Quinidine: A possible treatment for Migrating Partial Seizures of Infancy (MPSI) patients
Rajalaxmi Natarajan, PhD
Migrating partial seizures of infancy (MPSI) is a severe epilepsy syndrome that affects infants within the first 6 months of birth. It is characterized by focal seizures that originate from various regions in the brain, migrate to other regions and evolve into near-continuous episodes. Once such frequent seizures set in, cognitive and/or motor skills regress and language development slows. Prognosis for seizure control, neurological or psychomotor skill development or even survival beyond the first few years is poor in these patients.
Most MPSI patients do not respond to the available antiepileptic drugs. Apart from a recent study that reported limited success in controlling seizures with potassium bromide in 4 children,1 no treatment options exist for MPSI. Therefore, a recent case reported in the Annals of Neurology by Dr. David Bearden and his colleagues at the Children’s Hospital of Philadelphia2 about a child with MPSI who showed a marked decrease in seizure frequency, improvement in psychomotor and language skills after treatment with quinidine, is very interesting.
Spontaneous mutations in KCNT1 gene are the most common genetic cause of non-familial MPSI. KCNT1 gene encodes a class of sodium-activated potassium channel that is widely expressed in the nervous system and heart. During repetitive neuronal firing, these channels ensure that the membrane potential returns to its resting state. They also regulate the rate and enhance the accuracy of neuronal firing. Most MPSI patients have gain-of-function mutations in KCNT1 making these channels hyperactive. Thus, pharmacologic inhibition of KCNT1 activity could be a rational strategy for designing specific anti-MPSI drugs.
In this study, the authors used quinidine, a drug that has been shown to normalize aberrant KCNT1 function in cultured frog cells3, to inhibit KCNT1 mutation-induced seizures in a 3 year old girl. As an infant, this child had developed normally for the first 10 weeks of life after which she started exhibiting symptoms of MPSI, including frequent focal seizures, developmental delay and regression in motor skills. Treatments with many anticonvulsant drugs and ketogenic diet were not effective in controlling her seizures.
Whole-genome sequencing of her DNA identified the culprit behind this seizure disorder - a missense mutation in KCNT1. In an attempt to restore normal function of the KCNT1 channel, she was given quinidine in combination with on-going anticonvulsant drugs and ketogenic diet therapy. Within a week, her seizures stopped and after some dosage adjustments, she has remained seizure-free for more than 4 months.
Dr. Bearden and colleagues also report that during this time, the patient exhibited marked improvement in motor, cognitive and language skills. While they state that all developmental issues were not fully reversed in this patient, her outcomes were substantially better when compared to MPSI patients treated with anticonvulsants.
Although quinidine appears to be very promising, one needs to be cautious of potential side-effects since, so far, it has only been tested in a single MPSI patient. However, quinidine has been used to treat arrhythmias and malaria and there is some data regarding its use in pediatric patients, and so, it is reasonable to expect that it will be safe to use within the prescribed dosage limits.
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:
- Quinidine can adversely affect heart function and should be used cautiously with close monitoring when prescribed with other medications that may prolong the QT interval like heart medicines or anti-histamines.
- 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 has several drug-drug interactions, including altered metabolism of many antiepileptic medications.
Nevertheless, this case study offers a ray of hope for MPSI patients and opens the door to testing the efficacy of quinidine therapy in more MPSI patients. A controlled clinical trial is warranted and needed. Moreover, this study nicely illustrates the potential use of pharmacogenomics (use of techniques such as whole-genome sequencing) in identifying underlying molecular causes
- Carabello et al., Seizure. 2014 Jul 5. pii: S1059-1311(14)00197-6. doi: 10.1016/j.seizure.2014.06.016. Epilepsy of infancy with migrating focal seizures: Six patients treated with bromide.
- Bearden et al., Ann Neurol. 2014 Jul 16. doi: 10.1002/ana.24229. Targeted treatment of migrating partial seizures of infancy with quinidine.
- Milligan et al., Ann Neurol. 2014 Apr; 75 (4):581-90. doi: 10.1002/ana.24128. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine.
- Learn more about Malignant Partial Seizures of Infancy.