Paroxysmal events in a 37-year-old man with PLPHP deficiency

Multiple events were recorded during two different hospitalizations when he was 37 years old. "The semiology of the events was relatively stereotyped and consisted of dystonic facial grimacing, posturing of the upper arms, eye blinking, hand automatisms, and hyperkinetic behavior without a clear loss of contact." Scalp EEG recordings did not reveal any associated ictal abnormalities during these events, nor any change in the background, despite over 50 events per day. His interictal EEG was normal. This patient had presented initially at the age of 2 weeks with frequent clusters of brief flexion spasms lasting between 15 minutes to 2 hours, associated with apnea and worsening lethargy. An EEG at that time revealed background slowing and multifocal epileptic abnormalities. The events were considered epileptic but were unresponsive to nitrazepam, phenytoin, and prednisolone. Administration of intravenous pyridoxine resulted in cessation of the spasms and EEG normalization. He was diagnosed with presumed pyridoxine-dependent epilepsy and was prescribed pyridoxine supplementation combined with multiple antiepileptic medications. He continued to have clusters of events, lasting from 15 to 18 hours and requiring hospitalization, usually triggered by fatigue or stress, but EEGs during these events were uniformly normal. He gained early developmental milestones appropriately and has average intelligence. Neurologic examinations consistently documented nystagmus, dysarthria, clumsiness, truncal titubation, dysmetria, tremors, mild gait unsteadiness, and difficulty performing tandem gait. Because of the incomplete response to pyridoxine, normal EEGs, uncertainty in diagnosis, and concern of acquiring a neuropathy associated with high-dose pyridoxine treatment, pyridoxine was gradually weaned off over 2 years, beginning at the age of 35. One month after complete pyridoxine cessation, his clinical status rapidly deteriorated: (1) he developed episodes of paroxysmal dizziness, nausea, and vomiting, occurring eight times daily; (2) he lost 40 pounds over 3 weeks; and (3) his regular paroxysmal episodes increased to over 50 per day. He was hospitalized and treated as probable status epilepticus, but there was no response to intravenous antiepileptic medications. His paroxysmal events had long been considered epileptic, but the absence of any change in the EEG background, despite over 50 events per day on telemetry during the patient’s admission, is extremely unusual and considered inconsistent with epilepsy. Given the in-hospital video-EEG recordings, the possibility of a B6-responsive movement disorder is now strongly suspected by his neurologists, although epileptic seizures lacking scalp EEG correlation cannot be fully excluded. The patient carries two rare compound heterozygous variants in PLPBP (MIM ∗ 604436, NM_007198.3): a truncating frameshift variant c.370_373delGACA [p. Asp124LysfsX2] and a missense variant c.704 T>G [p.Val235Gly]). (Source: Alsubhi S, Osterman B, Chrestian N, Dubeau F, Buhas D, Srour M. Case report: PLPHP deficiency, a rare but important cause of B6-responsive disorders: a report of three novel individuals and review of 51 cases. Front Neurol 2022;13:913652. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)