In Memoriam: John F. Kurtzke, MD (1926-2015): A Founding Father of Neuroepidemiology and Pioneer of Modern Clinical Trial Design.

Abstract

On December 1, 2015, we lost one of the most influential contributors to the field of medical epidemiology, and in particular the man who is credited for performing the most systematic exploration of the geographic distribution patterns for the most common disabling neurologic disorder of young people, multiple sclerosis (MS). John F. Kurtzke, MD, graduated from the Cornell Medical College in 1952, and by 1956 he had ascended to the position of chief of neurology for the Veterans Administration in Coatesville, Pennsylvania. He would later serve as professor of neurology at Georgetown University from 1963 to 1995, during which time he conducted some of the most seminal investigations that collectively helped to establish the field of neuroepidemiology. The role of one ormore environmental factors, including infections, as a critical factor in thepathogenesis ofMS is now widely recognized. It was Kurtzke’s pioneering work that brought forth some of the most persuasive evidence to date supporting a putative role for an infectious agent as a contributing factor in MS. When the presence of the disorder was nearly unheard of on the remote Faeroe Islands and in Iceland, the recording of many cases of MS following the occupation of these territories by the British troops during World War II fostered Kurtzke’s exploration into the infectious etiologic hypothesis as a contributing factor in the development of MS.1-8 The contemporary framework for thepathobiological underpinnings ofMS is nowmost consistentwith that of an epigenetic disorder predicatedongenetic, environmental, nutritional, and behavioral factors, in conjunction with a factor acting as a trigger or “ignition switch.” Kurtzke’s observations and interpretive conclusions resonate with contemporary thinking, particularly given his hypothesis that a modifying etiological factor for developing MS appeared to be influenced by the location, with respect to equatorial latitude, of early life development,withmounting evidence that corroborates thepostulated role of vitaminDas a criticalmitigating influence potentially linked to its relationship to immune regulatorynetworks and thederivative achievement of self-tolerance. Kurtzke’s secondmajor accomplishmentwas thedevelopment of the disability status scale score, which catapulted the clinical assessment within clinical trials from the reporting of the assessor’s subjective impressions to the establishment of anobjective, reproducible, andstereotypedgold-standardneurological examination and status ascertainment.9,10 This formidable contribution to the field of medical therapeutics resulted in the transformation of clinical trial design for MS in particular and set forth objective standards for the characterization of clinical outcomes to be emulated for disabling neurologic disorders in general. Originally proposed in 1955 and 1961, Kurtzke formulated anordinal scale for the application inMSdrug trials (initially for the assessment of isoniazid as a treatment forMS) as a means to objectify the effects of putative therapies on the clinical disposition of neurologic disability in MS.9 Initially conceived as a scale from0 (no evidence of signs, symptoms, or report of disabling changes in neurologic functioning or status) to 10 (death due toMSor its complications), the scale was later transformed into 0.5-point steps (the Expanded Disability Status Scale score) to account for the functional integrity of eachof the functional systemscales such as abnormalities affiliated with each of the components of the neurological examination: vision, brainstem functions, pyramidal functions (strength, reflexes, tone), cerebellar functions, sensory functions, bowel-bladder-sexual functions, cerebral functions (depression, euphoria, reduced mentation), and ambulation.10 The scale is an ordinal scale, heavily weighted on the impact anddeterioration inwalking, othermotor functions, and, toadegree, sensoryandvisual functions.Notwithstanding the ordinal nature of the scale, theheavybias on ambulation, and John F. Kurtzke, MD