Valproate-induced Hyperammonemic Encephalopathy Presenting as Catatonia Rodrigo Pérez-Esparza, MD, MSc,*† Nelcy Oñate-Cadena, MD,* Jesús Ramírez-Bermúdez, MD, PhD,* and Mariana Espínola-Nadurille, MD, MSc* Abstract: Hyperammonemic encephalopathy secondary to the use of valproate is rare without evidence of hepatotoxicity, and it usually presents with confusion, agitation, irritability, cognitive disturbances, lethargy, coma, and death. We present the case of a 21-year-old woman presenting with catatonia as a manifestation of hyperammonemic encephalopathy that resolved with the normalization of ammonia and suspension of valproate. Key Words: hyperammonemia, catatonia, valproate, valproic acid, encephalopathy (The Neurologist 2018;23:51–52) C atatonia is a recognized motor dysregulation syndrome with signs and symptoms that include mutism, negativism, pos- turing, rigidity, staring, repetitive movements, and automatic obedience, among others. 1 Complications, regardless of the etiol- ogy, may be present in up to 85.7% of the patients, and include delirium, urinary tract infections, and pneumonia, which are associated with extended hospital stays and a worse prognosis. 2 Although originally recognized as a clinical manifestation of schizophrenia, it is now well-known that different medical and psychiatric conditions may present with this syndrome. 2,3 Among these, epilepsy has been repeatedly reported as a cause. 4 Also, several drugs have been implicated in the development of cata- tonia, including antipsychotics, antidepressants, steroids, 5 and antiepileptics. 6 Specifically, valproate-induced catatonia has been described during the treatment of schizoaffective disorder when initiated, in the presence of selective serotonin reuptake inhibitors and antipsychotics, and regardless of ammonemia. 7 We present the case of a woman with a personal history of epilepsy and intellectual disability who developed catatonia secondary to valproate-induced hyperammonemia. This case is mentioned in a previously reported case series of catatonia by our group. 2 CASE REPORT A 21-year-old woman presented to follow-up consultation with a 2-month progressive onset of rigidity, immobility, and negativism. She had a personal history of perinatal hypoxia, structural epilepsy, as well as intellectual disability. She was being treated for epilepsy with val- proate 800 mg (which she was taking since childhood) and clobazam 10 mg daily, and for behavioral symptoms with fluoxetine 20 mg and risperidone 2 mg daily (which she had been taking for over 3 y). She had a pattern of focal cognitive seizures, but had been seizure-free for 2 years upon arrival. After performing a neuropsychiatric examination, reported catatonic signs were confirmed along with echopraxia and catalepsy. A diagnosis of catatonia was made with a Bush-Francis Catatonia Rating Scale (BFCRS) score of 8 items for screening and a score of 19 for severity. She was initially treated as an out-patient with lorazepam which was titrated up to 6 mg daily without any response. She was admitted to the Neuropsychiatry Department for etiological diagnosis of the catatonic syndrome and treatment adjustment. Risper- idone and fluoxetine were suspended, and lorazepam was titrated up to 10 mg daily without response. Valproate blood levels were at 64.3 μg/mL, and ammonemia was at 421.63 μg/dL. Liver tests, creatine phosphokinase, and other blood tests were normal. Electroencephalography revealed a diffuse theta base-activity of 4 to 5 Hz, without epileptic activity or other focal abnormalities. Brain magnetic resonance imaging was performed and revealed a diffuse polimicrogyric pattern, white matter hypotrophy and a diminished callosal body, suggestive of brain dysgenesia. Possitron- emission tomography did not show focal abnormalities. Hyperammonemia was suspected to be the cause of catatonia. Valproate was gradually suspended and replaced with phenytoin 300 mg daily. Other measures to lower ammonemia were initiated, including L-carnitine 3 g daily, and neomicine 750 mg daily. Five days later, catatonic symptoms gradually responded, with a BFCRS score of 4 for screening and 8 for severity (staring, mutism, negativism, rigidity), and ammonemia was at 2.08 μg/dL. After phenytoin was initiated, she developed mild leukopenia and hypertransaminasemia which were considered as adverse effects after assessment by a trained Hematolo- gist. Phenytoin was withdrawn, and treatment with lorazepam and clobazam continued at 10 mg daily. She continued to show response until catatonia remitted and she was discharged. During a 6-month follow-up, lorazepam was tapered down until it was suspended, and she remained seizure and symptom-free with clo- bazam monotherapy, returning to her previous functionality at home. DISCUSSION To our knowledge, this is the first reported case of catatonia secondary to valproate-induced hyperammonemic encephalopathy with this chronic antiepileptic treatment. Unlike other reports of catatonia in patients with epilepsy, 4 the presentation of the syndrome in the patient described had no relation to seizures, modification of treatment, or psychosis. There was a probable cause-effect relationship between the presentation of catatonic signs and symptoms and hyperammonemia, as well as resolution after valproate was suspended and ammonia levels decreased. Valproate-induced hyperammonemia is rare without evidence of hepatotoxicity, and it usually presents as encephalopathy with confusion, agitation, irritability, cognitive disturbances, lethargy, coma, and death. 8,9 Ammonia crosses the blood-brain barrier, increasing glutamine levels, and inhibiting glutamate uptake, lead- ing to excessive glutamate receptor activity. 8 Glutamatergic and GABAergic dysfunction have been linked to the patophysiology of catatonia, 10 and therefore the dysregulation of these systems by ammonia may be responsible for the patient ’s clinical presentation. From the *Department of Neuropsychiatry, National Institute of Neurology and Neurosurgery; and †Addiction Research Laboratory, National Institute of Neurology and Neurosurgery, Mexico City, Mexico. The authors declare no conflict of interest. Reprints: Rodrigo Pérez-Esparza, MD, MSc, Addiction Research Laboratory, National Institute of Neurology and Neurosurgery, Insurgentes Sur 3877, La Fama, Tlalpan, Mexico City 14269, Mexico. E-mail: dr.rodrigope@ gmail.com. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1074-7931/18/2302-0051 DOI: 10.1097/NRL.0000000000000166 CASE REPORT/CASE SERIES The Neurologist  Volume 23, Number 2, March 2018 www.theneurologist.org | 51 Copyright r 2018 Wolters Kluwer Health, Inc. All rights reserved.