Epilepsy affects approximately 2 million Americans. While there is no cure for the disease, about 70 percent of those who have epilepsy can have their seizures controlled with medication, according to the National Institute of Neurological Disorders and Stroke.
However, migrating partial seizures of infancy (MPSI) is among the forms of epilepsy that present treatment challenges. A rare, severe form of epilepsy that generally presents in the first few months of life, MPSI is characterized by frequent, treatment-resistant seizures, resulting in developmental delays and disabilities, and often leads to death in childhood.
Spontaneous mutations in the potassium channel subunit gene KCNT1 are the most common known genetic cause of non-familial MPSI. Prior in vitro studies in cardiology indicate that the drug quinidine normalizes pathological potassium conductance in mutant KCNT1 channels when expressed in heterologous systems. Quinidine is predominantly used as an antiarrhythmic agent and has US Food and Drug Administration approval for that indication as well as for treatment of Plasmodium falciparum malaria.
Case study of patient with MPSI
These findings led CHOP pediatric neurologists David Bearden, MD, and Ethan M. Goldberg, MD, PhD, and colleagues at CHOP to consider quinidine as a rational therapy for seizure control in cases of MPSI associated with KCNT1 mutation. In a 2014 issue of Annals of Neurology, the team published a case study of a young patient with MPSI found to have an activating mutation in KCNT1 who showed a dramatic reduction in seizure frequency and improvement in psychomotor and language skills after treatment with quinidine.
At 10 weeks old, the child presented with symptoms of MPSI, including frequent focal seizures, developmental delay, and regression in motor skills. When the study team first saw the patient at age 2, she was experiencing between 5 and 20 seizures a day. Whole exome sequencing demonstrated a heterozygous missense mutation in KCNT1. Trials of multiple conventional anticonvulsant drugs in conjunction with the ketogenic diet were without benefit.
The child was given quinidine in combination with other anticonvulsant drugs and the ketogenic diet to restore normal function of the KCNT1 channel. Within a week, the seizures ceased and she remained seizure-free for six weeks. By the end of her seven-month treatment, the patient had been completely seizure-free for more than four months, and almost entirely seizure-free for more than 90 percent of her treatment time. Encouragingly, the patient showed developmental improvements, hitting several major milestones — saying her first words and then her first sentences.
Although the patient’s development has remained severely delayed — possibly because there was irreversible brain dysfunction prior to initiation of therapy — she has had a substantially better outcome in terms of seizure control and neurodevelopment than most patients with MPSI treated with anticonvulsants.
This case is one of the first examples of the identification of a genetic basis of a type of epilepsy and provides the first direct clinical evidence that quinidine may be an effective medication for epilepsy syndromes due to gain of function mutations in KCNT1.
“One of the exciting things about this case is it really illustrates a new paradigm in how people think about epilepsy treatment,” says Bearden. “The promise is that by identifying specific genes we can identify drugs that are more effective and have fewer side effects than currently available antiepileptic drugs.”
Bearden and team are now planning large-scale studies of patients with MPSI to definitively demonstrate the efficacy of quinidine, determine optimum dosing, and determine the effects of earlier initiation of therapy.
“This is an area where there has been a progression from purely lab science to translational research to clinical application,” says Bearden. “That’s exciting for the future; we hope to continue that progress.”
Quinidine clinical considerations
While it appears that quinidine could become an effective therapeutic option for MPSI cases attributable to KCNT1 dysfunction, it is important to be aware of the following caveats:
- QT prolongation is a common adverse effect, necessitating close EKG monitoring.
- Since quinidine is only a weak antagonist of KCNT1 and very little crosses the blood-brain barrier, it may not reverse all the pathological symptoms.
- Quinidine may not be able to reverse permanent damage caused by severe seizures or improper early development of the nervous system as a result of defective KCNT1.
- Quinidine is metabolized by enzymes in the liver and exhibits several drug interactions, inhibiting the metabolism of many antiepileptic medications.