Sunday, December 4, 2016

An attempt at targeted therapy: quinidine in KCNT1 positive epilepsy

Mikati MA, Jiang YH, Carboni M, Shashi V, Petrovski S, Spillmann R, Milligan CJ, Li M, Grefe A, McConkie A, Berkovic S, Scheffer I, Mullen S, Bonner M, Petrou S, Goldstein D. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol. 2015 Dec;78(6):995-9.

We report 2 patients with drug-resistant epilepsy caused by KCNT1 mutations who were treated with quinidine. Both mutations manifested gain of function in vitro, showing increased current that was reduced by quinidine. One, who had epilepsy of infancy with migrating focal seizures, had 80% reduction in seizure frequency as recorded in seizure diaries, and partially validated by objective seizure evaluation on EEG. The other, who had a novel phenotype, with severe nocturnal focal and secondary generalized seizures starting in early childhood with developmental regression, did not improve. Although quinidine represents an encouraging opportunity for therapeutic benefits, our experience suggests caution in its application and supports the need to identify more targeted drugs for KCNT1 epilepsies.

From the article

KCNT1 mutations have recently been implicated in a range of epilepsy syndromes including severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and epilepsy of infancy with migrating focal seizures (EIMFS). Mutations result in KCNT1 channel gain of function. This gain of function, the magnitude of which correlates with the clinical severity, can be reduced by quinidine in vitro.5 A recent case report described improvement in seizure control with quinidine in a patient with KCNT1-EIMFS.6 Here, we report 2 patients with different epilepsy phenotypes caused by KCNT1 mutations with different responses to quinidine therapy. We also analyze the cases for additional factors that might have resulted in variable therapeutic response and discuss how this could help development of future tailored therapies for such disorders. This work was approved by our institutional review board...

Our first patient had a severe presentation and did not respond to quinidine although she carries the Y796H mutation that was previously found in a family with ADNFLE, and that is on the more mild side of the in vitro functional spectrum. Our second patient had a favorable response albeit less so than the patient reported by Bearden et al, although the mutation he carries is the least sensitive mutation to quinidine in vitro. The patient of Bearden et al showed the best response, and carried the mutation that was the most sensitive to quinidine. This raises the possibility that the in vitro effect of quinidine may predict, in some but not in all patients, clinical response. The current limited and variable data, however, both in terms of in vitro effects and clinical responses makes it impossible to draw any clear conclusions about in vitro responses and clinical responses.  Thus, our data justifies a need for further studies of quinidine in KCNT1-related epilepsies, and illustrates that in vitro work can guide development and investigation of clinical therapies. Our cases also demonstrate that clinical response can vary. This cautions against wide and indiscriminate use of quinidine in patients outside carefully designed protocols and provides information that can help in the design of future controlled studies. Specifically, our data, combined with the previous work, make the important practical point that there is some phenotype– genotype correlation and that anyone considering quinidine therapy should first assess the quinidine response of the specific mutation found in the patient. We feel that this work will directly contribute to the more careful application of quinidine going forward, which is becoming a pressing concern as we learn of an increasing number of patients with mutations of unknown significance in KCNT1 being considered for quinidine therapy. We also note that making the case for this functional assessment before targeted treatment is initiated would have the additional benefit of ensuring that quinidine is not initiated when there is a benign variant, or a mutation that results in loss rather than gain of function, which is also becoming an increasing concern…

In conclusion, the therapeutic effects of quinidine in KCNT1 positive epilepsy remain largely unknown. The question of how much quinidine may help, if it all, and in which specific types of KCNT1 positive epilepsy and for which mutations can only be resolved by more detailed clinical evaluation, ideally using objective measurements of seizures since we may expect responses to be inflated by expectation in the absence of objective measures. Ideally, evaluation of quinidine in KCNT1 animal models would guide such clinical evaluations. Although the current limited data do not appear to support the idea of substantial clinical benefit of quinidine, quinidine does clearly illustrate a new potential paradigm for the development and clinical evaluation of genetically targeted therapies in epilepsy.

1 comment:

  1. Reif PS, Tsai MH, Helbig I, Rosenow F, Klein KM. Precision medicine in genetic epilepsies: break of dawn? Expert Rev Neurother. 2016 Nov 10:1-12.

    Therapy with current antiepileptic drugs aims at reducing the likelihood of seizure occurrence rather than influencing the underlying disease process. Therefore, antiepileptic drugs have an anticonvulsant rather than antiepileptic property. Areas covered: The increasing identification of genetic causes for epilepsy over the recent years improves the understanding of the underlying epileptogenic process and allows for the possibility of directed therapeutic approaches. An ideal antiepileptic therapy consists of a drug which is able to influence the functional changes caused by a specific pathogenic variant. In this review we will describe the current precision medicine approaches in genetic epilepsies in reference to the identified genetic etiologies. References for this review were identified through searches of PubMed and the authors' own files. Expert commentary: Currently established or investigated precision medicine treatments include the ketogenic diet in patients with GLUT1 deficiency, sodium channel blockers in patients with KCNQ2, SCN2A and SCN8A mutations as well as mTOR-inhibitors in mTORopathies. These predominantly represent already available treatments that were repurposed for use in epilepsy. The development of new therapeutic agents aiming at targets identified in genetic epilepsies will advance epilepsy treatment considerably.