Quinine in the Treatment of Malignant Migrating Partial Seizures in Infancy: A Case Report

The syndrome of malignant migrating partial seizures in infancy was first described by Coppola and colleagues in 1995. The International League Against Epilepsy defines this form of epilepsy as a seizure onset in the first 6 months of life, occurrence of almost continuous migrating polymorphous focal seizures, combined with multifocal ictal EEG discharges, and progressive deterioration of psychomotor development. Most cases are pharmacoresistant and have poor outcomes. A lot of publications described the trial of several medications such as Stiripentol, Rufinamide, Cannabidiol, and finally Ketogenic diet, to control the refractory devastating seizures. We describe a 13-month-old girl with malignant migrating partial seizures in infancy who was started on Quinine for the control of her refractory seizures after the trial of multiple antiepileptic medications that failed to control her seizures, including Clonazepam, Carbamazepine, Phenobarbitone, Phyntion, Midazolam, Valproate, Perampanel & Ketogenic diet, all were tried by different combination at different times. Finally, as malignant migrating partial seizures in infancy are sometimes linked to K channelopathy, a trial of Quinine was given in a dose of 30mg/kg/d. Patients showed an excellent response with control of clinical & electrographic seizures. Now she is seizure-free for five months and undergoing physiotherapy. She started rolling over but doesn't have much improvement in motor milestones, is not following or cooing, and is unable to say clear words. Keywords: MMPSI – malignant migrating partial seizures in infancy- Quinine – Intractable epilepsy- CPLANE-1 gene defect

SLC25A22 and Its Related Epileptic Encephalopathies

Epileptic encephalopathy is a condition in which seizures, electroencephalographic epileptiform abnormalities lead to a progressive deterioration of brain functions causing a significant psychomotor delay. One of the typical features of this heterogeneous and large group of severe disorders is the extremely early onset of seizures. The main causes of the epileptic encephalopathies include structural brain defects, inherited metabolic disorders; in this aspect, more than 100 genetic defects, including mutations in the solute carrier family 25 (SLC25A22) gene which encodes a mitochondrial glutamate carrier. To date, the main clinical phenotypes related to mutations of this gene are Ohtahara syndrome (or early infantile epileptic encephalopathy), early myoclonic encephalopathy and migrating partial seizures in infancy. In all the cases, prognosis is poor and no disease-modifying treatment is available in the present days.

Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox

Exome and targeted sequencing have revolutionized clinical diagnosis. This has been particularly striking in epilepsy and neurodevelopmental disorders, for which new genes or new variants of preexisting candidate genes are being continuously identified at increasing rates every year. A surprising finding of these efforts is the recognition that gain of function potassium channel variants are actually associated with certain types of epilepsy, such as malignant migrating partial seizures of infancy or early-onset epileptic encephalopathy. This development has been difficult to understand as traditionally potassium channel loss-of-function, not gain-of-function, has been associated with hyperexcitability disorders. In this article, we describe the current state of the field regarding the gain-of-function potassium channel variants associated with epilepsy (KCNA2, KCNB1, KCND2, KCNH1, KCNH5, KCNJ10, KCNMA1, KCNQ2, KCNQ3, and KCNT1) and speculate on the possible cellular mechanisms behind the development of seizures and epilepsy in these patients. Understanding how potassium channel gain-of-function leads to epilepsy will provide new insights into the inner working of neural circuits and aid in developing new therapies.

P.036 Targeted molecular therapy with quinidine for seizures in a neonate with KCNT1 mutation leads to poor response

Background: The KCNT1 gene encodes subunits of the Na+-activated K+ channel, widely expressed in the CNS. Mutations of this gene have been implicated in Malignant Migrating Partial Seizures of Infancy (MMPSI). This early-onset epileptic encephalopathy represents a challenge due to pharmacoresistance. The channel-specific mutation represents the potential for targeted pharmacotherapy. Quinidine is a partial antagonist of the KCNT1 encoded channel; patients with MMPSI have been reported to have responded to doses ranging 34.4/kg/d - 60mg/kg/d. We present a case of MMPSI with a KCNTI mutation (c.G1283A:p.R428Q) trialled on quinidine. Methods: Following ineffective trials of 6 anti-seizure medications, this patient was trialled on oral quinidine. This patient was titrated up to a dose of 52mg/kg/d. Twenty-four hour EEG monitoring prior to quinidine therapy, and at target dose were compared. Results: Prior to initiation of quinidine, this patient experienced 22 electrographic seizures over 24 hours. At target dose, this patient experienced greater than 70 seizures over 24 hours. Conclusions: Quinidine has previously been reported to be effective in patients with MMPSI with the same and different mutations. We report the second case of a patient with MMPSI and KCNT1 mutation R428Q with poor clinical response to quinidine.