sequel of cerebral malaria. The secondary thyroid insufficiency contributing to the delayed emergence from anesthesia. We also review the pertinent literature related to this rare sequelae of cerebral malaria and its perioperative implication to the anesthesiologist.

INTRODUCTION

Few literature review the complication and sequel of cerebral malaria on the central nervous system (CNS). About 3% of adults have sequel after cerebral malaria in the form of hemiplegia, cerebral palsy, cortical blindness, deafness, cerebellar ataxia and impaired cognition and learning. The perioperative management of concurrent surgical condition requires awareness of such CNS complication. The prognosis of any such surgical condition will depend on the severity of previous malaria and its sequel that can affect any organ system.[1] After patient consent, we present this case report in which a 37-year-old male hailing from a malarial endemic zone of India with a recent attack of cerebral malaria about 2 months ago. Now, presented with acute abdomen for perioperative care in our institute. This patient had secondary hypothyroidism due to pituitary insufficiency,[2] a rare sequel of cerebral malaria presenting as delayed emergence from anesthesia after emergency appendicectomy.

CASE REPORT

A 37-year-old male was admitted in our surgical ward with acute abdominal pain planned for emergency appendicectomy. He is from malaria endemic region of India. The present history of severe abdominal pain for past 2 days with fever, nausea, and vomiting. History of generalized malaise and weakness present for past 2 months. Ultrasound abdomen showed no remarkable features. Computed tomography abdomen showed thickening of the appendicular wall. Before 2 months, he was diagnosed with cerebral malaria and was on ventilatory care in our institute. Peripheral smear examination showed 2.5% parasitemia. He was treated with quinine for 6 days after peripheral smear became negative.

His laboratory investigation showed normal serum Creatinine, electrolytes, liver function tests except for elevated C-reactive protein that was 168 mg/L. His total white cell count is 18,000 cells/cu.mm, predominant neutrophilia. The patient was planned for emergency laparoscopic appendicectomy under general anesthesia. The patient was accepted as ASA physical status I E. Premedicated with fentanyl 100 mcg intravenous (i.v), and midazolam 1 mg i.v. Monitoring includes pulseoximetry, capnometry, 5 lead electrocardiography, temperature probe and noninvasive blood pressure. He was induced with propofol 100 mg i.v, paralyzed with injection vecuronium 5 mg i.v and intubated with 8 size oral cuffed endotracheal tube. Maintained with sevoflurane 2% in 35% oxygen and 65% nitrous oxide. The surgery was uneventful and was completed by 2 h. Postoperative analgesia was provided with injection paracetamol 1 g i.v and port-site local anesthetic infiltration done.

No maintenance bolus of muscle relaxant was needed. The patient failed to recover from the neuromuscular blocker even after 2 h of the last dose of relaxant. Neuromuscular monitoring with train-of-four (TOF) showed only two twitch response at the end of the procedure. Hypoglycemia and hypothermia were ruled out. Arterial blood gases showed no evidence of acid base or electrolyte disturbance. It showed: FiO2-1.0, pH - 7.37; PO2-417 mmHg; PCO2-38.2 mmHg; SaO2-99.9%; HCO3-21.3 mmol/L; lactate - 1.8 mmol/L Na - 137.9 mmol/L; K - 3.98 mmol/L and Cl - 97.7 mmol/L. The anesthetic gas monitor was connected to the patient, and end-tidal sevoflurane was found to be zero.

After 1 h of completion of surgery, the patient showed signs of recovery from muscle relaxant. The TOF slowly recovered and ratio was 0.7. Reversed with i.v neostigmine 3 mg and glycopyrrolate 0.6 mg i.v but patient was not arousable.

Two hours from the completion of surgery, he was responsive to verbal commands but had poor muscle tone. Assisted ventilation with measures to keep the patient warm has been done throughout the period of care using warm air blanket. After 2 h of delay in emergence from anesthesia, the patient was extubated and shifted to intensive care area.

Physician opinion leads us to likely diagnosis of undetected hypothyroidism. Entire endocrine screening was done and his serum thyroid stimulating hormone (TSH) was 0.01 μIU/ml and serum free T4-0.5 ng/dL, serum free T3-250 pg/dL and early morning serum cortisol - 0.1 μg/dL. This laboratory picture supported hypopituitarism. Adrenocorticotropic hormone (ACTH) stimulation test showed secondary adrenal insufficiency. Magnetic resonance imaging brain showed increased size and thickening of the pituitary gland. The patient was treated with tablet wysolone 10 mg BD and thyronorm 75 μg OD. The patient was discharged after 5 days and advised for regular follow-up. No further workup is done expecting spontaneous recovery of hypopituitarism.

DISCUSSION

The main pathological mechanism behind cerebral malaria is cytoadherence phenomena resulting from expression of falciparum erythrocyte membrane protein[3] in the red cell membrane. The other mechanism being immune mediated capillary disintegrity, endothelial activation and microvascular thrombo inflammatory responses.[4] This mechanism can affect the capillary beds and can cause obstruction and hemorrhages in all organ systems including the hypothalamo pituitary portal system. Previous studies[5] showed occurrence of secondary thyroid and adrenocortical insufficiency in cerebral malaria. These patients have blunted adrenocorticotropic[6] and TSH response to stimulation from hypothalamus in absolute and relative terms. The author reasoned this to parasitic sequestration within hypothalamo-pituitary portal system. This is confirmed by a study examining the postmortem brain tissue of fatal cerebral malaria.[7] Most of this pathology are reported to be transient and in nonfatal cases expected to recover in about 6 months.

We report one such nonfatal case of falciparum cerebral malaria in a patient hailing from malaria endemic zone in India. The patient presented atypically as delayed emergence from general anesthesia because of the secondary hypothyroidism due to pituitary insufficiency as explained above. He was taken for emergency laparoscopic appendicectomy after about 2 months of recovery from cerebral malaria. Hypothyroidism is a known cause of delayed emergence from anesthesia.[8] He showed laboratory evidence of hypopituitarism with decreased function of thyrotrophs and corticotrophs. The ACTH stimulation test showed secondary adrenal insufficiency. Though he doesn’t show any symptoms and signs of acute cerebral malaria at this admission, hypopituitarism can be part of complication of recent cerebral malarial infection. Evidences show that the hypothalamo pituitary thyroid and adrenal axis takes 3–12 months to recover after trauma and infective causes of hypopituitarism.[910] It can also be a part of the immune mediated sequel-postneurological malaria syndrome.[11]

About 3% of adults with cerebral malaria have sequelae such as hemiplegia, cerebral palsy, blindness, deafness, cerebellar ataxia and impaired cognition and learning.[12] Hypopituitarism as a rare sequel of cerebral malaria has been reported earlier.[2] The majority of these deficits improve or resolve completely within 6 months.

Postneurological malaria syndrome was defined in the presence of neurological or psychiatric symptoms within 2 months after recovery of acute illness. This implies in a patient who is smear negative after being positive during acute illness or in the case of cerebral malaria that the patient recovered complete consciousness.[11] The manifestation includes confusion, psychosis, seizure, aphasia, myoclonus, catatonia, and ataxia. The elevated cytokine levels, including Tumor necrosis factor -alpha, interleukin-2 (IL-2) and IL-6 supports the underlying immune mechanism.[12]

CONCLUSION

The anesthesiologist particularly practicing in developing countries should be aware of Hypopituitarism, as a rare sequel of cerebral malaria and its perioperative implications.