I remember reading this paper when it was published in 2008, feeling like I was reading the case report of a patient I had struggled to diagnose as a resident. Years prior to this article, I admitted a 24-year old graduate student from a psychiatric facility after having a seizure. She had been in good health until having an episode of acute depression with psychosis. After a week in the inpatient psychiatric facility, she seized. When she arrived at our hospital, she had a depressed level of consciousness and had developed chorea. She, of course in retrospect, must have had NMDAR-encephalitis which we did not have a name for at the time.

Dalmau J et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies

When reading this article by Dalmau et al. at the time of publication as well as re-reading it now, I remember how it impressed on me several things. First, the wide-range of patients with movement disorders that we care for—from acute onset like dystonic reactions and autoimmune chorea to very chronic processes like Parkinson disease and essential tremor. Second, how important the search for the cause and the proper treatment whether in the acute or chronic setting. And finally, as I recollected late nights on call returning to this patient’s room wanting an answer, this paper shows how important it is to go back to the bedside and wonder and to question in order to stimulate the field forward with new answers and new treatments.

Dr. Pirio Richardson is Associate Professor and Vice Chair of Faculty Development at the University of New Mexico Department of Neurology as well as serving as the Acting Chief of the Neurology Service for the New Mexico VA Healthcare System. She has an active research program focused on dystonia, clinical trial readiness and noninvasive neurostimulation in movement disorders and traumatic brain injury. She is a member of the IAPRD website committee.

I am likely biased in my choice of a milestone article, partly because my publications have focused on behavioral problems in PD, particularly psychosis, but probably more because I was the Principal Investigator and first author of this study. The study was funded by the Orphan Drug Division of the Food and Drug Administration. There was a widespread belief that the NIH would not fund studies that fell in the then-netherworld that was the interface between neurology and psychiatry. This was the first multi-centered, double blind, placebo controlled treatment trial of any intervention for any behavioral problem in Parkinson’s disease. As such, there were no validated measures for treatment response so several were used, with the overarching question being, not so much efficacy, but tolerance in terms of motor effect. The power analysis was for side effects, not benefits. The study was a great success. The drug was not only markedly beneficial in every metric but improved tremor without worsening any motor function. The psychiatric benefit was as large or larger than any psychiatric improvement for any psychiatric condition, reported then and now. The doses used were miniscule compared to those used in schizophrenia but the risk of granulocytopenia is thought to be the same so close blood monitoring is still required. The difficulties using clozapine have led to numerous trials of newer antipsychotics but, more importantly, established a beachhead for the expansion of research into non-motor aspects of PD.

Parkinson Study Group. Low dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. N Eng J Med 1999;140(10):757-63.

Joseph H. Friedman, MD, FAAN, FANA, did his neurology residency training at the Neurological Institute of New York, 1979-82, then moved to Rhode Island. He has the Stanley Aronson Chair in Neurodegenerative Diseases at Butler Hospital and is Professor and Chief of the Division of Movement Disorders in the Dept of Neurology of the Warren Alpert Medical School of Brown University, and Adjunct Professor in the School of Pharmacy of the University of Rhode Island. He has served on the editorial boards of Parkinsonism & Related Disorders and Movement Disorders, and was Editor in Chief of the Rhode Island Medical Journal from 1999-2018. He was an original member of the Parkinson Study Group, a member of its Executive Committee, and has been clinical director of the American Parkinson’s Disease Information and Referral Center since 1984. His research has focused on behavioral aspects of Parkinson’s Disease.

A 33year old man with Parkinson’s disease of 7 years duration, well controlled on levodopa (300 mg/day) and pramipexole (4.5mg/day) came to the hospital for a check-up. He tried to grope a nurse and was arrested for sexual misbehaviour. The patient was released after the neurologist testified that the behaviour was secondary to the use of dopamine agonists. His impulse control disorder (ICD) was controlled after stopping pramipexole and increasing levodopa dose. This power of dopaminergic agonists to cause havoc in the lives of patients both professionally and personally has been well documented in the Dominion study by Daniel Weintraub et al. Among the 3090 PD patients who were evaluated, 13.6% had ICDs. The use of a dopamine agonist resulted in increased risk of developing ICDs with an odds ratio of 2.72. This study was the first to look a large population of PD patients with ICDs. This has changed the pattern of treatment of PD patients with a careful and watchful prescription of dopaminergic agonists worldwide. This has also helped us in understanding the impact of basal ganglia on reinforcement learning. The search for the perfect therapy for Parkinson’s disease goes on . . .

Weintraub D, Koester J, Potenza MN, Siderowf AD, Stacy M, Voon V, Whetteckey J, Wunderlich GR, Lang AE. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol. 2010 May;67(5):589-95.

Dr Rukmini Mridula Kandadai is currently working as an Associate Professor in Department of Neurology, Nizam’s Institute of Medical Sciences, Hyderabad, India. She completed her training in Neurology in the same Institute in 2008 and is working with Prof. Rupam Borgohain in the field of movement disorders. She is a clinician and is a part of STN-DBS team in NIMS and follows more than 400 patients who have undergone implantation. Her current research is on the impact of lead positioning on the motor and non-motor changes after STN DBS. She is a founding member of Movement Disorders Society of India as well as the Parkinson’s Research Alliance of India.

A Parkinson patient is referred to your clinic. The man can’t walk but claims that he can ride a bicycle! This sounds absurd, but it was actually documented by Snijders and Bloem in a novel case study of a man from The Netherlands who had full-blown Parkinson’s disease. In a video that went viral in 2010, the man fluidly rides his bicycle through a parking lot (and out into the street) yet cannot walk once he dismounts. It inspires me to see the enormous potential of people with advanced stage Parkinson’s disease. In addition, this article illustrates how little we understand about Parkinson’s disease, how much there is left to discover about the workings of the parkinsonian brain, and the efficacy of non-pharmacologic therapies. Snijders and Bloem teach us that conventional thinking won’t change health care when it comes to Parkinson’s. This is an exciting field that is still wide open for discovery, education, exploration, collaboration, and innovations in methodologies, concepts, instrumentation and interventions.

Snijders AH, Bloem BR. Images in clinical medicine. Cycling for freezing of gait. N Engl J Med. 2010 Apr 1;362(13):e46. doi: 10.1056/NEJMicm0810287.

Dr. Hirsch completed NIH training in neurorehabilitation research and Parkinson’s disease at Johns Hopkins (‘96-‘99) and advanced training in movement disorders at the Heinrich-Heine University of Dusseldorf, Germany (2000). His current research is focused on understanding how physical exercise and social capital (which deals with issues of trust and the value of networks to connect patients to communities) affect neuroplasticity in the basal ganglia and how changes in basal ganglia function affect physical and social performance. Dr. Hirsch is a member of the PRD Editorial Board and Chair of the Neurodegenerative Diseases Networking Group of the American Congress of Rehabilitation Medicine.