Targeted Treatment of Migrating Partial Seizures of Infancy with Quinidine

BRIEF COMMUNICATION

Targeted Treatment of reported KCNT1 mutations in MPSI are gain of function mutations leading to constitutive activation of the Migrating Partial Seizures of channel; therefore, pharmacologic inhibition of KCNT1 might be a potential target. Whereas KCNT1 is not Infancy with Quinidine affected by any conventional anticonvulsants, it is a known target of several cardiac drugs, including the anti- David Bearden, MD,1 arrhythmic drug quinidine, which operates as a pore 12 Alanna Strong, PhD,2 blocker. Prior in vitro studies indicate that quinidine Jessica Ehnot, PharmD,3 normalizes pathological potassium conductance in 1 mutant KCNT1 channels when expressed in heterologous Marissa DiGiovine, MD, 13 Dennis Dlugos, MD, MSCE,1 and systems. This suggests that quinidine might be a rational therapy for seizure control in cases of MPSI Ethan M. Goldberg, MD, PhD1 associated with KCNT1 mutation. Here we report a case of a patient with MPSI and Migrating partial seizures of infancy is an early onset epileptic encephalopathy syndrome that is typically a missense mutation in KCNT1 (c.1283G>A; resistant to treatment. The most common cause is a p.Arg428Gln) treated with quinidine therapy targeted gain of function mutation in the potassium channel specifically at reduction of pathologically increased KCNT1. The antiarrhythmic drug quinidine is a partial antagonist of KCNT1 and hence may be a candidate KCNT1 channel–mediated potassium conductance. This drug for treatment of this condition. We report the case is illustrative of a new paradigm in epilepsy treat- case of a child with migrating partial seizures of ment in which rapid identification of genetic mutations infancy secondary to an activating mutation in KCNT1 treated with quinidine. Treatment with quinidine was could lead to targeted treatments with greater efficacy correlated with a marked reduction in seizure fre- and fewer side effects than is possible with currently quency and improved psychomotor development. available antiepileptic drugs. ANN NEUROL 2014;00:000–000 Case Report Clinical Course and Diagnostic Workup igrating partial seizures of infancy (MPSI) is an The patient is a now 3-year-old female who was born at Mearly onset epileptic encephalopathy characterized term to nonconsanguineous parents. There was no family by randomly migrating focal seizures and psychomotor history of seizures or other neurologic disorders. Devel- 1 deterioration. Seizures are resistant to treatment with opment proceeded normally for the first 10 weeks of life, conventional anticonvulsants, and the syndrome generally at which point the patient presented to medical attention carries a poor prognosis in terms of seizure control, neu- with seizures characterized by brief episodes of eye devia- rodevelopmental outcomes, and life expectancy, although tion, lip smacking, and alternating unilateral motor activ- 2,3 some variability has been reported. The disorder begins ity. EEG showed a pattern characteristic of MPSI, with in infancy with focal seizures accompanied by a charac- focal seizures migrating between left and right hemi- teristic migrating ictal pattern on electroencephalogram spheres (Fig 1). General physical and neurologic exami- (EEG) that often evolves into near-continuous seizures. nations were otherwise normal, as was magnetic reso- Death, usually from intractable seizures or respiratory nance imaging of the brain. The patient had a thorough complications, often occurs within the first years of life.4 MPSI is associated with mutations in a variety of genes, From the 1Division of Neurology, Children’s Hospital of Philadelphia, including PLCB1, TBC1D24, SCN1A, SCN2A, Philadelphia, PA; 2Perelman School of Medicine, University of 5–10 SLC25A22, and KCNT1. A recent study utilized Pennsylvania, Philadelphia, PA; and 3Department of Pharmacy, Upstate whole exome sequencing in 12 patients with MPSI and Golisano Children’s Hospital, New York, NY. found KCNT1 mutations in 6, suggesting that KCNT1 is Address correspondence to Dr Bearden, 10th Floor, Colket Transla- 9 tional Research Building, 3400 Civic Center Blvd, Philadelphia, PA the most common known genetic cause of MPSI. 19104. E-mail: [email protected]

KCNT1 (also known as Slo2.2, Slack, and KCa4.1), View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana. encodes the pore-forming alpha subunit of a sodium- 24229 activated potassium channel that is highly expressed in Received May 7, 2014, and in revised form Jul 13, 2014. Accepted for 11 both neurons and cardiomyocytes. Importantly, all publication Jul 14, 2014.

VC 2014 American Neurological Association 1 ANNALS of Neurology

FIGURE 1: Electroencephalogram at initial presentation. (A) Focal seizure originating from right temporal lobe. (B) Several sec- onds later, seizure has migrated to the left. evaluation for etiology, all of which was negative or nor- frequency, and the patient continued to have 5 to 20 mal other than whole exome sequencing, as documented seizures per day. The ketogenic diet reduced seizure fre- in Table 1. Whole exome sequencing demonstrated a quency to an average of 5 seizures per day. However, by heterozygous missense mutation in KCNT1 7 months of age, the patient exhibited developmental (c.1283G>A; p.Arg428Gln), which affects a highly con- arrest followed by regression with minimal voluntary served residue in the C-terminus of the protein. This movement. By age 2 years, seizures had progressed to mutation has been previously described in 3 patients include life-threatening apneic episodes. Given the with MPSI.9 patient’s worsening clinical picture, consideration was made of a trial of quinidine, and the patient’s parents Treatment Course consented to its off-label use. Trials of multiple medications alone and in various com- binations, including phenobarbital, levetiracetam, phenyt- Initiation of and Response to Quinidine Therapy oin, topiramate, valproic acid, lamotrigine, clorazepate, A timeline of the patient’s response to therapy is pre- gabapentin, and clobazam, were without effect on seizure sented in Table 2. The patient was admitted to the

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TABLE 1. Summary of Diagnostic Testing

Serum Testing Cerebrospinal Fluid Studies Genetic Testing

Electrolytes Cell count, protein, and glucose SNP microarray Liver function tests Neurotransmitters Mitochondrial genome sequencing Urine organic acids Amino acid quantification 38 gene infantile onset epilepsy panel Serum amino acids Lactate and pyruvate Whole exome sequencing Lactate and pyruvate Acylcarnitine profile SNP 5 single nucleotide polymorphism.

hospital for initiation of therapy in September of 2013 at >6lg/ml). After a treatment duration of >7 months, the the age of 25 months. She was continued on a drug regi- patient was having seizures only during periods of inter- men of topiramate, levetiracetam, clobazam, and gaba- current illness, and as of July 2014 she had been seizure pentin as well as the ketogenic diet. A test dose of oral free for >4 months. There have been no adverse effects quinidine sulfate 25mg (2mg/kg body weight) was given, secondary to quinidine. Blood counts, liver function followed by a 4-day dose titration to a goal dose of tests, and electrocardiograms (EKGs) have been moni- 100mg every 6 hours (33mg/kg/day). After approxi- tored frequently and have remained normal. mately 1 week on her target dose of quinidine, the patient’s seizures ceased, and she remained seizure-free Discussion for 6 weeks. Developmentally, the patient showed Here we report the case of a patient with MPSI found to improved head control and increased spontaneous move- have an activating mutation in KCNT1 who showed a ment and alertness, and spoke her first words. However, dramatic reduction in seizure frequency after initiation of seizures returned after 6 weeks at a frequency of 0 to 2 quinidine. This case provides the first direct clinical evi- seizures per day. The quinidine dose was then increased dence that quinidine may be an effective medication for to 42mg/kg/day, and seizures once again resolved. Serum epilepsy syndromes due to gain of function mutations in quinidine levels were followed and ranged from 1.5 KCNT1. KCNT1 encodes the pore-forming subunit of to 4lg/ml (typical therapeutic range for arrhythmias 5 the sodium-activated potassium channel Slack, which 2–5lg/ml, and toxicity is thought to occur at levels plays a role in action potential repolarization, and

TABLE 2. Timeline of Treatment and Response

Day of Treatment Event

Day 0 Patient having 5–20 seizures per day, minimal psychomotor development Day 1 Test dose of quinidine initiated Day 4 Quinidine increased to 33mg/kg/day Day 11 Seizures resolve Days 11–53 Patient remains seizure-free, some improvement in psychomotor development Day 54 Seizures recur, patient begins having 0–2 seizures/day Day 56 Quinidine increased to 42mg/kg/day Day 61 Seizures again resolve Days 61–180 Patient seizure-free except in the setting of acute infection; patient says first words; quinidine dose weight-adjusted to maintain level of 2–5lg/ml Days 180–210 Patient completely seizure-free; patient says first complete sentence

Month 2014 3 ANNALS of Neurology repetitive firing.14 KCNT1 may also play a role in neuro- In conclusion, this case suggests that quinidine development through its interaction with the fragile X may be at least partially effective in the treatment of mental retardation protein (FMRP).15 MPSI associated with activating KCNT1 mutations. Fur- Quinidine is predominantly used as an antiarrhyth- ther studies are needed to definitively demonstrate the mic agent and has US Food and Drug Administration efficacy of quinidine, determine optimum dosing, and approval for that indication as well as for treatment of determine the effects of earlier initiation of therapy. This Plasmodium falciparum malaria. Quinidine is well case illustrates the potential power of genetic analysis in absorbed in the gastrointestinal tract and is rapidly and the evaluation of the early onset epileptic encephalopa- widely distributed throughout the body, although its cen- thies in revealing novel, personalized therapies for this tral nervous system penetration is relatively poor.16,17 class of disorders. However, clinicians should always Quinidine is extensively metabolized in the liver by the exercise rigor in determining mutation pathogenicity and cytochrome-P450 enzyme system.16 Thus, quinidine mechanism of disease before embarking on targeted ther- exhibits many drug–drug interactions including inhibi- apy, as in this case the normalization of KCNT1 chan- tion of the metabolism of many antiepileptic medica- nels with quinidine had previously been described, giving tions. Due to the effects of quinidine on cardiac conduct- us more than just a theoretical justification for the use ance, QT prolongation is a common adverse effect. of quinidine.13 Finally, this case demonstrates that earlier Therefore, quinidine should be used with caution in genetic testing may be key to optimizing response to combination with other medications that may prolong therapy. the QT interval, and close EKG monitoring should be considered.16 Limited data describing the use of quinidine in Authorship pediatric patients for indications other than malaria are D.B. conceived of the study idea, wrote significant available, but the usual dosing range is 15 to 60mg/kg/ portions of the manuscript, and revised and edited the day in 4 or 5 divided doses with a maximum single dose manuscript. A.S. wrote significant portions of the of 600mg and a maximum daily dose of 3,000 to manuscript and revised and edited the manuscript. J.E. 4,000mg/day.18,19 Dosing for use as a KCNT1 inhibitor was involved in initial treatment planning, wrote the has yet to be established, and thus we based our dosing section of the manuscript on quinidine pharmacology, on previously established dosing for other indications to and revised and edited the manuscript. M.D. and minimize potential cardiac toxicity. D.D. reviewed all EEGs, chose EEG screen shots, and Although the patient did show dramatic improve- revised and edited the manuscript. E.M.G. was ment with quinidine, the patient did not initially achieve involved in initial treatment planning, wrote significant complete seizure freedom, and her development has portions of the manuscript, and revised and edited the remained severely delayed. There are a variety of explana- manuscript. tions for what might be viewed as an incomplete treatment response. Quinidine is a weak antagonist of Potential Conflicts of Interest KCNT1 channels and has relatively poor blood–brain Nothing to report. barrier penetration and hence may not have achieved suf- ficient concentrations in the brain to normalize pathological KCNT1 conductance. Second, given the hypothe- sized developmental function of KCNT1 channels via References interaction with FMRP, it is possible that there was irre- 1. Coppola G, Plouin P, Chiron C, et al. Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia versible brain dysfunction prior to initiation of therapy 1995;36:1017–1024. due to aberrant neurodevelopment. Finally, she may have 2. Marsh E, Melamed SE, Barron T, et al. Migrating partial seizures suffered permanent brain injury due to the effects of fre- in infancy: expanding the phenotype of a rare seizure syndrome. quent seizures. It is possible that earlier initiation of Epilepsia 2005;46:568–572. quinidine, such as at onset of epilepsy, might have pro- 3. Mctague A, Appleton R, Avula S, et al. Migrating partial seizures of infancy: expansion of the electroclinical, radiological and patho- duced better results. However, it is worth noting that our logical disease spectrum. Brain 2013;136:1578–1591. patient has had a substantially better outcome in terms 4. Coppola G. Malignant migrating partial seizures in infancy: an epi- of seizure control and neurodevelopment than most lepsy syndrome of unknown etiology. Epilepsia 2009;50(suppl 5): 49–51. patients with MPSI reported in the literature, especially 5. Poduri A, Heinzen EL, Chitsazzadeh V, et al. SLC25A22 is a novel when compared to the natural history of other children gene for migrating partial seizures in infancy. Ann Neurol 2013;74: 1,3,9 with known KCNT1 mutations. 873–882.

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6. Poduri A, Chopra SS, Neilan EG, et al. Homozygous PLCB1 dele- 13. Milligan CJ, Li M, Gazina EV, et al. KCNT1 gain-of-function in two tion associated with malignant migrating partial seizures in epilepsy phenotypes is reversed by quinidine. Ann Neurol 2014; infancy. Epilepsia 2012;53:e146–e150. 75:581–590.

7. Milh M, Falace A, Villeneuve N, et al. Novel compound heterozy- 14. Brown MR, Kronengold J, Gazula VR, et al. Amino-termini iso- gous mutations in TBC1D24 cause familial malignant migrating forms of the Slack K1 channel, regulated by alternative pro- partial seizures of infancy. Hum Mutat 2013;34:869–872. moters, differentially modulate rhythmic firing and adaptation. J Physiol 2008;586:5161–5179. 8. Freilich ER, Jones JM, Gaillard WD, et al. Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy. 15. Brown MR, Kronengold J, Gazula VR, et al. Fragile X mental retar- Arch Neurol 2011;68:665–671. dation protein controls gating of the sodium-activated potassium channel Slack. Nat Neurosci 2010;13:819–821. 9. Barcia G, Fleming MR, Deligniere A, et al. De novo gain-of- function KCNT1 channel mutations cause malignant migrating par- 16. Quinidine sulfate [package insert]. Corona, CA: Watson Laborato- tial seizures of infancy. Nat Genet 2012;44:1255–1259. ries, 2009.

10. Dhamija R, Wirrell E, Falcao G, et al. Novel de novo SCN2A muta- 17. Kusuhara H, Suzuki H, Terasaki T, et al. P-glycoprotein mediates tion in a child with migrating focal seizures of infancy. Pediatr the efflux of quinidine across the blood-brain barrier. J Pharmacol Neurol 2013;49:486–488. Exp Ther 1997;283:574–580.

11. Yuan A, Santi CM, Wei A, et al. The sodium-activated potassium 18. Lexi-Comp OnlineTM. Lexi-Drugs Online: Quinidine. Hudson, channel is encoded by a member of the Slo gene family. Neuron Ohio: Lexi-Comp, Inc; 2014; accessed March 31, 2014. 2003;37:765–773. 19. Luedtke SA, Kuhn RJ, McCaffrey FM. Pharmacologic management 12. Yang B, Gribkoff VK, Pan J, et al. Pharmacological activation and of supraventricular tachycardias in children. Part 2: Atrial flutter, inhibition of Slack (Slo2.2) channels. Neuropharmacology 2006;51: atrial fibrillation, and junctional and atrial ectopic tachycardia. Ann 896–906. Pharmacother 1997;31:1347–1359.

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