Investigation of Possible Periodic Paralysis (P3) James Cleland, MBChB Assistant Professor Department of Neurology University of Rochester

Background I The diagnosis of typical periodic paralysis is usually straightforward, however patients with atypical symptoms pose diagnostic challenges and may comprise a larger number than those with typical symptoms. There is no single “gold-standard” that is available for routine clinical use

Background II A variety of abnormalities in blood potassium levels have been described with exercise Abnormal drop in size of muscle response (CMAP) following brief exercise has been reported in many types of periodic paralysis Reduced muscle fiber conduction velocity (MFCV) has been reported in HypoPP

Unanswered Questions in PP Does whole body exercise (eg. cycle ergometry) raise the sensitivity of the long exercise CMAP test? Is measurement of MFCV a sensitive and specific diagnostic test for all types of PP? Does the response hypokalemic and/or hyperkalemic challenge (a) improve diagnostic sensitivity, and (b) predict the genetic mutation in patients with periodic paralysis? Is clinically definite but genetically negative periodic paralysis a distinct entity?

“P3” study: design IRB protocol for 3 day admission to the clinical research center at the University of Rochester 35 patients 10 healthy volunteers 5 subjects with HypPP, 5 with HOPP 5 subjects with ATS 10 subjects with possible PP, seen in our clinic, stratified according to pre-test probability of PP: Low – atypical attacks with or without response to therapy Medium – atypical attacks with response to therapy, or typical attacks without response to therapy High – typical attacks with or without response to therapy, with or without family history of PP or documentation of potassium abnormality during attack.

“P3” study: hypotheses That the exercise CMAP test following 30 mins bicycle exercise at 100W will be more sensitive for the diagnosis of PP than the standard exercise test study. That the combination of oral glucose and potassium with serial potassium measurements, response to exercise will predict the genetic defect in PP That MFCV measurement will have high diagnostic sensitivity and specificity for PP

“P3” study: timeline as of 2004 Present IRB protocol in development In process of acquiring a cycle ergometer Negotiating acquisition of electrodiagnostic equipment for the study Dec 2004 Submit IRB protocol Jan 2005 Submit MDA grant proposal ?April 2005 Begin admission of subjects to CRC

“P3” study: timeline as of 2005 Present IRB protocol in development In process of acquiring a cycle ergometer Purchased electrodiagnostic equipment for the study August 2005 Submit funding request to AANEM Fall 2005-Spring 2006 Obtain IRB approval Hopefully secure funding July 2006 Begin admission of subjects to CRC

“P3” study: goals To determine the optimum algorithm for the diagnosis of PP To further genotype-phenotype correlations in patients with PP To develop a “streamlined” facility for the evaluation of patients referred to our institution “one-stop shopping” To identify potential subjects for CINCH studies

The future of PP Establish accurate and cost-effective diagnostic algorithms for PP Increase physician and public awareness of PP Facilitate more widespread availability of genetic testing for PP Characterize relationship between PP symptoms and genetic defect Develop and bring to trial new therapies for PP

The future of PP The dedication of PP patients and their families and their willingness to travel long distances and undergo uncomfortable testing for the “greater good” is truly remarkable Together, patient and researcher can collaborate with synergistic results

N of 1 trials: Fundamentals and possibilities James Cleland, MBChB Department of Neurology University of Rochester Rochester NY

The “N-of-1” trial Synonyms: Single-patient trials (SPT), individualized medication effectiveness tests (IMET) Similar to a crossover trial by design Repeated randomized exposure to intervention and placebo to determine efficacy in individuals Treatment periods generally 4-6 weeks, but will depend on the rapidity of onset (and offset) of the treatment and other factors specific to disease being studied

N-of-1 trial design RANDOM ALLOCATION

Therapeutic trial in ATS 15 individual “N of 1” trials 8 centers Two phases, each 18 weeks I – potassium vs. placebo II- acetazolamide vs. placebo (potassium will be continued) Primary outcome measures Cardiac rhythm disturbances QT interval PP attack frequency/severity reported as per CINCH ATS study IVR

PHASE I (Potassium vs. placebo)   4-DAY INPATIENT ADMISSION AT START OF PHASE I WEEK 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 AT HOME: K+ level X Holter monitor Coordinator call Subject to call in to interactive voice response to report each attack PHASE II (Acetazolamide vs. placebo) AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II