Prolonged unconsciousness in perampanel overdose

Abstract

Clinical experience of perampanel overdoses is markedly limited and the relevant literature is sparse. Perampanel is a novel antiepileptic drug (an amino-3-hydroxy-5-methyl-4-isoxazlepropionic acid glutamate receptor antagonist) with a long half-life, which is used for the adjunctive treatment of epilepsy. The literature available identifies a potential for prolonged unconsciousness in overdose. We report a case of prolonged unconsciousness for 14 days following a perampanel overdose of 3.5 times the maximum daily dose, requiring protracted intubation and ventilation on intensive care, with eventual complete neurological recovery. This represents the longest known period of unconsciousness with full recovery and the first reported in a perampanel naïve patient. This case helps to inform decision-making in critical care, particularly the early consideration of admission and intubation. It highlights that while perampanel overdose may not initially cause systemic effects such as cardiac toxicity, it can cause protracted altered consciousness with secondary compromise requiring prolonged intensive care management.

Background

Perampanel (Fycompa manufactured by Eisai) is a novel, non-competitive, amino-3-hydroxy-5-methyl-4-isoxazlepropionic acid glutamate receptor antagonist available since 2012 for the adjunctive treatment of epilepsy. It has been shown to reduce seizure frequency in a concentration-dependent manner,¹ and dosage is with an oral preparation at a maximum of 12 mg/day.² While the optimum therapeutic range has not been identified the posited reference range is currently 0.25–2.85 µmol/L (0.1–1 mg/L).³ Clinical experience of overdoses of this medication is markedly limited and there is no substantial literature available to guide the management of such cases.

Early animal studies identified that perampanel freely penetrates the blood–brain barrier following oral administration⁴ and is known to have a long metabolic half-life of up to 129 hours,⁵ highlighting a potential for prolonged unconsciousness in overdose.⁶ We present a case of perampanel overdose with disordered consciousness for 14 days, the longest known period prior to complete neurological recovery. This case helps to frame clinical expectations, guides management decisions and contributes to the minimal literature available.

Case presentation

A man in his 20s with no known health problems was found unconscious at home by his family surrounded by evidence of an overdose of his partner’s medications. He was urgently brought to hospital by ambulance with clinical suspicion of a first suicide attempt. A mixed overdose of perampanel, levothyroxine and pregabalin, medicines to which he had received no prior exposure, was identified. The exact doses taken were unclear, but a clinical impression was formed that 42 mg of perampanel had been ingested orally (3.5 times the maximum daily dose of 12 mg) alongside trivial amounts of levothyroxine (200 µg) and pregabalin (300 mg) from review of medication packets. No evidence of any coadministration of alcohol or illicit drugs was found. The patient’s attendance at hospital occurred approximately 4 hours after the suspected time of overdose.

Initial clinical assessment identified a fluctuating conscious level (Glasgow Coma Score ranging from 7 to 10) with periods of severe agitation interpolated in profound stupor. Minimal responsiveness to noxious stimuli was noted, and occasional spontaneous repositioning of all limbs was seen. Pupillary reflexes were intact and there was no clear evidence of a focal cranial or peripheral nerve deficit. Airway reflexes were preserved and there was no evidence of respiratory, haemodynamic, renal or other non-neurological compromise.

Hospital admission was arranged under the Acute Medical Team for ongoing close monitoring of vital signs and general supportive care while awaiting neurological improvement and subsequent psychiatric review.

Investigations

Initial laboratory investigations on presentation included the analysis of full blood count, urea and electrolytes, liver function, coagulation profile and an arterial blood gas analysis. These were all unremarkable. Testing for paracetamol, salicylate and alcohol levels was also negative.

An initial CT scan of the brain identified no intracranial pathology. ECGs did not reveal any abnormalities on admission or subsequently.

Differential diagnosis

On admission a working diagnosis of a first suicide attempt via polypharmacy overdose was formed, with the chief concern being for perampanel toxicity. Other pathologies such as a postictal state or intracranial haemorrhage were considered but felt to be unlikely on clinical grounds. Investigations were ordered to help exclude these differential diagnoses and management of the case progressed using this working diagnosis.

Treatment

General supportive care with close observation of vital signs was initially provided on an acute medical ward. On day two of the patient’s admission, however, further periods of marked agitation requiring intermittent restraint by multiple personnel to prevent injury were noted, within ongoing deranged consciousness —clinical expectation had been for a substantial neurological improvement by this timepoint. This coincided with the development of a severe hypoventilatory Type-2 Respiratory Failure and an Aspiration Pneumonia warranting review by the Intensive Care Team. On intensive care assessment endotracheal intubation for airway protection was performed, mandatory ventilation commenced and sedation with propofol and fentanyl started. The patient was then admitted to Intensive Care for further management. Haemodynamic support and renal replacement therapy were not required.

An Acute Respiratory Distress Syndrome subsequently developed on day three of admission, which was identified on serial chest radiographs and clinical review. This was managed with intermittent pronation, paralysis and bronchoscopy for secretion clearance. Advice was sought from a specialist Extracorporeal Membrane Oxygenation (ECMO) referral centre, but significant improvement over the course of the following two days meant that ECMO was not required. Microbiological advice was also received recommending co-amoxiclav and metronidazole cover for Aspiration Pneumonia to which the patient responded. The National Poisons Information Service was consulted for management advice and general supportive care was recommended with no specific treatment warranted.

The patient remained neurologically inappropriate on prolonged daily sedation holds with ongoing stupor and periods of agitation. High intervening sedation requirements were noted despite attempts to minimise this and the patient remained intubated and mechanically ventilated for a total of 12 days. Cerebrospinal fluid (CSF) sampling was not performed due to concerns over spontaneous movements despite high sedation levels and electroencephalography was not available. A repeat CT scan of the brain performed on day six of admission to investigate other potential causes of continued depressed consciousness did not reveal any new intracranial pathology. Advice received from a consultation with the Neurology service recommended ongoing supportive care with the aim of minimising sedation exposure.

General supportive care continued to be provided over subsequent days and a minor improvement of the patient’s conscious level was noted on day 12 during a planned sedation hold. This led to a trial of extubation which was successful.

Outcome and follow-up

The patient returned fully to normal consciousness at day 14 of admission with no evidence of any persisting focal neurological deficit. No delirium or other disorder of cognitive function was identified. Physiotherapy input was gained to assist mobilisation and plans for discharge were commenced.

A psychiatric assessment was conducted following the patient’s return to normal consciousness. This was reassuring. The patient was subsequently discharged home with information provided on the mental health resources available to him in the community. A review is planned in the Intensive Care Follow-Up Clinic in 6 months to a year’s time. He remains well in the community at present with no neurological concerns.

Discussion

Outside of initial trial data, two cases of perampanel overdose were identified on review of the medical literature, one with a full recovery at day eight following an overdose of 3.3 times the upper limit of the recommended daily dose⁷ and one where the patient was lost to follow-up with persisting neurological deficits at day 12 following a suspected overdose of 25 times the upper limit.⁸ This case represents the longest known period of altered consciousness with complete neurological recovery and the only known case where the patient had no prior exposure to perampanel. We know of no clinical guidelines for managing perampanel overdose at present.

The initial clinical trials for perampanel reported the most common adverse effects at therapeutic dosing to be dizziness, somnolence, fatigue and irritability.⁹ Less commonly ataxia, dysarthria and memory impairment were identified. Concerns over increased suicidality on regular administration have also been raised in the literature. The medication package insert for perampanel identifies the possibility of euphoria, altered mental status and aggression with supratherapeutic doses.¹⁰ The likelihood of experiencing such adverse effects with perampanel has been modelled as dose dependent, increasing significantly with higher doses.¹

This report reveals that acute perampanel overdose may not initially cause systemic effects such as cardiac toxicity or metabolic disturbance but can cause protracted altered consciousness with secondary compromise. This may require prolonged periods of endotracheal intubation before a possible complete recovery.

Patient’s perspective.

I remember flashes of awareness with strange sounds and moving images before I came fully back to myself. I find it hard to pinpoint what these were particularly as I felt so weary at the time and for a long time afterwards too. My thoughts seemed like they were moving through mud and it seemed to take ages to process anything that was going on. I am glad to be back to myself though and as my strength returns and my mind clears I feel positive about the future.

Learning points.

This case is noteworthy as it contributes to the sparse literature available on perampanel overdose, particularly as it represents the only known case where the overdose occurred in a perampanel-naïve patient. This helps to inform decision making within Critical Care especially as it highlights that prolonged altered consciousness can occur in overdose with a complete neurological recovery remaining possible. This will materially affect discussions of prolongation or withdrawal of care, tracheostomy consideration and how best supportive care can be provided over a prolonged intensive care admission.

Specific learning points from this case:

• Early consideration of airway protection with endotracheal intubation is likely to help prevent secondary respiratory compromise.

• Early Intensive Care admission even when no non-neurological compromise exists may be beneficial for the patient over the longer term.

• The likelihood of experiencing adverse effects with perampanel is dose dependent, increasing significantly at higher exposures. We suggest that perampanel-naïve patients may be at a potentially greater risk of severely prolonged unconsciousness than those who are habituated to the medicine but further work would be needed to confirm this.