Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes unveiled by valproate
A 12-year-old boy presented with headache, vomitings, and seizures of two weeks duration. The headaches were predominantly left-sided, severe, throbbing, associated with vomiting, lasting each time for 1-2 hours, and recurring 2-3 times in a day. There was no postural or diurnal variation of the headaches nor any associated fever, neck pain, visual symptoms, or focal neurological deficit. On second day of the onset of headache, he had three episodes of GTCS. He presented to us almost two weeks into the illness wherein the seizures did not recur, but the headache persisted. He was started on Sodium Valproate 400 mg/day, but within two days of starting treatment, he experienced worsening of headache, repeated bouts of vomiting, and recurrence of seizures. The child became very dull and lethargic. He also developed certain new symptoms in form of pain and weakness in lower limbs, with difficulty in getting up from squatting position, and requiring one person support for walking. There was no history of any difficulty in gripping or slippage of slippers, any weakness in upper limbs, sensory loss, limb incoordination, bladder bowel or cranial nerve involvement.\nHis general physical and systemic examination was unremarkable; in particular, there was no fever, jaundice, abdominal tenderness, or any organomegaly. The child was conscious, oriented to time, place and person but very lethargic and irritable. There were no signs of meningeal irritation. On motor system examination, muscle tone and nutrition was normal. There was tenderness over muscles of arms and thighs, and he did not allow formal testing of muscle power, though he was moving all limbs equally in bed. Deep tendon reflexes were normally elicitable, and planters were bilaterally flexors. Sensory examination was normal, and there were no cerebellar signs.\nHis routine investigations including hemogram, complete blood count, renal function tests, and serum electrolytes were normal. There was a worsening of liver functions as well as a rise in LDH and CPK levels after starting Valproate []. His serum lactate was 16.7 mg/dl (normal range 8-16 mg/dl). Viral markers including HIV, HBsAg, and anti-HCV all were all negative.\nHis X-ray chest, USG abdomen, 2D-Echo all were normal. MRI brain revealed an acute infarct in left occipito-temporal region and an old infarct in right occipito-temporal area [Figure -] with normal MR angiogram and MR venogram [Figure and ]. A possibility of valproate-induced myositis and hepatotoxicity were considered with probability of an underlying mitochondrial disorder, likely MELAS.\nValproate was stopped, and patient was loaded with intravenous Levetiracetam 1000 mg and continued on maintenance dose of 500 mg twice-daily. He started improving within 24 hours, became more active, pain and weakness in limbs decreased and abated completely over the next five days. There was no recurrence of seizures. The laboratory parameters also improved subsequently after stopping valproate [].\nMuscle biopsy from vastus lateralis revealed maintained fascicular architecture with minimal variation of fiber size. Intermyseal and perimyseal connective tissue was unremarkable. NADH and SDH stain revealed normal fiber typing and myofibrillar architecture. No ragged red fibers were identified on Gomori trichrome stain. After two weeks of hospital stay, he was discharged on Levetiracetam (500 mg twice-daily), CoQ10 (30 mg twice-daily), Levocarnitine 330 mg twice-daily), and cocktail of multivitamins (B complex including B1, B2, B12, folate, niacin, biotin, pyridoxine; vitamin A, vitamin C, along with iron, zinc, magnesium, chromium, selenium, L-methionine, L-arginine).