Posterior reversible encephalopathy syndrome due to hypercalcaemia: a rare cause

Abstract

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological entity described by Hinchey et al in late 90’s, characterised by variable associations of seizure activity, consciousness impairment ranging from confusion to coma, headaches, visual abnormalities, nausea/vomiting and focal neurological signs. Common causes are accelerated hypertension, eclampsia, preeclampsia, cytotoxic drug use and autoimmune diseases like systemic lupus erythematosus.

We report a case of PRES in a 62-year-old female patient due to hypercalcemia secondary to vitamin D toxicity on treatment with calcium supplements and vitamin D for secondary hypoparathyroidism. She had seizures and visual defects on presentation which recovered completely with treatment of hypercalcemia.

Background

Posterior reversible encephalopathy syndrome (PRES) is a neurological symptom complex usually secondary to malignant hypertension, endothelial injury due to cytotoxic drugs like cyclophosphamide and autoimmune condition, reversible with prompt recognition and early treatment. Blood pressure reduction to 160/100 mmHg or mean arterial pressure reduction by 25% within 6 hours should be achieved with oral or intravenous drugs in cases associated with severe hypertension. Hypercalcemia is a rare cause of PRES.

Serum calcium fluctuations are common in patients with secondary hypoparathyroidism. Regular follow-up of serum calcium is must for patients on active vitamin D and calcium supplementation as both hypo and hypercalcemia can lead to life threatening complications.

Case presentation

A 62-year-old woman diagnosed case of secondary hypoparathyroidism, post thyroidectomy for papillary carcinoma thyroid was diagnosed with severe hypocalcemia following medication discontinuation. She was treated with injectable calcium gluconate, oral calcium carbonate 4 gm/day and active vitamin D 0.5 mcg/day. The dosage of active vitamin D was gradually increased to 1 mcg/day with serial monitoring of serum calcium. Her serum calcium rose from 5.8 mg/dL to 7.2 mg/dL (normal range 8.8–10.3 mg/dL). The patient was advised to follow-up weekly on outpatient basis for dose modification. However patient was lost to follow-up.

A month later she presented to emergency room with history of an episode of generalised seizure followed by altered sensorium. Her blood pressure was 160/90 mmHg. She was irritable and had paucity of movements of left upper and lower limbs with positive Babinski sign. Patient was treated adequately with antiepileptic drug and there was no recurrence of seizure. A non-contrast CT scan of brain was normal.

Investigations

Her labs showed serum calcium of 18.3 mg/dL, blood urea and serum creatinine were 98 mg/dL (normal range 15–40 mg/dL) and 1.6 mg/dL (normal range 0.7–1.3 mg/dL) respectively. QTc interval was 325 ms. An MRI of brain done to exclude cerebrovascular accident and cerebral infarction showed T2 fluid attenuated inversion recovery (FLAIR) hyper intensities in bilateral occipital lobes and left frontal lobe without diffusion restriction s/o PRES as in figures 1 and 2.

Figure 1.

MRI brain showing T2 FLAIR hyperintensities in left frontal cortex and bilateral occipital cortex.

Figure 2.

MRI brain showing T2 FLAIR hyperintensities in bilateral occipital cortex.

Differential diagnosis

Stroke—intracranial haemorrhage was considered in view of sudden onset of symptoms with hypertension, was ruled out as non-contrast CT brain was normal.

Metabolic seizures due to sodium abnormalities and hypoglycaemia were conclusively ruled out at presentation.

Treatment

She was hydrated with intravenous normal saline. Her serum calcium reduced to13.5 mg/dL and 10.1 mg/dL on subsequent days. Blood pressure was controlled with tablet amlodipine 2.5 mg/day. She regained normal sensorium on day 4 of illness, when serum calcium was 9.8 mg/dL. Her visual defects improved by day 7. Renal parameters normalised with hydration to blood urea of 34 mg/dL and serum creatinine of 1.2 mg/dL. When serum calcium dropped to 8.1 mg/dL, she was restarted on tablet rocaltrol 0.25 mcg/day and tablet calcium carbonate 500 mg thrice a day.

Outcome and follow-up

Visual complaints completely recovered, she had no neurological deficits on discharge. The patient is on regular follow-up and doing well.

Discussion

PRES is an acute encephalopathy characterised by diverse neurological symptoms, including headaches, seizures, focal neurological deficits and visual disturbances with typical symmetric hyper intense changes in posterior circulation areas of brain on T2 and FLAIR MRI sequence. Various risk factors, such as severe hypertension, eclampsia and exposure to immunosuppressant medication like cyclophosphamide are well known.^1–4 However, the occurrence of PRES associated with hypercalcemia is a rare phenomenon.⁵

Clinical presentation most commonly present are secondary generalised seizures (70%–90%), conscious impairment (13%–90%), visual disturbances (4%–60%), headache (25%–50%) and acute hypertension (65%–80%) as described in various case series. Less commonly status epilepticus and focal neurological deficits may be seen at presentation.^1–9 Although our patient presented with all of above mentioned complaints headache, altered consciousness and rarely convulsions may be attributed to severe hypercalcemia.¹⁰

Typically, diagnosis is based on imaging. A high index of suspicion prompts early imaging. CT of brain is usually unyielding at the time of presentation, although follow-up CT may demonstrate hypodense lesions after 48 hours. MRI brain is more sensitive investigation, typically showing symmetric hyperintense lesions on T2 and FLAIR sequences without diffusion restriction, predominantly in the posterior occipital and parietal lobes of the brain although basal ganglia, frontal and temporal lobes and asymmetric involvement are described.⁸

PRES is characterised by vasogenic oedema predominantly in posterior circulation. The mechanism to explain this are poorly understood. One proposed theory is loss of cerebral autoregulation in response to sudden hypertension leading to vasospasm, increased capillary filtration and oedema. In a study by Fugate et al, mean systolic and diastolic blood pressures were 190 and 104 mmHg, with more than 50% patients having new onset hypertension, whereas blood pressure in our patient was 160/90 mmHg. The rate of rise in blood pressure was more important than absolute value.³ Another theory is that of endothelial dysfunction resulting in oedema predominantly seen with cytotoxic drugs, toxins and sepsis. Although hypercalcemia triggered vasospasm due to increased actin-myosin coupling is thought to be the main mechanism behind hypercalcemia induced PRES, MRI brain in few cases was also s/o combined vasogenic and cytotoxic oedema.^11–13 Another study by Niellsen et al showed endothelial dysfunction and systolic blood pressure rise were observed in healthy volunteers following infusion of calcium.¹⁴ It is likely that a combination of these proposed theories may lead to PRES in hypercalcemia. Our patient had new onset hypertension, severe hypercalcemia and acute kidney injury on presentation.

Treatment of PRES is mainly removal of inciting agent and blood pressure reduction acutely by 20%–25%. Hypercalcemia treatment depends on degree of calcium elevation. The mainstay of treatment is hydration with normal saline at the rate of 2–4 L/day followed by loop diuretics after adequate volume replenishment. Intravenous bisphosphonates are given when mechanism of hypercalcemia is due to osteoclastic bone resorption.¹⁵ Hypercalcemia due to vitamin D toxicity is reversible with withdrawal of drug as half-life of active vitamin D is 24 hours. Our patient was managed with aggressive hydration with normal saline and withdrawal of calcium and vitamin D supplements. Serum calcium decreased to normal and sensorium normalised.

Learning points.

• Secondary hypoparathyroidism patients need lifelong calcium and vitamin D supplementation.

• Regular follow-up of serum calcium levels are important to avoid under and over treatment related problems.

• Early recognition and correction of inciting factors will lead to complete recovery of neurological symptoms of Posterior reversible encephalopathy syndrome (PRES).