Valproate-Induced Nonhyperammonemic Encephalopathy with Electroencephalogram Background Slowing and Triphasic Waves

Dear Editor, Valproic acid (VPA) is a broad-spectrum anti-seizure medication (ASM) that is being used in epilepsy patients with generalized and less frequently focal seizures. It is also commonly utilized by psychiatrists for mood stabilization. Physicians are aware of its common side effects such as weight gain, tremors, disturbed liver function tests, and thrombocytopenia. Rarely, it has also been reported to cause encephalopathy which is usually characterized by acute onset of impaired consciousness, increased seizures, and focal neurological symptoms.[1] Patients may also present with abnormal behavior, ataxia, sensory disorders, visual impairment, catatonia, and status epilepticus.[1] Valproate-induced encephalopathy (VIE) is reported to have an incidence of 0.1%–2.5%.[1] It usually has a temporal relationship with VPA initiation or increment of its dose. Diagnosis of VIE in the presence of normal ammonia levels is difficult and challenging leading to misdiagnosis and unnecessary laboratory investigations. To the best of our knowledge, only three cases of VIE with normal ammonia levels have been reported so far.[2–4] Herein, we present a similar case aiming to increase the awareness of physicians about VIE with normal liver function tests, VPA, and ammonia levels. A 63-year-old female patient developed myoclonic jerks in her left arm 2 months ago. She also reported a tonic–clonic seizure of unknown onset. Electroencephalogram (EEG) revealed multifocal epileptiform discharges. She was already on lamotrigine (100 mg/day) and valproic acid (VPA, 1000 mg/day) treatment and, therefore, had not been prescribed additional ASMs. She also received 300 mg quetiapine twice a day for control of her schizoaffective disorder. Other medical comorbidities were hypertension, type 2 diabetes mellitus, and primary hypothyroidism for which she took 150-μg levothyroxine and 10-mg perindopril daily. Family history was unremarkable. During her follow-up, she developed an acute alteration of behavior and agitation that was clinically compatible with delirium. There was no history of fever, headache, nausea-vomiting, or seizure exacerbation. The doses of her current medications were stable, and she had not received any other new drugs. Her vital signs were within normal limits and her physical examination was unremarkable. On neurologic examination, she was drowsy and disoriented providing inappropriate answers to questions. There was no meaningful verbal output. She stared and cried when she was asked questions. There were no focal neurologic deficits or signs of meningeal irritation. She remained confused over the next 2 days. Extensive work-up including complete blood count, liver function tests, kidney function tests, blood sugar, thyroid function tests, routine urine examination, venous blood gas analysis, and blood and urine culture tests were normal, as well as her electrocardiogram and chest X-ray. Cranial magnetic resonance imaging was unremarkable. However, routine EEG showed diffuse slowing of the background with scattered triphasic waves suggesting toxic-metabolic encephalopathy [Figure 1a]. Her serum VPA level was 55, 24 (50–100 mg/L), and her serum ammonia level was 39, 9 (20–120 μg/dl). Despite the normal level of these parameters, a VIE was suspected. Her Naranjo’s Adverse Drug Reaction Probability Score was 7. Valproate was discontinued, and no other medications were started. She improved rapidly within 2 days, and her control EEG was within normal limits [Figure 1b]. She remained clinically stable on follow-up.Figure 1: Moderate EEG background slowing characterized by theta-delta waves and scattered triphasic waves (a), control EEG reveals 8 Hz posterior dominant alpha activity (b). EEG: ElectroencephalogramRisk factors for VIE include concomitant use of other drugs (e.g., phenobarbital (PHB), phenytoin (DPH), levetiracetam (LEV), topiramate (TPM)), ornithine transcarbamylase deficiency, younger age, and dose and serum level of VPA.[1] Diagnosis is made on the clinical grounds. High blood levels of ammonia and low levels of carnitine are suggestive. Liver function tests and VPA dose or level may be normal. Very rarely, even ammonia levels may be within normal limits.[2–4] Different mechanisms have been proposed for VIE, namely hyperammonemia, L-carnitine deficiency, and urea cycle enzyme dysfunction.[1] There may as well be genetic predisposition to VIE or mitochondrial DNA abnormalities.[1] It has been claimed that other compounds including toxic metabolites of VPA or other organic acids may be responsible for encephalopathy, in patients with normal ammonia. Interestingly, it has also been proposed that brain ammonia concentration can be high even though the serum ammonia level is normal.[5] Our patient did not have symptoms of urea cycle disorders, so we did not ask for further laboratory tests. She also received quetiapine which may have contributed to the development of VIE. It has been reported that the addition of quetiapine to VPA in two patients with acute mania led to the development of delirium.[6] Hence, a drug–drug interaction may have led to the development of delirium in our patient, however, she had been taking these drugs for years. Interestingly, VIE has also been reported to occur with chronic exposure.[5] It can be speculated that at some point, her carnitine may have decreased to symptomatic levels, rapidly turning back to normal levels after discontinuation of VPA. Unfortunately, we were unable to look at serum carnitine levels due to technical reasons. At this point, the reason why our patient developed VIE remains enigmatic. EEG in patients with hyperammonemic VIE can be normal or indicate the presence of triphasic waves, generalized slowing, frontal intermittent rhythmic delta activity, or status epilepticus.[1,7] In the three patients with nonhyperammonemic VIE, EEG showed background slowing only. In our case, EEG was very helpful as it demonstrated the presence of background slowing together with triphasic waves suggesting toxic-metabolic encephalopathy. The primary treatment of VIE is the withdrawal of VPA. The time of symptom resolution is different among patients although most of them recover within a few days. L-carnitine supplementation may also be recommended. Hemodialysis may be applied in severe cases. In summary, VPA may induce encephalopathy or delirium even with chronic exposure. The dose and serum level of VPA, liver function tests, and blood ammonia level may be normal. EEG may show changes compatible with toxic-metabolic encephalopathies. Withdrawal of VPA leads to prompt improvement of symptoms. A high index of suspicion and awareness of nonhyperammonemic encephalopathy are needed for correct diagnosis in such patients. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.