Neurology -- Correspondence for Frank et al., 65 (7) 1101-1103

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Correspondence published:

What is the risk of sham surgery in Parkinson disease clinical trials? A review of published reports: William Landau (8 March 2006)

Reply from the authors: Samuel A. Frank, Karl Kieburtz, Robert Holloway, and Scott Y.H. Kim (8 March 2006)

What is the risk of sham surgery in Parkinson disease clinical trials? A review of published reports 8 March 2006

William Landau,
Washington University School of Medicine
660 S. Euclid Avenue, St. Louis, MO 63110
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Re: What is the risk of sham surgery in Parkinson disease clinical trials? A review of published reports

landauw{at}neuro.wustl.edu William Landau

After nearly a century of uncontrolled neurosurgical efforts to ameliorate symptoms of parkinsonism, it is good to know of the evolving consensus that new research must provide reliable double-blind control strategies. [1,2] If the only distinction required of a phase 3 study were the difference between placebo suggestibility and certain biological proof of the injectate’s theoretical mechanism, then a scalp incision/burr hole double-blind control would provide adequate protocol design.
But the stubborn complexity of the pathophysiological circuitry of parkinsonism, along with the theoretical baggage of various invasive techniques, leads to the logical necessity for brain penetration control data.
Experience provides evidence for four possible classes of clinical effects; unfortunately, they are not mutually exclusive.
1. Psychogenic placebo effect, prejudicial tilted judgment, often shared by observers as well as subjects. Argument that such improvement is negligible is unjustified.
2. The theoretical biological effect, somehow equivalent to total restoration of normal functional neuronal circuitry, has been accomplished. Conceptually competent candidate agents have included natural or artificial trophic or growth substances that reverse cellular degeneration, resurrect sick synapses, or supplement transmitter substance; viable cells that passively extrude functional chemicals or become intimately involved in synaptic circuitry control; powerful new structural agents like genes and stem cells; carrier substances like viruses and gelatin globs. Clinical improvement alone is inadequate proof of mechanism.
3. Acutely or subsequently, there are positive symptoms and signs of tissue injury like intractable movements, dementia, Lhermitte phenomenon, nausea, anorexia, vomiting, weight loss, hyponatremia, and depression. [3,4] Mechanisms of injury are secondary problems.
4. Improvement of parkinsonian symptoms may be the direct consequence of non-specific injury of neural tissue in many regions, a remarkable paradox of parkinsonian pathophysiology. [5,6] Some prematurely enthusiastic claims for cure by adrenal and embryonic brain stem transplantation were based upon effects too acute to be attributable to physiological mutation. But now the long term efficacy of subthalamic nucleus inactivation/lesion is well established.
Possible injurious effects that must be considered are not only mechanical, but also immediate and delayed toxic, infectious, inflammatory, antigenic, and neoplastic phenomena. [7] It follows that control experiments must include full doses of all of the potentially injurious agents that accompany the putative curative stuff. The ethical risk for human subjects will be best limited by more thorough and prolonged primate model studies that have become common custom. The burden of prime prototypes must be a rigorous challenge of the therapeutic hypothesis using pertinent physiological, pathological, and histochemical methods that cannot be readily engaged in human subjects.
Disclosure: The author reports no conflicts of interest.

Reply from the authors 8 March 2006

Samuel A. Frank,
Boston University
715 Albany St., C329, Boston, MA 02118,
Karl Kieburtz, Robert Holloway, and Scott Y.H. Kim
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Re: Reply from the authors

samfrank{at}bu.edu Samuel A. Frank, et al.

We agree with Dr. Landau that the safety and efficacy evaluation of new interventions requires well-designed trials that include a placebo control condition. Even though the majority of PD experts agree with the use of a placebo surgery in well-designed trials, there remains debate about the degree of invasiveness of the control. [2] In addition, potential research subjects need to have a say in what is permissible.
There is literature representing the opinion of neurologists and ethicists but little to formally represent patient opinions. Before we inject “the putative curative stuff,” we should assess patients willingness to participate knowing they may receive a “potentially injurious agent.” From previous trials, we know that at least a small number of people are willing to participate in such research.

References
1. Frank S, Kieburtz K, Holloway R, Kim SYH. What is the risk of sham surgery in Parkinson disease clinical trials? A review of published reports. Neurology 2005;65:1101-1103.
2. Kim SYH, Frank S, Holloway R, Zimmerman C, Wilson R, Kieburtz K. Science and ethics of sham surgery: A survey of Parkinson disease clinical researchers. Arch Neurol 2005;62:1357-1360.
3. Anderson FH, Lehrich JR. Lhermitte sign following head injury. Arch Neurol 1973;29:437-438.
4. Kordower JH, Palfi S, Chen E-Y, et al. Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease. Ann Neurol 1999;46:419-424.
5. Landau WM. Artificial intelligence: The brain transplant cure for parkinsonism. Neurology 1990;40:733-740.
6. Landau WM. Special Correspondence, Reply to Letters to the editor: Tissue transplants for PD. Neurology 1994; 44:573-577.
7. Folkerth RD and Rudso R. Survival and proliferation of nonneural tissues, with obstruction of cerebral ventricles, in a parkinsonian patient treated with fetal allografts. Neurology 1996;46:1219-1225.
Disclosure: The authors report no conflicts of interest.