Recurrent Seizures in an Adolescent Female-A Daunting Puzzle

Introduction

Acute intermittent porphyria (AIP) is presented with vague abdominal and neuropsychiatric manifestations. Although these symptoms can be easily recognized in retrospect, the diagnosis continues to be a great challenge, requiring a strong index of suspicion.[1] We describe a patient who presented with recurrent abdominal pain and seizures, in association with hyponatremia and hypokalemia, eventually diagnosed to have AIP secondary to hydroxymethylbilane synthase deficiency.

Case Description

A 15-year-old female presented to our emergency department with four episodes of generalized tonic-clonic seizures over the past 24 h. On examination, she was pale and drowsy, but devoid of any focal motor deficit. Her blood pressure was 130/80 mm Hg, pulse rate was 108/min, temperature was 36.8 degree Celsius, and random blood sugar level was 112 mg/dL. Two months prior to presenting to us, she started experiencing recurrent episodes of vague abdominal pain, which would last for several minutes to hours and resolve spontaneously. Two weeks earlier, she had a similar episode associated with acute urinary retention, for which she was treated with injection furosemide, injection amikacin, injection pantoprazole, and laxative elsewhere.

Evaluation in our hospital revealed anemia with hemoglobin of 9.2 g%, total white blood count of 10,300 cells/cu.mm, differential count showing 85% polymorphs, 13% lymphocytes, 2% eosinophils, and platelet count of 3.12 lakh cells/cu.mm. Peripheral smear study revealed normochromic normocytic anemia. Urinalysis was unremarkable. Her blood urea was 17 mg/dL and serum creatinine-1.1 mg/dL. Serum electrolytes showed presence of hyponatremia (Sodium = 103 mEq/dL) and hypokalemia (Potassium = 3.0 mEq/dL). Her magnesium was 3.9 mg/dL and phosphorus was 4.1 mg/dL. Initial computed tomography imaging of the brain was unremarkable.

She was euvolemic, and in view of acute severe symptomatic hyponatremia and hypokalemia, she was treated with intravenous 3% saline and potassium infusion. She was also initiated on intravenous phenytoin at a loading dose of 15 mg/kg followed by maintenance dose of 100 mg thrice a day for seizures. After 3 days of treatment, she recovered without any neurological deficit and her sodium and potassium levels gradually became normal.

Two days later, she developed status epilepticus again. Her electrolytes revealed sodium of 111 mEq/dL and potassium of 2.3 mEq/dL. She was again initiated on intravenous 3% saline and potassium supplements. She recovered without any neurological deficit. Her repeat urinalysis was normal.

Magnetic resonance imaging of the brain showed T2 fluid attenuated inversion recovery (FLAIR) hyperintensity in the right frontal lobe and subcortical U-fibers, in which case, the differentials thought of were posterior reversible encephalopathy, extra pontine myelinolysis, and post-ictal changes. However, in the absence of an acute rise in blood pressure and renal failure, posterior reversible encephalopathy was unlikely.

She was clinically euvolemic. Hyponatremia evaluation revealed serum sodium of 111 mEq/dL, serum osmolality of 244 mOsm/kg, urine osmolality of 440 mOsm/kg, urine sodium of 88 mEq/dL, serum uric acid of 2.8 mg/dL, serum creatinine of 0.9 mg/dL, serum cortisol of 15 mg/dL, and thyroid-stimulating hormone of 3.5 mIU/L. She was not on any diuretics. Hence, a diagnosis of syndrome of inappropriate anti-diuretic hormone (ADH) secretion was entertained. On evaluation, there was no evidence of any infection, organic neurological disorders, or malignancy. She was not on any antipsychotic therapy.

During the hospital stay, she continued to have muscle cramps with severe spasmodic episodes of abdominal pain, which now subsided on treatment with opioids. Ultrasonogram of the abdomen revealed sludge in the gall bladder, normal-sized kidneys, normal pelvicalyceal system, and a normal urinary bladder. Computed tomography of the abdomen revealed multiple tiny gall stones. Serum Amylase (275.9 U/L) and lipase (486.4 U/L) were elevated. During this episode of acute abdomen, her urine was noticed to have a reddish hue, which did not further change color on standing. Repeat urinalysis did not show any active sediments.

For the management of symptomatic gallstones, laparoscopic cholecystectomy was contemplated. Meanwhile, she again presented with acute abdominal pain and was treated with opioids. During this episode, her urine was noticed to be of port-wine color, which aroused a strong suspicion of porphyria. Hence we proceeded with the screening test for porphyria, i.e, the Watson Schwartz method which turned out to be positive [Figures 1 and 2] Also examination under ultraviolet lamp showed pink fluorescence at 410 nm. A 24-h urinary assay for porphobilinogen (PBG) and aminolevulinic acid (ALA) was done and they turned out to be normal, probably because it was done after the acute episode had subsided. However, with a strong suspicion of porphyria, analysis of the hydroxymethybilane synthase (HMBS) gene encoding HMBS was done using targeted next-generation sequencing. It revealed a heterozygous missense variant in exon 13 of the HMBS gene on chromosome 11 that resulted in the amino acid substitution of arginine for glycine at codon 280 (chr11:g. 118963657G>A; Depth of coverage: 60×) (p.Gly280Arg; ENST00000278715.3). The observed variant lies in the porphobilinogen deaminase and C-terminal domain of the HMBS protein and has previously been reported in a patient affected with acute intermittent porphyria, thus confirming the diagnosis in our patient.[2] She was started on intravenous glucose following which she became better. Anticonvulsants were stopped. She was advised high carbohydrate diet with added salt, lifelong. She is currently doing well and is on an OPD basis follow-ups.

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Figure 1

On addition of 1 ml of Ehrlich reagent (4-dimethylaminobenzaldehyde) to 1 ml of urine produces port wine color in patient's urine containing PBG

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Figure 2

Chloroform is added to the test tubes, mixed well and allowed to settle. Two immiscible layers are formed; with chloroform being heavier, sinks to the bottom and urine being aqueous, stays on top with red color

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Discussion

AIP is an autosomal dominant disorder occurring due to partial deficiency of PBG deaminase activity (also, called hydroxymethyl bilane synthase). The first case of porphyria probably sulphonal induced was described by Stokvis in the year 1889.[3] The prevalence of HMBS gene variants in the general population is 1/1675, which might be an underestimation in view of non-specific clinical symptoms and the diagnosis requires a strong index of suspicion by the clinicians.[4] HMBS deficiency leads to accumulation of porphyrin precursors, such as 5-ALA and PBG, which tends to increase greatly in conditions where heme synthesis in liver is upregulated, such as calorie restriction, infection, menstrual cycle, and also due to cytochrome P450 enzyme inducers. The acute episode of AIP is characterized by the neurovisceral attack, which is characterized by intermittent severe abdominal pain, nausea, vomiting, constipation or diarrhea, urinary retention or Incontinence, hypertension, tachycardia, and complicated by neuropsychiatric manifestations such as agitation, confusion, peripheral neuropathy, and coma. Typically, AIP crises occur frequently in post-pubertal females.[5] Hence, under normal circumstances, the enzyme deficiency does not result in crises. Acute diffuse abdominal pain, which does not respond to typical analgesics, but in turn, which may worsen, is the earliest and one of the most characteristic symptom. Notably, hyponatremia is the most common electrolyte disturbance that occurs secondary to gastrointestinal loss, less intake, renal loss, and inappropriate secretion of ADH.[6] Patients may present with symptoms of peripheral neuropathy, whereas the most severe CNS impairment may lead to seizures, respiratory failure, and death. Psychiatric findings include delirium, psychosis, hysteria, anxiety, apathy or depression, and sometimes coma.[7].

Conclusion

AIP should be considered in the differential diagnosis in patients presenting with non-specific abdominal and neuropsychiatric symptoms. Prevention of triggering factors plays a key role in the management of AIP, along with measures to prevent the accumulation of porphyrin precursors.