, Volume 4, Issue 2, pp 199-204

First online:

Challenges in the design and conduct of therapeutic trials in channel disorders

  • Shannon L. VenanceAffiliated withUniversity of Western OntarioDepartment of Clinical Neurological Sciences, London Health Sciences Centre Email author 
  • , Barbara E. HerrAffiliated withThe Channelopathy Project, University of Rochester School of Medicine and Dentistry
  • , Robert C. GriggsAffiliated withThe Channelopathy Project, University of Rochester School of Medicine and Dentistry


Neurologic channelopathies are rare, inherited paroxysmal disorders of muscle (e.g., the periodic paralyses and nondystrophic myotonias) and brain (e.g., episodic ataxias, idiopathic epilepsies, and familial hemiplegic migraine). Mutation is necessary but not sufficient for phenotypic expression and there are no simple phenotype-genotype relationships. Attacks may be spontaneous or triggered, with affected individuals often asymptomatic and neurologic ally normal between attacks. Performance of daily activities may be affected by the unpredictable nature; often late-onset degenerative changes cause permanent disability; for example, muscle atrophy and fixed weakness in periodic paralysis and cerebellar atrophy and progressive ataxia in the episodic ataxias. Currently, the natural history of these disorders is being defined. Clearly, the established methodologies for randomized controlled clinical trials are not feasible for rare diseases and innovative trial design is essential. There is a requirement for clinically relevant outcome measures for episodic disorders. Increasing our knowledge of the pathophysiology will help in targeting and designing rational therapeutic approaches. We will use the current understanding of the neurological channelopathies to illustrate some of the opportunities, challenges, and strategies in bringing safe and effective treatments to patients. There are reasons for optimism that new partnerships between clinical investigators, government, patient advocacy groups, and industry will prevent symptoms and progression of the neurological channelopathies.

Key Words

Neurological channelopathies trial design outcome measures rare diseases n-of-1 studies