Introduction
Lance Adams syndrome (LAS) is characterized by chronic action or intention myoclonus resulting from cerebral hypoxia occurring in about 0.5% of patients.1 Clinical presentation is usually 48 hours to several weeks after the anoxic injury.2 The myoclonus is activated by movement and tactile stimulation and abates with rest. There are no controlled studies assessing treatment of LAS.2 Treatment response has been reported with several antiseizure medications including valproic acid, levetiracetam, lacosamide, and clonazepam.3–5 However, the myoclonus in LAS can be quiet disabling and refractory to several medications, with frequently partial response.2
Perampanel, a non-competitive antagonist of amino-3-hydroxy-5methyl-4 isooxazoleproprionic acid (AMPA) glutamate receptor,6 has demonstrated some efficacy in myoclonic epilepsy7,8 and other types of myoclonus. Here, we report significant benefit in a patient with LAS treated with add on perampanel and provide a brief review the relevant literature regarding the use of perampanel in Lance-Adams syndrome.
Case Report
A male patient in his 30s was found pulseless with unknown down time. Initially, he was in ventricular fibrillation which progressed to asystole, then pulseless electrical activity. Return of spontaneous circulation was achieved after about 20 minutes from initial resuscitation. Initial electoencephalography (EEG) revealed near continuous generalized periodic discharges with spike-wave morphology at about 2–2.5 Hz with frequent evolution into electroclinical seizures, consistent with post anoxic status epilepticus. The patient was treated with intravenous anesthetics, levetiracetam, lacosamide, and valproic acid. The patient developed post anoxic myoclonus within 1 week from cardiac arrest. Anti-seizure medication doses were adjusted with marginal improvement. After prolonged hospitalization, the patient was discharged to a rehabilitation facility with a cerebral performance category scale of 3 and a Glasgow outcome scale of 3.
The patient continues to suffer from intractable myoclonus despite being treated with multiple anti-seizure medications including brivaracetam, valproic acid, and clonazepam. Nine months following initial anoxic insult, the patient was admitted for anti-seizure medication management. Continuous video EEG revealed bilateral central maximum spike and polyspike and slow wave complexes in waking and sleep and innumerable epileptic myoclonic jerks. Electrographically, the myoclonic jerks were preceded by bilateral synchronous spike and polyspike and wave complexes (Fig. 1). Perampanel was gradually added to his medication regimen. Perampanel was up-titrated to 12 mg daily over 1–2 weeks. This has resulted in significant improvement in frequency and severity of myoclonus for about 6 months. The patient tolerated perampanel without major adverse effects.
Discussion
Perampanel is currently indicated as adjunctive therapy and monotherapy for focal seizures, as well as adjunctive treatment for primary generalized tonic-clonic seizures.6 In this case report, we add to the body of literature supporting the use of perampanel in treating refractory Lance-Adams syndrome.
Perampanel is the first selective noncompetitive AMPA receptor antagonist to be successfully developed to treat epilepsy.6 The efficacy and safety of perampanel was demonstrated in three large randomized control trials and extension studies.9–13 A dose of 4 mg/day was found to be the lowest effective dosage and doses of 8 mg/day and 12 mg/day were effective against placebo with only moderate increase in efficacy at 12 mg/day when compared to 8 mg/day. Utilizing pooled data, the reduction in mean seizure frequency were 23.3% at 4 mg/day, 28.8% at 8 mg/day, and 27.2% for 12 mg/day dose groups. Responder rates were 28.5% for 4 mg/day, 35.3% for 8 mg/day, and 35% for 12 mg/day.6
In general, myoclonus can be classified by its pathophysiologic etiology and by its clinical presentation. In the former case, this classification includes cortical myoclonus, cortical-subcortical myoclonus, subcortical/nonsegmental myoclonus, segmental myoclonus, and peripheral myoclonus.14 Classification by clinical presentation includes physiologic myoclonus, essential myoclonus, epileptic myoclonus, and symptomatic myoclonus (progressive myoclonic epilepsy syndromes, neurodegeneration, inflammation, metabolic conditions, drug induced, and post hypoxia).14
There have been several case reports and case series that have demonstrated the efficacy of perampanel in progressive myoclonic epilepsies,7,8 non-epileptic myoclonus, in refractory status epilepticus,15 including post-anoxic myoclonic status epilepticus,16,17 and in Lance-Adams syndrome.18–27
The pathophysiological mechanism of LAS is unclear but has been hypothesized to originate in the cortex/subcortex. The generation of myoclonus is thought to be due to abnormal levels of neurotransmitters, abnormal low levels of serotonin and gamma-amino butyric acid (GABA).28,29 Treatment with L-5-hydroxytryptophan (a serotonin precursor) demonstrated some success in controlling myoclonus and is thought to do so by increasing the low levels of serotonin. Anti-seizure medications such as benzodiazepines and valproate have been efficacious in cases of LAS due to their increasing levels of GABA in the synapse.30
The mechanism by which perampanel appears to be an effective adjunctive treatment in LAS is unclear. Perampanel works on excitatory glutamatergic neurons. Perampanel works to modify the synaptic transmission at the cortical-subcortical level and may decrease excitation at the synaptic level.31 A subset of patients with cortical myoclonus demonstrated giant somatosensory evoked potential (SEP) reflecting cortical hyperexcitability.32 One study showed that patients who responded to low dose perampanel had a decrease in the amplitude and increase in the latency of giant SEP (temporal dispersion). The authors hypothesized based on the SEP findings that perampanel inhibited and dispersed epileptic cortical hyperexcitability with hyper-synchronization in the primary motor cortex.33
While there have not been any controlled studies assessing the efficacy of perampanel in LAS, multiple case reports and case series supporting its efficacy do exist.5–14 In Table 1 below we have summarized the results of these studies.
Growing evidence exists for perampanel as an adjunctive treatment in patients with post hypoxic myoclonus or LAS. Perampanel has been used effectively to treat other forms of myoclonus including those in progressive myoclonic epilepsies, non-epileptic myoclonus, and in refractory status epilepticus including post-anoxic myoclonic status epilepticus. This brief review of the available literature, though limited to case reports and case series, suggests a potential role for perampanel in patients with LAS. Further study is certainly warranted including controlled trials of perampanel use in post hypoxic myoclonus.
