A Patient with Thyroid Storm Presenting with Apathetic Thyrotoxicosis and Features of Meningoencephalitis

Introduction

T hyroid storm is a severe and potentially life-threatening exacerbation of thyrotoxicosis, usually characterized by hyperthermia, tachycardia, severe agitation, and altered mental state. However, these features may not be evident in patients with an apathetic presentation. The diagnosis of thyroid storm can only be differentiated from uncomplicated thyrotoxicosis on a clinical basis, as laboratory findings are indistinguishable from each other (1). Here we report a patient with thyroid storm who had an apathetic presentation as well as initial features mimicking meningoencephalitis.

Patient

A 67-year-old Chinese woman presented to the Emergency Department, at Alexandra Hospital, Jurong Health Services, Singapore, with a 2-day history of drowsiness, generalized weakness, and fever. Her family had noted her to have loss of appetite, loss of weight that was unquantifiable, lethargy, and hand tremors in the preceding few weeks. She had no complaints of palpitations, heat intolerance, anxiety, or dyspnea.

There was no known personal history of thyroid disease, recent surgery, or iodine exposure, but she had a positive family history of thyroid disorder in that her mother had hyperthyroidism. She had a background history of hyperlipidemia, hypertension, and a right subcortical lacunar infarct 2 months before the current admission. During the admission for cerebrovascular accident, she had no clinical manifestations of hyperthyroidism, and she had subsequent full functional recovery. She was taking simvastatin, amlodipine, and aspirin for the above conditions.

On initial assessment she was thin and lethargic. Her Glasgow Coma Scale was 15, blood pressure was 163/77 mmHg, and heart rate was 110 per min and regular. Her mucous membranes were dry. She was afebrile. A small diffuse goiter was noted along with a thyroid bruit. She had a fine tremor of the hands, but no Graves' ophthalmopathy, pretibial myxedema, or thyroid acropachy. Her cardiovascular examination revealed a soft pan-systolic murmur; otherwise, her respiratory and abdominal examination was normal and she was not jaundiced. Neurological examination revealed generalized weakness, with a power grade of 4/5 by medical research council criteria on the right, and 3/5 on the left. A Babinski response was present on the left; the other reflexes were normal. The cranial nerve examination was normal and her neck was supple. She had no rash, and was not hyperpigmented.

Thyroid function tests were performed in view of tachycardia and these were diagnostic of primary hyperthyroidism as the free thyroxine level was elevated to 100 pmol/L (normal: 11.8–24.6 pmol/L) and the serum thyroid-stimulating hormone level was suppressed to 0.008 mIU/L (normal: 0.270–4.20 mIU/L). Her tests for autoimmune thyroid antibodies were an elevated thyroid-stimulating hormone receptor antibody titer of 40.0 IU/L (positive > 2.0 IU/L), elevated anti-thyroperoxidase antibody titer of 408 IU/mL (normal: 5–34 IU/mL), and elevated anti-thyroglobulin antibody titer of 620 IU/mL (normal: 10–115 IU/mL). These were consistent with Graves' thyrotoxicosis. Her baseline random evening serum cortisol level was 449 nmol/L (normal range for nonstressed state: 171–536 nmol/L). Full blood count showed leucocytosis, with a total white cell count of 13.12 × 10⁹ cells/L (normal: 4–11 × 10⁹ cells/L), mild neutrophilia with a neutrophil count of 8.29 × 10⁹ cells/L (normal: 2.00–7.50 × 10⁹ cells/L), and normal platelet count and hemoglobin concentration. She had normal renal function but had hypokalemia with serum potassium of 2.4 mmol/L (normal: 3.5–5.1 mmol/L). Serum bicarbonate, calcium, and magnesium levels were normal. Her liver function tests revealed a mildly elevated aspartate aminotransferase of 41 U/L (normal: 10–30 U/L), but were otherwise unremarkable. The electrocardiogram showed sinus tachycardia. Serum C-reactive protein was mildly elevated to 6.1 mg/L (normal: 1.0–5.0 mg/L), but serum procalcitonin was not elevated; it was 0.27 ng/mL (normal: 0.5–2.0 ng/mL). The initial chest radiograph was normal, and the blood culture was negative. Computed tomographic brain scan revealed bilateral external capsule infarcts (age indeterminate).

On repeat assessment a few hours later, she had hyperthermia with a temperature of 39°C, blood pressure of 106/54 mmHg, and persistent tachycardia of 120/min. She became drowsy. On neurological examination, she developed neck rigidity, positive Kernig's sign, absent Doll's reflex with sluggish pupillary reaction to light, and miosis (both pupils were 2 mm in diameter). On limb examination, there was increased tone, and positive Babinski response bilaterally, with generalized weakness (medical research council power of 2 bilaterally).

Thyroid storm was diagnosed on the basis of thyrotoxicosis complicated by neurological, cardiovascular, and thermoregulatory dysfunction. The possibility that meningoencephalitis was present and had precipitated thyroid storm was considered.

She was transferred to the Intensive Care Unit, during where she was intubated and started on mechanical ventilation for airway protection. She was treated with propylthiouracil (PTU) 600 mg loading, followed by PTU 200 mg every 6 hours and Lugol's iodine 10 drops every 8 hours starting 2 hours after the first PTU dose. Initially, beta-blockade with intravenous esmolol was given in view of borderline hypotension. This was switched to propranolol 40 mg every 6 hours after her blood pressure stabilized. Intravenous hydrocortisone 100 mg every 8 hours was administered. Cholestyramine 4 g was given every 12 hours for a day. She did not require any inotropic support.

In view of initial clinical suspicion of meningoencephalitis, intravenous ceftriaxone (given at meningitic doses) and intravenous acyclovir were initiated. Magnetic resonance imaging of the brain showed chronic lacunar infarcts in bilateral pons. Lumbar puncture investigations was negative for central nervous system infection. The cerebrospinal fluid white cell count was 0 cell/μL, with protein concentration of 0.3 g/L (normal: 0.1–0.5 g/L) and glucose of 6.6 mmol/L (with paired capillary blood glucose of 11 mmol/L). Additional studies of cerebrospinal fluid (gram stain, fungal smear, Indian ink preparation, acid fast bacilli smear, molecular study for tuberculosis by polymerase chain reaction, cultures for bacteria, acid fast bacilli and fungi, polymerase chain reaction for Herpes Simplex Virus, and neurotrophic virus panel [Mumps, measles, HSV 1 & 2, poliovirus 1, 2 & 3, coxsackie A & B, echovirus, enterovirus]) were all negative. Electroencephalogram showed no epileptiform activity, but it was suggestive of a moderately severe generalized encephalopathy. Her serum vitamin B12 level was normal. Transthoracic two-dimensional echocardiography showed an ejection fraction of 65%.

Clinically, she improved after receiving treatment for her thyroid storm. Her heart rate was controlled, and her consciousness level improved by day 4 of admission. This was accompanied by resolution of her meningism, and upper motor neuron signs. She was extubated on day 4 of admission. Table 1 shows the trend of her thyroid function tests over the subsequent weeks. Of note, her total triiodothyronine level was no longer elevated by day 4 of admission, and her free thyroxine level had normalized by day 11 of admission.

Her PTU dosage was reduced gradually. She was taken off ceftriaxone and acyclovir after her initial microbiological investigations were negative. However, she had poor cough reflex attributed to metabolic encephalopathy from thyrotoxicosis, and suffered recurrent mucus plugging with resultant lung collapse-consolidation, necessitating two further intubations for mechanical ventilation. She eventually stabilized from the acute illness 1 month later. A short Cosyntropin test done then showed normal adrenal response with a baseline morning serum cortisol of 390 nmol/L, and a peak cortisol level of 543 nmol/L (normal: basal morning serum cortisol >300 nmol/L; normal peak serum cortisol response to Cosyntropin >550 nmol/L in nonstressed state) (1,2). Her hypokalemia resolved subsequently. PTU was subsequently switched to carbimazole.

Discussion

Thyroid storm is a rare and potentially fatal complication of hyperthyroidism. Early recognition and treatment is essential in reducing its morbidity and mortality. Therapy for thyroid storm has improved markedly, so that the mortality rate has dropped from 100% in the 1920s to 20%–30% in recent series. Burch and Wartofsky (3) have proposed a diagnostic point scale for thyroid storm, in which a score of 45 and above is highly suggestive of thyroid storm. Our patient scored 60 on this scale. The diagnosis of thyroid storm was initially not considered due to her apathetic presentation. Her definitive response to antithyroid drug, iodide, and steroid therapy supported the diagnosis of thyroid storm.

Apathetic thyrotoxicosis is a rare presentation of thyroid storm. Lahey (4,5), in 1931, first drew attention to the clinical entity of apathetic thyrotoxicosis. A review of the literature revealed 15 case reports of thyroid storm in which apathy and/or coma was the initial manifestation. The majority of the patients were women. Their age ranged from 3 to 77 years of age, but occurrences were most common between the 4th and 6th decades (6 –21).

Our patient might have relative adrenal insufficiency in view of her baseline random evening serum cortisol level of 449 nmol/L done when she was critically ill. The Cosyntropin stimulation test was not done initially. In critical illness, functional hypoadrenalism is likely if random serum cortisol level is below 416 nmol/L, and unlikely if random serum cortisol level is above 944 nmol/L. For values of random serum cortisol between 416 and 944 nmol/L, a rise in cortisol response of 250 nmol/L in response to Cosyntropin test is required to exclude hypoadrenalism (22,23).

The neuromuscular disorders that are associated with hyperthyroidism include thyrotoxic myopathy, periodic paralysis, myasthenia gravis, exophthalmic ophthalmoplegia, and thyrotoxic neuropathy. Thyroid hyperactivity can also affect the central nervous system, resulting in confusion, behavioural abnormalities, coma, or seizures. In a review by Shaw et al. (24), 9 cases of pyramidal tract dysfunction were reported to be associated with hyperthyroidism. Some features included spastic weakness, hyperreflexia, clonus, extensor plantar responses, impaired vibration and proprioceptive sensation, and urinary incontinence. A group of patients had combined lower and upper motor neuron signs, mimicking motor neuron disease. Treatment of the hyperthyroidism usually resulted in resolution of neurological signs (25 –30). However, to our knowledge, there has yet to be a case report of thyroid storm with manifestations of meningism. A causal relation between our patient's meningism and hyperthyroidism was likely, as investigations showed no evidence of any other intracranial cause and her neurological signs resolved with antithyroid treatment.

The pathophysiological basis of these neurological manifestations in hyperthyroidism is unknown. Improvement of some clinical features (attention and concentration) with beta-blocker suggests a role for hyperthyroid-induced hyperactive adrenergic system, possibly disrupting the adrenergic pathways between the locus ceruleus and frontal lobe that subserve attention and vigilance (31). Others propose that hyperthyroidism may produce oxidative stress, producing neuronal injury (32).

Conclusion

Apathetic thyrotoxicosis is a rare presentation of thyroid storm. We have reported a patient with thyroid storm presenting with apathetic thyrotoxicosis, manifesting as coma with meningism, mimicking meningoencephalitis. These resolved once treatment for thyroid storm was instituted. Early recognition and treatment is essential in reducing its morbidity and mortality.