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Noteworthy Advances in Movement Disorders
DBS, Tourette Syndrome, and Genetics of Sporadic and Familial Parkinson Disease

Research in movement disorders made big strides in 2006, according to Joseph Jankovic, MD, professor of neurology and director of the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston, TX. Dr. Jankovic highlighted exciting findings in a wide range of areas, including deep-brain stimulation (DBS), drug therapies, and disease genetics.

DEEP BRAIN STIMULATION

DBS has been a hot topic for several years. It is already an established treatment for selected patients with Parkinson disease (PD), and promising results in patients with depression and epilepsy have made headlines. Now Tourette syndrome and generalized dystonia are claiming a place on the list.

In one study (N Engl J Med 2006;355:896–908), 156 patients with advanced PD and severe motor symptoms were randomized to either bilateral stimulation of the subthalamic nucleus, or to best medical treatment. Patients who had DBS improved significantly more than people in the medication group. The downside: neurostimulation was also associated with 10 severe adverse events, including one death from intracerebral hematoma during surgery; compared to only three serious events in the medication group, the difference was significant.

The risk of adverse events must be weighed against the superior clinical results of DBS, Dr. Jankovic said. At Baylor, more than 600 patients with PD have had DBS. Their rates of serious adverse events, including a single seizure (1.3 percent) and intracerebral hemorrhage (0.6 percent) were low but still cause for concern. He recommended that DBS be reserved for people who have troublesome symptoms despite optimal medical therapy.

DBS proved superior to sham stimulation of the globus pallidus internus (GPi) in a controlled, randomized study of 40 patients with primary segmental or generalized dystonia (N Engl J Med 2006;355:20–32).The primary end point was change in symptom severity within three months, as measured by the movement subscore on the Burke-Fahn-Marsden Dystonia Rating Scale. “These findings are similar to our experience with DBS in patients with generalized dystonia,” Dr. Jankovic said.

TOURETTE SYNDROME

The Tourette syndrome (TS) study included only two patients, but was noteworthy because a different site was stimulated in each case: the thalamus in “Patient 1,” a 45-year-old man, and the GPi in “Patient 2,” a 27-year-old man (Mov Disord 2006;21:709–713). Both patients had longstanding TS and were either unresponsive to conservative treatment, or had experienced intolerable side effects from drug treatment. At one-year follow-up, the target tics had decreased from 20 to three per minute in one patient and from 28 to two per minute in the second. All major tics and compulsions disappeared. These findings are consistent with evidence that TS arises from abnormal activity in the basal ganglia-thalamocortical circuit, the authors wrote.

“We have also used the GPi as the target and found robust benefit not only in tics but also in the obsessive-compulsive behavior” of patients with TS [Mov Disord 2000;15:869–72], Dr. Jankovic said. However, he cautioned, “Until a well-designed, multicenter study is performed, the question of what the optimal surgical target is for patients with TS will not be answered.”

PD AND IMPULSE Control Disorders

The first published report of an impulse control disorder (ICD) related to PD involved compulsive gambling and appeared in 2000 (Mov Disord 2000;15:869–872). Since then, more data have shown that ICD is a real and troubling untoward effect of dopaminergic agents used to treat PD. Two studies published in 2006 add to that growing body of evidence.

The first (Arch Neurol 2006;63:969–973) reported on 272 PD patients, including 137 who were taking a dopamine agonist. Of the entire cohort, 11 tested positive for an active ICD at screening, with pergolide the agent most frequently implicated. Compulsive gambling and compulsive sexual behavior were equally common. Only dopamine agonist use and a history of ICD symptoms prior to PD diagnosis were significant predictors of an active ICD.

In the second study (Neurology 2006;67:1258–1261), investigators in the United Kingdom studied 66 men and 34 women with PD and found six men and three women with one or more ICDs, an overall prevalence of 9 percent. All of those patients were taking dopamine agonists. They were also on levodopa therapy when the ICD symptoms began. Of the psychoactive medications taken by all subjects, only dopamine agonists as a class were associated with ICD, with an odds ratio of 11.9 (p<0.0001). Depressed mood and irritability were other ICD risk factors.

Despite these findings, the authors strike a cautious note, writing, “it cannot be established that dopamine agonist therapy alone places patients at a greater risk for ICDs.” Dr. Jankovic acknowledged that ICDs are rare, but believes neurologists should warn patients about this potential adverse effect when prescribing dopaminergic agents.

ADVANCES IN DRUG THERAPY

Dr. Jankovic singled out studies targeting Huntington disease (HD) and essential tremor to illustrate progress in drug treatment.

Eighty-four ambulatory patients with HD participated in a randomized, placebo-controlled trial of tetrabenazine (TBZ), a dopamine-depleting agent expected to receive FDA approval this year (Neurology 2006;66:366–372). The patients took TBZ in a maximum daily dose of 100 mg (N=54) or a placebo (N=30) for 12 weeks. TBZ proved superior to the placebo on the primary outcome variable, a favorable change in the Unified Huntington's Disease Rating Scale, and in secondary and exploratory outcome variables such as clinical global improvement and level of depression.

Figure

Dr. Joseph Jankovich: “Until a well-designed, multicenter study is performed, the question of what the optimal surgical target is for patients with TS will not be answered.”

On the other hand, the drug elicited no significant changes in other functional outcomes measured, serving as “a reminder that chorea is only one of many sources of disability for patients with HD,” the authors wrote. Adverse effects associated with TBZ included drowsiness, insomnia, depression, parkinsonism, and akathisia.

Neurologists should also consider TBZ when treating people with certain drug-induced movement disorders. Dr. Jankovic co-authored a review of metoclopramide, which is widely prescribed for treating gastric motility problems (Nat Clin Pract Gastro Hep 2006;3:138–148). Unfortunately, “metoclopramide continues to be the most common cause of tardive dyskinesia,” he told Neurology Today. “Besides withdrawing the drug, TBZ may provide effective relief for patients with metoclopramide-induced tardive dyskinesia.”

Meanwhile, topiramate showed promise in the management of essential tremor in a double-blind study of 208 elderly patients, confirming the findings of earlier, smaller studies (Neurology 2006;66:672–677). These patients all had moderate to severe essential tremor of the upper limbs. They were randomized to receive either topiramate (108) or placebo (100) for 24 weeks. Topiramate was administered either as monotherapy or as an adjunct to existing therapy in a mean final dose of 292 mg per day. Patients in the topiramate group experienced a mean improvement of 29 percent in the Fahn-Tolosa-Marin Tremor Rating Scale, compared to 16 percent in the placebo group (p<0.001). Other functional improvements associated with topiramate involved motor tasks, writing, and speaking. The drug did cause several treatment-limiting adverse effects, including paresthesia, nausea, problems with concentration or attention span, and somnolence.

GENETIC ADVANCES

Two papers on genetics illustrate the enormous progress made in the understanding of movement disorders and the questions that remain. In one, the authors found that the G2019S mutation of the LRRK2 gene is strikingly common among North African Arabs and Ashkenazi Jews with familial and, even more intriguingly, sporadic PD, suggesting that this mutation is a significant PD risk factor in this population (N Engl J Med 2006;354:422–423).

“This is consistent with our findings, because about 11 percent of the Ashkenazi Jewish patients evaluated at the Baylor Parkinson's Disease Center and Movement Disorders Clinic have an LRRK2 mutation,” Dr. Jankovic pointed out. According to the National Human Genome Research Institute (NHGRI), LRRK2 mutations are responsible for 5 percent to 10 percent of dominantly inherited PD.

The authors of the second paper reviewed recent advances in the genetics of PD and their impact on current and future treatment and research (Ann Neurol 2006;60:389–398). Only in the last 10 years have investigators accepted that PD may have a genetic component, thanks in part to the cloning of five genes: LRRK2, SNCA, PRKN, DJ-1, and PINK1.

The NHGRI estimates that PINK1 mutations cause about 2 percent of early-onset cases of PD. However, there's not yet enough evidence to link mutations in all of these genes to a single pathophysiological pathway, although hints of a few critical common processes are starting to emerge. Any unique or specific pathologic features associated with each gene have yet to be identified, which adds to the uncertainty surrounding their role in the etiology of PD. Lewy bodies are always associated with SNCA, sometimes with LRRK2, and almost never with PRKN; whether they occur with DJ-1 or PINK1 is still unknown. Also unknown is the contribution, if any, that these genes make to sporadic PD. It is assumed that the pathogenesis of genetic and sporadic cases is the same, but this assumption is unproven, the authors warn.

Answers to these questions will help identify target proteins and pathways for basic and clinical research. Of course, it also raises disturbing questions about testing people for the mutations associated with PD.

All in all, said Dr. Jankovic, “These genetic discoveries present new challenges for clinicians who must learn how to interpret the findings and use the growing number of commercially available DNA tests in genetic counseling of PD patients and their families.”

REFERENCES

Deuschl G, Schade-Brittinger C, Krack P, et al. A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med 2006;355:896–908.
Kupsch A, Benecke R, Maller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006;355:20–32.
    Ackermans L, Temel Y, Cath D, et al. Deep brain stimulation in Tourette's syndrome: two targets? Movement Disorders 2006;21:709–713.
    Pontone G, Williams JR, Bassett SS, et al. Clinical features associated with impulse control disorders in Parkinson disease. Neurology 2006;67:1258–1261.
    Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology 2006;66:366–372.
    Pasricha PJ, Pehlivanov N, Sugumar A, et al. Drug Insight: from disturbed motility to disordered movement – a review of the clinical benefits and medicolegal risks of metoclopramide. Nat Clin Pract Gastro Hep 2006;3:38–148.
      Ondo WG, Jankovic J, Connor GS, et al. Topiramate in essential tremor: a double-blind, placebo-controlled trial. Neurology 2006;66:672–677.
      Lesage S, Darr, A, Tazir M, et al. LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N Engl J Med 2006;354:422–423.
      Hardy J, Huaiban C, Cookson MR, et al. Genetics of Parkinson's disease and parkinsonism. Ann Neurol 2006;60:389–398.
      Deng H, Le W, Guo Y, Hunter CB, Xie W, Huang M, Jankovic J. Genetic analysis of LRRK2 mutations in patients with Parkinson disease. J Neurol Sci 2006;251:102–6.
      Shahed J, Poysky J, Kenney C, Simpson R, Jankovic J. GPi deep brain stimulation for Tourette syndrome improves tics and psychiatric co-morbidities. Neurology 2007;68:159–160.