Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 20th WFN - World Congress on Parkinson’s Disease and Related Disorders

Geneva, Switzerland / December 8-11 2013

Geneva - Parkinson’s disease (PD) was historically thought to be caused by abnormally low levels of dopamine. Low levels of dopamine eventually led to the cardinal symptoms of PD including bradykinesia, rigidity and tremor. It is now known that PD is multi-factorial in etiology and that many different mutations can give rise to familial PD. There is insufficient evidence to support a neuroprotective effect from any current PD therapies. However, a number of factors are strongly predictive of PD risk, allowing for identification of at-risk patients during the earliest stages of the disease. Early identification of these patients will give physicians a larger window of opportunity to intervene once neuroprotective agents are identified. In the interim, PD is still symptomatic and there are a number of agents that are capable of targeting specific symptoms.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

As argued by Dr. Amos Korczyn, Sackler School of Medicine, Tel Aviv University, Israel (Abstract 89), not all criteria by which Parkinson’s disease (PD) has been classically described remain true. At least a proportion of PD is, for example, genetically determined. "Results from our centre show that among the Ashkenazi Jews, one-third of patients with PD carry a genetic mutation in either the glucocerebrosidase gene (GBA) or the leucine-rich repeat kinase (LRRK2) gene," he said. "So it’s not true that PD is non-familial."

Moreover, many environmental factors including exposure to toxins and head trauma have been implicated in the etiology of PD; others, including coffee consumption and cigarette smoking, appear to protect against it. "In other words, there is phenotypic convergence where the same clinical manifestations of PD appear but they are caused by multiple different etiologies,"
Dr. Korczyn emphasized. An increasing number of mutations have been identified over the past number of years that either cause PD or increase the risk of developing it.

Factors Predicting PD

As speakers here suggested, identification of causative genetic factors should help clarify underlying disease mechanisms giving rise to PD. "Genetically-determined PD also provides unparalleled ways to study pre-motor manifestations,"
Dr. Christian Wider, University of Lausanne, Switzerland said (Abstract 33). As he described, various imaging studies have shown that significant differences can be detected in brain function and performance tasks between carriers of different PD mutations and non-carriers well before patients present with symptomatic PD.

On the other hand, genetic testing for all but highly select patient groups is unlikely to ever be feasible and even if a mutation is identified, it does not change treatment choice at present. A more predictable way of identifying patients at increased risk for PD is to assess them for REM sleep behaviour disorder (RBD). Patients with RBD act out physically during REM sleep—kicking, pushing, yelling, a sign of aberrant sleep behaviour.

Dr. Ronald Postuma, Associate Professor of Neurology, McGill University, Montreal, and colleagues found that, at 5 years, approximately 20% of one group of idiopathic RBD patients had developed a neurodegenerative disease (PD, Lewy body dementia, Alzheimer’s disease, multiple system atrophy) while at 12 years, over half of the same group of patients had developed one of the same diseases (Neurology 2009;72:1296–1300). As he also discussed (Abstract 8), if a patient has RBD with normal olfaction, their risk of developing a neurodegenerative disease over the next 5 years ranges from between 15 to 20%. "However, if olfaction is abnormal, the risk of developing a neurodegenerative disorder increases by up to 65%," Dr. Postuma said.

Similarly, about 80% of PD patients have a reduced ability to sort colours. Colour vision is also abnormal in most RBD patients. There is evidence that colour vision can also predict PD in RBD patients, where those with normal colour vision have about a 25% risk of developing PD in the future, while the risk of PD approaches 75% in RBD patients with abnormal colour vision as Dr. Postuma noted. "RBD has by far the highest specificity of any clinical marker with up to a 100% risk of developing a neurodegenerative disease if patients are followed long enough," Dr. Postuma concluded. "So by identifying at-risk patients early, we have a major opportunity in which to intervene."

MAO-B Inhibitors

To date, there is not enough evidence to support a neuroprotective effect from any of the current agents used to treat PD. Based on his own retrospective review, Dr. Dwight Stewart, Cambridge Neurology, Cambridge, Ontario, nevertheless suggests that rasagiline, an irreversible monoamine oxidase type B (MAO-B) inhibitor which can be administered as monotherapy or as adjunctive therapy in early and advanced disease, appears to offer patients a "smoother" ride through the course of their disease.

In his retrospective chart review of patient visits between 1999 and 2013 (E poster 590), Dr. Stewart identified 417 patients,
254 of whom were rasagiline-naïve and 163 of whom had been exposed to the MAO-B inhibitor. In the MAO-B inhibitor experienced arm, some 120 patients had stayed on treatment for between 1 to 6 years, while 43 discontinued treatment. Charts were reviewed to determine which medications were used over repeated office visits. When the usage of levodopa, dopamine agonists or anticholinergic medications were compared, there was no difference between the two groups. A levodopa equivalence (LDE) calculation was done for treated and treatment-naïve patients. "What we found was that patients who were on rasagiline had
about 40% less LDE medication per year than those who were not, so patients were able to maintain functionality on a lower LDE dose," Dr. Stewart reported. The incidence of dyskinesia and freezing (16.7% vs 34.9% and 3.3% vs 18.6% respectively, continuing vs discontinued treatment) was also numerically lower among MAO-B inhibitor recipients.

Another irreversible MAO-B inhibitor, selegiline, is also used to treat PD and can be given as monotherapy or adjunctive therapy. In a comparison of adverse drug reactions (ADRs), Lloret et al. (Abstract 250) found that the frequency of impulse control disorder and somnolence was lower with both selegiline and rasagiline compared to ropinirole as reported in a French PharmacoVigilance Database. Overall, both MAO-B inhibitors demonstrated good tolerability, with orthostatic hypotension and psychosis being more common with selegiline and headaches, renal and musculoskeletal ADRs being most common with rasagiline.

Exercise in PD

Evidence of a possible neuroprotective action from exercise in PD has also been explored but results have been obscured by evaluating the effect of exercise in different stages of the disease and in patients receiving a variety of treatments. In a randomized, controlled study designed to test whether a multidisciplinary intensive rehabilitation treatment (MIRT) program slowed disease progression, Dr. Giuseppe Frazzitta, Head, Parkinson Disease Rehabilitation and Neurorehabilitation, Moriggia-Pelascini Hospital, Gravedona ed Uniti, Italy and colleagues assigned 40 newly diagnosed PD patients to intensive rehabilitation or control (E poster 591).

At 2 years, Dr. Frazzitta and colleagues found that there was only a slight trend towards an increased need for treatment in MIRT patients compared to a significant increase in the need for therapy among controls. The percentage of patients in monotherapy dropped from 100% at 1 year to 75% at 24 months but this still compared favourably to control patients, only 40% of whom were still on monotherapy at 6 months and only 20% at 12 months. "MIRT can slow down the progression of motor decay in early stage disease and possibly modify the course of disease," the group concluded. "And results suggest a possible neuroprotective aspect of exercise on PD."

PD and Other Disorders

Another common sleep disorder in PD patients is restless leg syndrome (RLS). "RLS can occur if you use levodopa and it can get worse, with 30 to 80% of patients developing augmentation with levodopa use," Dr. Wolfgang Oertel, Professor for Neurology, Philipps University, Marburg, Germany said (Abstract 9). In a long-term trial of idiopathic RLS patients without PD (Lancet Neurol 2011;10:710-20), Dr. Oertel and colleagues reported that provided physicians used the registered dose of rotigotine, a dopamine agonist, augmentation rates occurred in only 5% of RLS patients over 5 years, "so if you have PD and RLS, you should treat with a long-acting dopamine agonist," he said.

Spanish investigators under Pagonabarraga (Abstract 251) also reported that the use of rotigotine in selected patients with complaints of interrupted sleep was associated with a significant improvement in sleep fragmentation and global sleep quality, the latter predominantly and independently associated with improvement in RLS-like symptoms. Melone et al. (E poster 589) similarly reported a "marked" improvement on several aspects of sleep dysfunction in PD patients reporting difficulties in initiating and maintaining sleep after they had received the combination of levodopa plus rasagiline over a treatment interval of 12 weeks.

Conclusion

Treatment of PD is still symptomatic and there are a number of agents that are capable of targeting specific symptoms including levodopa, dopamine agonists, anticholinergics, COMT and MAO-B inhibitors. As with other neurodegenerative disorders, PD has a long prodromal phase. Should potent neuroprotective agents be identified, this long prodromal stage will offer a window of opportunity during which physicians may be able to modify the course of the disease and improve patient outcomes. Until such agents are available, there is evidence that MAO-B inhibition, as well as exercise rehabilitation, may slow disease progression

.