Book Review

The Case of the Frozen Addicts: How the solution of an extraordinary medical mystery spawned a revolution in the understanding and treatment of Parkinson's disease

N Engl J Med 1996; 335:2002-2003December 26, 1996

Article

The Case of the Frozen Addicts: How the solution of an extraordinary medical mystery spawned a revolution in the understanding and treatment of Parkinson's disease
By J. William Langston and Jon Palfreman. 309 pp. New York, Pantheon, 1996. $25. ISBN: 0-679-42465-2

This book dramatically recounts the discovery of the cause of a local outbreak of sudden, severe parkinsonism in a group of young adults in northern California and how this discovery led to greater insight into Parkinson's disease. Langston is the Bay Area neurologist who reported the event and led a team of investigators to pinpoint the toxicant responsible for the acute loss of dopamine-containing neurons in the substantia nigra, causing the parkinsonism in these patients. The story unfolds and builds suspense as Langston and his colleagues determine that the toxicant is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP was the unwanted product resulting from a short step in the planned synthesis of an illicit type of synthetic heroin that was sold on the streets to addicts. The book describes how Langston, beginning with this discovery, went from being a general clinical neurologist to becoming a well-respected and widely known clinical and scientific investigator of Parkinson's disease.

Medical writer and coauthor Palfreman helps weave a highly readable and spellbinding medical detective tale. The book opens with the unfortunate victims becoming immobile (“frozen”), unblinking, and mute only hours after injecting the street drug. As can be imagined, Langston and colleagues at Santa Clara Valley Medical Center were perplexed by the strange state of the first patient they encountered. On examining the patient's girlfriend and finding her in a similar frozen state, Langston and his neurology colleague, Phil Ballard, realized there must be a connection.

As luck would have it, Ballard attended a party given by a neurologist friend. The two chatted about interesting medical problems; the other neurologist, James Tetrud, had also just encountered two young people in the same physical state. All four affected persons were heroin addicts. After Langston went on television to alert the community about bad “heroin” being sold on the street, a viewer told him of two additional patients.

Langston obtained leftover samples of the powder that the victims had injected and shared them with law-enforcement agents who were already actively pursuing, capturing, and prosecuting illicit street chemists producing addictive “designer drugs.” Law-enforcement chemists showed that the samples did not contain heroin but an analogue of meperidine (Demerol), although the exact chemical structure still eluded them. Fortunately, one of the chemists recalled reading three years earlier, in an obscure psychiatry journal, about an unusual case of a youth who had synthesized his own narcotics and came down with sudden, severe parkinsonism. National Institutes of Health (NIH) biochemist Sanford Markey had identified several meperidine analogues, including MPTP, in the youth's chemical flasks. But MPTP failed to induce parkinsonism in rats, and NIH scientists were not certain which of the analogues, if any, was responsible for the youth's impairment. Levodopa treatment was effective in this case, but the youth died 18 months later of an overdose of cocaine. The brain showed a selective destruction of the dopamine neurons in the substantia nigra.

Langston then consulted with Ian Irwin, a chemist at Stanford University, who determined that of the different meperidine analogues reported by the NIH scientists, only one fit the mass spectroscopic analysis carried out on the powder injected by Langston's patients — namely, MPTP. After Langston phoned Markey and told him about his patients, the NIH scientists renewed their interest and began to pursue the scientific investigation of MPTP. One NIH scientist had two of Langston's patients come to the NIH for studies, and it was shown that MPTP induced permanent parkinsonism in monkeys. Langston, meanwhile, worked with his colleagues to confirm this animal model and to provide tissue specimens to his collaborating neuropathologist, Lysio Forno, who described the animal pathology.

The race was on to achieve scientific prominence, reminding one of the competition described in James D. Watson's The Double Helix: A Personal Account of the Discovery of the Structure of DNA (New York: Atheneum, 1968). Langston reported the discovery of his six patients in a February 1983 issue of Science just as the NIH team's discovery of the primate model was accepted by the Proceedings of the National Academy of Science. Langston's article brought him instant fame, and the scientific community bought out the stock of MPTP from its chemical supplier. The discovery of MPTP-induced parkinsonism stimulated many new investigations and prompted new investigators to work in Parkinson's disease research. This heightened activity led eventually to the knowledge that MPTP had to be oxidized by the enzyme monoamine oxidase to yield the actual toxin, the positively charged metabolite MPP+. Subsequently, the mechanism of action of MPP+ as a mitochondrial toxin (which interferes with complex I) led to the finding that in Parkinson's disease itself there is decreased complex I activity in the substantia nigra.

Unfortunately, the patients with MPTP-induced parkinsonism had severe complications from levodopa, much as had Oliver Sacks's postencephalitic patients, as described in his book Awakenings (Harmondsworth, United Kingdom: Penguin Books, 1976). Langston's patients had uncontrollable dyskinesias, deep “off” states of parkinsonism (in which levodopa is temporarily and frequently not effective), and drug-induced personality changes and psychosis. The book tells how some of these patients underwent transplantation of fetal dopamine neurons and have shown improvement, as subsequently reported in the Journal (Widner H, et al., 1992;327:1556-63).

In addition to the story of scientific pursuit and discovery, the book describes the personalities of a number of scientists who had a role in the story, the advances in understanding Parkinson's disease, the use of the MPTP primate model to test new drugs and surgical treatments, and the politics of transplantation of fetal dopamine neurons in patients with Parkinson's disease.

The book should be enjoyed by physicians and scientists as well as the public. It is as absorbing as a good mystery, as entertaining as an exciting novel, and as enlightening as a good biography.

Stanley Fahn, M.D.
College of Physicians and Surgeons of Columbia University, New York, NY 10032

Citing Articles (1)

Citing Articles

1. 1

   Jordi Bové, Celine Perier. (2011) Neurotoxin-based models of Parkinson's disease. Neuroscience
   CrossRef