Complete recovery after severe myxoedema coma complicated by status epilepticus

Abstract

We report a case of life-threatening myxoedema presenting with hypothermia, hypotension, bradycardia, pericardial effusion and deep coma. The condition was complicated by prolonged status epilepticus. The optimal treatment strategy has been debated over the years and the literature is briefly reviewed. Treatment with l-thyroxine (LT4) monotherapy without initial loading dose and with no l-triiodothyronine (LT3) treatment was successful with full recovery after hospitalisation for more than a month. Myxoedema coma is a rare, reversible condition with a high mortality and should be considered as a differential diagnosis in medical emergencies.

Background

This manuscript describes a case of deep myxoedema coma (MC). This rare endocrine emergency may pose a diagnostic challenge as the symptoms overlap with other more common critical conditions.

The patient surprisingly survived despite complicating status epilepticus, which is usually a grave prognostic sign.

The treatment for this condition is debated. We describe an intentionally cautious but successful treatment and review the literature.

Case presentation

A 72-year-old woman was found in her home in a comatose state. She had a Glasgow Coma Scale (GCS) Score of 3, one pupil was dilated and a cerebral haemorrhage was suspected. Owing to hypoventilation, she was endotracheally intubated and brought to the emergency room. She had not been hospitalised over the past 10 years and took no prescription medicine. Alcohol overuse was initially suspected and later confirmed.

Vital signs on arrival were a core temperature of 30°C (86°F), hypotension (65/40 mm Hg) and fluctuating oxygen saturation. Physical examination revealed generalised and facial non-pitting oedema, periorbital oedema, coarse hair and desquamation of the skin.

An ECG showed low voltage, sinus bradycardia, long QT-interval and a first degree AV-block (figure 1). Arterial blood gas analysis was normal apart from p-lactate of 2.8 mmol/L and haemoglobin of 4.2 mmol/L. P-Sodium was 154 mmol/L, probably due to an initial administration of hypertonic saline.

Figure 1.

ECG showing first degree atrioventricular block and low voltage.

CT of the head and truncus revealed no brain pathology but showed a large pericardial effusion as the only abnormal finding (figure 2).

Figure 2.

CT scan on arrival showing a large pericardial effusion.

In the intensive care unit (ICU) the patient was placed on mechanical ventilation. Circulation was dependent on vasopressor support with norepinephrine, and rewarming was initiated with an inflatable air cover (‘Bair-Hugger’, Arizant Healthcare, 3M, USA) along with empirical antibiotic treatment. A pericardial effusion of 900 mL was evacuated, but the need for vasopressor support to maintain a mean arterial pressure above 60 mm Hg was unchanged. After ICU admission, myoclonia and seizures were noticed, and an EEG showed status epilepticus, which was treated with a valproate loading dose followed by maintenance infusion.

Thyroid status revealed thyroid-stimulating hormone of 52.45 mIU/L (range 0.3–4.5), total triiodothyronine (T3) of <0.75 nmol/L (below detection limit) and total thyroxine (T4) of <14 nmol/L (below detection limit). Thyroid hormone binding capacity was slightly elevated. Thyroid peroxidase antibody was normal. Additional laboratory tests showed normal cardiac troponins, liver parameters, creatinine, C-reactive protein, leucocytes, p-ethanol, p-paracetamol, p-salicylate and p-glucose. Cerebrospinal fluid had elevated protein but was otherwise normal. Myoglobin and creatine kinase were unremarkably elevated to 773 µg/L and 7319 U/L, respectively.

Collectively, the findings supported the diagnosis of severe MC, classically manifesting with hypothermia, pericardial effusion, circulatory depression, deep coma and the described thyroid status as hallmark features. Treatment with 100 µg intravenous l-thyroxine (LT4) per day was initiated. No initial loading dose was given nor was l-triiodothyronine (LT3) treatment administered. In addition, intravenous hydrocortisone of 100 mg×3 per day was initiated. On resuming gastrointestinal function on day 7, treatment continued with 100 µg LT4 orally daily.

The condition improved over days to weeks. Seizure activity was registered clinically and on EEG intermittently from day 1 to day 6, after which the patient gradually regained consciousness. ECG voltage increased and the AV-block disappeared over days. The patient was discharged from the ICU to the ward on day 25. Profound lethargy persisted during the following weeks. Hormone treatment was titrated and she was slowly mobilised. Clinical improvement expectedly preceded biochemical normalisation as T3 and T4 did not reach normal levels until the end of the hospital stay. The classical clinical symptoms diminished and the patient's appearance normalised. The patient was discharged to her home after 45 days.

Discussion

MC is a well-known but rare endocrine emergency demanding prompt diagnosis and treatment. The diagnosis of MC is often delayed due to the rarity of the condition.

The symptomatology overlaps with other critical conditions that are more frequently encountered in the emergency room or ICU such as shock, sepsis, hypothermia, intoxication and stroke. Mortality rates of 80% have previously been reported, but have now declined.¹ However, the condition still carries an overall mortality of 25–60% even with prompt diagnosis and treatment.^2–5

Cardinal symptoms are central nervous system dysfunction, defective thermoregulation and cardiopulmonary decompensation. Typical laboratory findings are hyponatraemia, hypoglycaemia, hypocortisolism and low serum osmolality in addition to the changes in thyroid hormone status. Progression from severe hypothyroidism to MC is often precipitated by other conditions such as infection, gastrointestinal bleeding, cold exposure, trauma or anaesthesia.⁶ In many reported cases labelled MC, the patients were, paradoxically, not comatose, and actual coma is unusual even in severe hypothyroidism.⁷ Patients may present with an array of neurological symptoms such as headache, cranial nerve palsy, stupor, delirium, neuropathy, impaired cognition and reflex changes, and may display psychiatric symptoms.^{8 9} Spinal fluid protein is usually elevated, probably due to increased meningeal permeability and cerebral blood flow, and metabolism has been shown to be decreased.¹⁰

Coma at the time of presentation, and low GCS and higher APACHE II scores correlate with poorer outcome. Convulsions in MC have been described as a grave prognostic sign,⁶ and several reported cases with this complication were fatal.¹¹ We know of one previous report of a patient with MC and status epilepticus with favourable outcome.¹² The present patient presented with seizures and myoclonia on arrival in the ICU, which implies poor prognosis. The cause of generalised seizures in MC is unknown. It has been speculated to arise from oedematous expansion of intracerebral, extracellular fluid, possibly in connection with disturbed antidiuretic hormone secretion, hyponatraemia and hypoventilation.¹²

Cardiovascular symptoms, as present in this patient, include heart failure, pericardial effusion, bradycardia, ECG-changes such as AV-block, long QT-interval,¹³ T-wave changes, low voltage¹⁴ and cardiac ischaemia.¹⁵ In addition, decreased sympathetic activity, and decreased sensitivity to α-adrenergic and β-adrenergic stimulation, are present¹⁶ despite increased circulating catecholamines.¹⁷ This suggests some peripheral resistance to catecholamines in the hypothyroid state. These factors may explain the patient's poor initial response to and continuing need for vasopressors, and warrants cautious use of vasopressors and inotropes as thyroid hormones are replenished.

Long-standing controversy surrounds the optimal thyroid hormone treatment strategy for MC.^18–20

Most studies of treatment effects are small and case-based or retrospective in nature. Discussions of the treatment strategy pertain to whether LT4 alone, LT4 combined with LT3 or LT3 alone should be recommended and whether high or low doses, including a loading dose, should be used, and route of administration. T3 is more biologically active, onset of action is rapid and treatment does not depend on tissue 5′ deiodinases conversion of T4, which is impaired in hypothyroidism. T3 also more readily crosses the blood–brain barrier²¹ and could theoretically be preferred in comatose patients. However, the rapid onset of action may lead to cardiac instability, and treatment with LT3 is associated with increased amounts of cardiovascular events, arrhythmias and mortality.^{2 22} The sensitivity of the circulatory system to adrenergic stimulation rises before the increase in capacity to perform maximal work. This may explain the documented fatal outcomes stemming from myocardial infarction and circulatory failure. T4 is less biologically active and undergoes conversion to T3 in peripheral tissues. Peripheral conversion of T4 to T3 allows gradual T3 delivery to organs even with LT4 monotherapy. Intravenous and oral LT4 have both been suggested although oral administration carries risks of malabsorption as many patients have gastric atony or ileus. A retrospective analysis of 11 patients with MC, focusing on predictors of poor outcome, concluded that LT3 treatment should be avoided.²² Some authors conclude that younger patients with no cardiac disease can perhaps be treated with LT3 and higher LT4 loading doses, when given orally or via a nasogastric tube.² Oral treatment via nasogastric tube may be as efficacious as intravenous therapy if gastrointestinal function is intact.²⁰ Yamamoto et al² reviewed 87 cases of fatal MC investigating dosage regimens’ association with mortality and found that high-dose LT4 (>500 µg/day) and high-dose LT3 (>75 µg/day) were both associated with increased mortality, especially in elderly patients. The study also suggested better survival with low-dose LT4 treatment but concluded that low-dose LT4 or LT3 is safe and recommendable. Several authors recommend intravenous LT4 monotherapy^{23 24} but some reviews also suggest addition of LT3 in selected patients.^{20 25} Thus for elderly, fragile or cardiac unstable patients the use of intravenous LT4 as monotherapy is recommended. Some authors recommend administration of a loading bolus of intravenous LT4 of 200–500 µg, as this seems safe, bringing up circulating levels of T4 quickly and boosting peripheral T3-conversion. In one prospective study, this appeared to reduce mortality.³ In the present case, no LT3 and no bolus of LT4 was given because of the fragility of the patient, and due to the risk of cardiac complications. We administered 100 µg intravenous LT4 daily. As daily replacement dose for primary hypothyroidism is about 75–150 µg,^{23 26} our treatment regimen was intentionally conservative.

This report describes a case of severe MC complicated with status epilepticus. Previously, there have been very few reports describing a favourable outcome. After 1.5 months of LT4 monotherapy treatment, in combination with supportive measures, the patient was discharged with no sequelae. MC with status epilepticus is a serious and rare combination that should be recognised by healthcare providers to ensure prompt diagnosis and treatment.

Learning points.

• Myxoedema coma is a rare but treatable endocrine emergency and must be considered as a differential diagnosis, when relevant, as symptoms overlap with other more common critical conditions.

• Treatment may be successful with intravenous l-thyroxine monotherapy.

• There are extremely few previous reports of myxoedema coma with complicating status epilepticus describing a favourable outcome.