The Early Use of Blinding in Therapeutic Clinical Research of Neurological Disorders

We sought to identify early uses of blinding in therapeutic clinical trials of neurological disorders by multiple search methods. A 1784 report by Benjamin Franklin and others described the evaluation of the use of Mesmerism to treat neurological and other syndromes including headache and epilepsy, using blindfolds and screens. This report demonstrated the usefulness of blinding to reduce bias in clinical research, yet despite this early discovery, blinding was not widely accepted or routinely used until the 20 century. Blinded clinical trials began to be used for various neurological syndromes in the 1950s, sporadically at first and then increasing in frequency in subsequent years. The reason for this delay is unclear, but we propose several hypotheses. DOI : 10.14302/issn.2470-5020.jnrt-15-803 Corresponding author: Matthew B. Jensen, MD, 1685 Highland Ave, room 7273, Madison, WI 53705-2281, 608-263-5448, fax 608-263-0412, jensen@neurology.wisc.edu


Introduction:
Blinding/masking the allocation of subjects to treatment groups in therapeutic clinical research is now a well-established method to reduce the chance of bias and erroneous conclusions about safety or efficacy. 1

Methods
Books and articles covering the history of neurology and the history of clinical research were reviewed for the likely timeframe of introduction of blinding. [1][2][3][4][5] We searched PubMed, Google Scholar, and Project MUSE in early 2011 with combinations of the terms "neurology," "treatment," "blind," and "placebo." During initial searches we identified 10 neurological disorders that appeared to be the most likely candidates for the earliest use of blinded trials, and repeated the searches substituting the name of each of these disorders for the term "neurology." We then reviewed articles from these searches from the 1950s and 1960s to find the earliest examples of blinding for each disorder, and reviewed the references of the included articles. For an estimated timeline, PubMed was then searched using the limit of "clinical trial" with the terms of each of the 10 neurological disorders, "treatment," and "blind" to determine the number of publications matching these search criteria for each decade after the 1950s; all the matching studies reported in the 1950s are discussed below. After the 1950s, only the initial reports for the 10 neurological disorders that had not already been reported are discussed below.

Results
We found one report from 1784, then a handful of reports from the 1950s, with a subsequent accelerating pace of reports as discussed below and estimated in Table  Based on their initial findings, the commissioners asked, "Why did this agent produce no effect upon Genevieve Leroux, who was in a perpetual state of convulsions?" The next experiment was done on one of the A third single-blind study was the 1954 report of a four-way crossover study of artane, panparnit, hyoscine, and placebo for Parkinsonism. 10 In this study, "All medicaments, including placebo, were prepared in identical capsules which were not distinguishable in appearance... by the use of the placebo any tendency to respond because of the psychologic factors involved in treatment rather than the specific pharmacologic properties of the drug could also be evaluated." Blinding in an epilepsy trial made its appearance in the 1955 report of a single-blind study of five drugs for "petit mal epilepsy," where each group was crossedover with placebo. 11 That same year a report appeared of the first double-blind neurology trial we could find of a new compound for Parkinsonism. 12 In an effort to reduce the placebo effect, all subjects were given "inert tablets resembling" the study drug, and "Patients who In 1956, a double-blind study was reported of cortisone therapy for headache after pneumoencephalography. 13 In this study, the investigators performed In 1957, a study was reported of the use of digestive enzymes for multiple sclerosis that was, for the most part, double-blind. 14   intramuscularly. 21 The authors noted the difficulties of assessing a therapy for this condition, due to the "enthusiastic response of a parent, distressed by the progressive disability seen in his child." In this study, the placebo group was given oral calcium lactate pills, but they were "not given inert intravenous infusions and intramuscular injections as it was felt that this was hardly justifiable; a similar plan was adopted by the In 1971, a double-blind study was reported of isoprinosine for amyotrophic lateral sclerosis. 23 The authors stated a common ethical concern with the use of placebo control groups, "Since the disease is progressive and the pathology presumably irreversible, moral issues were involved in a double-blind study. If some participants did not receive the medication, they would not derive benefit from the study." To address this, the investigators enacted a compromise solution: "The study was, therefore, set up that any patient who felt that the medicine he was taking was ineffective would be placed on the other one after a minimum of ninety days. This guaranteed that each participant would receive the true  (Table 1).

Discussion
In 1940 It is now known that Case 4 was Lou Gehrig, by whose name the disease is commonly known in the United States. Despite the reported results, other sources confirmed that his disease was progressive until it eventually killed him in 1941. 24 It seems that the temptation to believe and the desire to see positive down each of its beliefs and tenets. 28

Conclusions
We found evidence that blinding in therapeutic clinical research for neurological disorders was discovered and well-reported in the 18 th century, but did not appear to enter modern trials until the 1950s, with increasing use in each subsequent decade. The cause for this delay is unclear. Perhaps, among so many other things, the neurologist Hughlings Jackson was correct when he said: "It takes 50 years to get a wrong idea out of medicine, and 100 years to get a right one into medicine." 29