Rufinamide Adjunctive Therapy Reduced Atypical Absence Seizures on EEG: Case Report and Review of the Literature
Rufinamide (RUF) is an FDA-approved triazole derivative for adjunctive therapy in Lennox-Gastaut syndrome (LGS) in ages 4 years and above.
Atypical absence seizures (AAS) are generalized seizures associated with slow spike-wave complexes .
We present a case of AAS where adjunctive off-label RUF resulted in significant improvement in seizure frequency and duration as demonstrated on EEG.
Materials and Methods:
A 9 year-old boy presented with a history of pausing while playing, walking and talking.
He was first diagnosed 6 years ago with partial seizures based on an outside EEG with focal right temporal epileptiform discharges, and was started on oxcarbazepine (OXC), which caused crying and sedation.
He then saw another neurologist who diagnosed him with atypical absence seizures (AAS) and changed his OXC to ethosuximide (ETX), which improved seizure frequency and duration but did not resolve the seizures. Adjunctive levetiracetam (LEV) was ineffective and lamotrigine (LTG) caused a diffuse rash.
He saw a third neurologist who added valproic acid (VPA), which caused severe temper tantrums. Topiramate (TPM) affected his cognition.
Even on ETX 250mg twice daily monotherapy he continued to have staring spells with eyelid fluttering, lasting less than 1second in clusters, at times none for 1-2 weeks. This was once associated with a 1-2 second generalized jerking episode and speech arrest.
He was born full-term weighing 6 pounds 2 ounces. There was a history of benign neonatal jaundice. There was no history of developmental delay. He was academically superior, reading several grades above his age. He would have temper tantrums at home and outside but none at school, which was not related to his seizures, and for which he was seeing Psychiatry.
Past medical history was significant for growth delay with low levels of growth hormone.
Review of systems, family history and social history were all negative.
On exam he was 50.0 inches tall (5th percentile) and weighed 52.6 lbs (25th percentile). Neurological exam was normal. Hyperventilation (HVT) did not activate any episodes.
His initial EEG (Figure 1) on ETX 250mg twice daily monotherapy revealed a total of seventeen 3-4 Hz generalized irregular spike-polyspike complexes, with fifteen activated by intermittent photic stimulation(IPS), lasting a total of 49.6 secs (3.3% of the entire recording). At that time he was having clusters of seizures once every 1-2 weeks.
RUF 400mg twice daily was added to ETX without any side-effects.
His repeat EEG (Figure 2) while on RUF 400mg twice daily and ETX 250mg twice daily 3 months after his first EEG showed total twenty-five runs of 3-4Hz generalized irregular spike-polyspike complexes during post-HVT and activated by IPS, at a total amount 16.4 secs (1.08% of the entire recording) , with the total duration of epileptiform discharges having decreased by 67%. He was having clusters of seizures every 3-4 weeks, showing clinical improvement. RUF levels at a dose of 33mg/kg/day were 19.8 mcg/mL(therapeutic range5-48 mcg/ mL) at the time of his repeat EEG. He was lost to follow-up; he had been on RUF for over 6 months without any recurrent seizures or side effects.
This was a case of atypical absence seizures (AAS) resistant to ETX monotherapy (at the optimal dose for his age at 20mg/ kg/day) and other commonly prescribed antiepileptics, where RUF had to be used as a last resort in order to control the seizures.
Although not fulfilling the classical definition of AAS this case was considered to be such as: A. Polyspike (and not single spike) activity was noted on the EEG. B. IPS rather than HVT activated the epileptiform discharges. However, unlike classic AAS: A. He was very intelligent . B. He was unable to respond at all during the episodes. C. He did not have LGS. D. The frequency of the epileptiform discharges was 4Hz and not slower. He had only a couple of episodes of myoclonic jerks, making the diagnosis of myoclonic absence epilepsy less likely. Absence seizures with polyspike-onset 3-Hz generalized spike wave complexes (as in this case) suggest an intermediary form of IGE that may be drug resistant .
RUF is a triazole derivative which was FDA approved in 2008 for the adjunctive treatment of seizures associated with LGS in children 4 years and older and adults.
RUF inhibits Nav1.1 activation . Although there are no reports of Nav1.1 mutations causing AAS or CAS, NaV1.1 mutations with complete loss-of-function cause severe myoclonic epilepsy of infancy (SMEI ) and missense mutations cause generalized epilepsy with febrile seizures plus (GEFS+) . A NaV1.6 mutation leading to loss of function was found to cause absence seizures in mice .
Currently, evidence-based guidelines for managing AAS are lacking. VPA and ETX are classically the preferred treatments for AAS, both of which this patient had tried.
with LGS, we were able to achieve a decrease in seizure frequency by 50% at far lower levels .Our patient had tolerated RUF well; he could not tolerate OXC, VPA, LTG, or TPM, and LEV was ineffective.RUF appears to be the most promising new antiepileptic drug for AAS and possibly for myoclonic absences . A12-week randomized, placebo-controlled study involving 139 patients with LGS revealed that the frequency of AAS had decreased by 50.6% in the RUF group versus 29.8% in the placebo group . RUF might also be effective in treating other forms of epilepsy [11-13]. A retrospective analysis involving 3 cases of refractory epilepsy with myoclonic absences reported the efficacy of RUF as adjunctive therapy . Another retrospective analysis reported its efficacy in migrating partial epilepsy of infancy . There was also a report of RUF controlling seizures in methyl malonic aciduria . Large-scale, randomized, placebo-controlled studies are in need to demonstrate the efficacy and safety of RUF as adjunctive therapy in AAS.In conclusion, our case suggests that RUF may be a safe and effective option for adjunctive therapy in AAS.Acknowledgement
This was a non-funded study. The author has no financial relationships to disclose.
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