4-Aminopyridine (4-AP) is indicated for the improvement of walking speed and motor fatigue in multiple sclerosis (MS). An overdose in 4-AP can produce detrimental side effects. In the majority of cases, overdose is accidental and related to an error in the compounding of the drug [
A 58-year-old woman with a medical history of secondary progressive MS was admitted to the emergency department (ED) for convulsive status epilepticus. Before admission, the Kurtzke Expanded Disability Status Score (EDSS) was 6.5/10. The patient was treated by 4-AP (10 mg orally, bid) for more than 3 years, without previous adverse effects. In addition, she was also receiving baclofen (10 mg bid), levothyroxine 50
A few minutes after the ingestion of a single pill of 4-AP, she started to complain from severe abdominal pain. The pill came from a new box of a pharmacy preparation that was supposed to contain 10 mg of 4-aminopyridine per pill. Less than one hour after the ingestion, she developed rigidity, ocular revulsion, alteration of consciousness, and finally generalized tonic-clonic seizures. The first medical rescue team administered intravenous diazepam before hospital admission. On arrival in the ED, the patient had a Glasgow Coma Scale (GCS) score of 9 (E1V4M4). After recurrence of generalized tonic-clonic seizures, she received 2 mg lorazepam and 2 mg midalozam as intravenous bolus and a loading dose of 1200 mg valproic acid intravenously. Orotracheal intubation was required for mechanical ventilation. Sedation was obtained by continuous infusion of midazolam (5 mg/h) and propofol (100 mg/h). In the intensive care unit (ICU), after the regression of the effects of the neuromuscular blocking agent used for intubation, no hypertonia was observed. However, facial myoclonus rapidly reappeared. Antiepileptic therapy included a continuous intravenous infusion of valproic acid (1 mg/kg/h) together with levetiracetam (750 mg orally, bid). This resulted in the complete disappearance of any myoclonic or epileptic activity. Routine laboratory investigations were not relevant. Toxicological screening performed after ICU admission failed to reveal the presence of other substances than the patient’s usual medications; there was no evidence for baclofen overdose. Brain magnetic resonance imaging (MRI) was similar to that obtained a few months before and confirmed the stability of the lesions related to MS. Double inversion recovery sequence imaging demonstrated the presence of intracortical demyelinating lesions in the insula and left parietal cortex. The patient was monitored in the ICU by continuous electroencephalographic (EEG) recording. The first EEG recording, performed upon admission to the ICU 12 hours after initial symptoms, showed generalized slowing at 6-7 cycles per second with abundant irregular spike- and polyspike-waves on the left frontocentral regions (Figure
EEG recordings performed upon admission of the patient to the ICU (a) and at day 8 (b). (a) EEG traces show continuous epileptiform spikes and spike-waves at 2 Hz on the left frontocentral regions on a generalized slowed background intermixed with medicamentous beta waves. (b) EEG shows irregular short bursts of slow spikes and delta waves on the left frontocentrotemporal regions. Background activity at day 8 still shows diffuse beta waves, of medicamentous origin.
Sedative drugs (midazolam 6 mg/h and propofol 200 mg/h) were maintained for 5 days for prevention of recurrent seizures. From day 1 to day 6, the GCS never exceeded 7 (E2V1M4). Starting from day 7, the patient was able to open the eyes spontaneously, but there was no interaction with the environment and no response to verbal command. On day 8, the patient was able to move spontaneously the four limbs. On day 11, she had a clear motor response (M6) to verbal command. Extubation was possible on day 12. She presented a painful dysphonia due to right vocal cord paresis. She had difficulties in understanding complex commands and remained confused. The patient developed left basal pneumonia as a late complication in the ICU. She was transferred to the neurology department on day 13. In addition to the altered cognitive state, the patient’s neurological examination showed marked left predominant spastic paraparesis. Walking was impossible. The patient presented urinary retention and dysphagia. Cognitive testing revealed memory, executive, language, attentional, and visual-spatial difficulties. The EDSS was 8.5/10. EEG performed on day 22 showed a restored reactive structured background rhythm at 8.5–9.5 cycles per second, with predominant delta waves on the left frontal region, rarely intermixed with isolated slow spikes. On day 34, she was admitted to the rehabilitation ward, still confused and bedridden. She benefited from intensive physiotherapy, speech therapy, bladder training, and cognitive rehabilitation during 2.5 months. At discharge, she was able to walk a few meters with bilateral aid but needed partial aid with transfers. She could also swallow liquids and solid food. Her cognitive status and bladder function were partially improved. Her EDSS was 7/10.
The box containing the remaining pills was brought by the family to the hospital for toxicological analysis. A pill was analyzed by high performance liquid chromatography (HPLC) coupled to ultraviolet (UV) detection and was compared to a standard pill of 10 mg of 4-AP prepared by the hospital pharmacy. The 4-AP content of the pill that was ingested by the patient was at least 8 times greater (>80 mg) than the standard. The pharmacist admitted that each pill was erroneously prepared with a concentration of 100 mg.
The exact pathophysiology of 4-AP toxicity remains to be elucidated. 4-AP is a potassium channel-blocking drug. The prolongation of the action potential may facilitate calcium entry into the cell; the increased influx of calcium is thought to enhance neurotransmission by releasing acetylcholine. Accidental 4-AP overdose may result in serious neurological events ranging from dystonia to altered consciousness and seizures [
In conclusion, for the intensive care physicians, it is important to be aware of the clinical and electrophysiological specificities relating to 4-AP overdose, in order to avoid unnecessary treatments for nonconvulsive status epilepticus, together with prolonged sedation, mechanical ventilation and ICU stay.
The authors declare that there is no conflict of interests regarding the publication of this paper.