The safety and tolerability of rotigotine transdermal system over a 6-year period in patients with early-stage Parkinson's disease.

J Neural Transm. 2013 Mar 19. [Epub ahead of print]

Giladi N, Boroojerdi B, Surmann E.

Source

Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Sackler School of Medicine, Tel-Aviv University, 6 Weizmann Street, 64239, Tel-Aviv, Israel

Abstract

This open-label extension (SP716; NCT00599196) of a 6-month, double-blind, randomized study (SP513) investigated the safety and tolerability of rotigotine transdermal system over up to ~6 years in patients with Parkinson's disease (PD; early-stage PD at double-blind enrollment). Eligible patients completing the 6-month study received optimal dose open-label rotigotine (≤16 mg/24 h) for up to ~6 years. Adjunctive levodopa was permitted. Primary outcomes included adverse events (AEs) and extent of rotigotine exposure. Analysis of adjunctive levodopa use, dyskinesias [unified Parkinson's disease rating scale (UPDRS) IV], and efficacy (UPDRS II + III total score) were also assessed. Of 381 patients enrolled in the open-label extension, 52 % were still in the study at time of closure; 24 % withdrew because of AEs and 6 % because of lack of efficacy. Patients received rotigotine for a median duration of 1,564.5 days (~4 years, 3 months; range 5-2, 145 days). 69 % of patients started supplemental levodopa; median time to levodopa was 485 days (~1 year, 4 months). Most common AEs (% per patient-year) were somnolence (18 %), application site reactions (12 %), nausea (9 %), peripheral edema (7 %), and fall (7 %). AEs indicative of impulsive-compulsive behavior were recorded in 25 (7 %) patients. Dyskinesias were experienced by 65 (17 %) patients; the majority [47 of 65 (72 %)] reported first dyskinesia after starting levodopa. Mean UPDRS II + III total scores remained below double-blind baseline for 4 years (assessment of all patients). In conclusion, rotigotine was generally well tolerated for up to ~6 years in patients with early-stage PD. The AEs reported were in line with previous studies of rotigotine transdermal system, with typical dopaminergic side effects and application site reactions seen.

Pedunculopontine nucleus: Functional organization and clinical implications.

Neurology. 2013 Mar 19;80(12):1148-1155.

Benarroch EE.

Source

From the Department of Neurology, Mayo Clinic, Rochester, MN.

Abstract

The pedunculopontine tegmental nucleus (PPN) is a neurochemically and functionally heterogeneous structure that occupies a strategic position in the dorsal tegmentum of the midbrain and upper pons. The PPN contains cholinergic, γ-aminobutyric acid (GABA)ergic, and glutamatergic neurons; it receives direct input from the cerebral cortex, is reciprocally connected with the basal ganglia, and provides inputs to the thalamus and motor areas of the brainstem and spinal cord. Via these connections, the PPN is involved in mechanisms of cortical arousal and behavioral state control and participates in control of locomotion and muscle tone. The PPN is affected in Parkinson disease (PD) and atypical parkinsonian syndromes such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Involvement of the PPN may have an important role in gait impairment in these disorders. The development of PPN deep brain stimulation (DBS) for treatment of this disabling symptom has also provided some insight into the function of the PPN in humans. There have been several recent reviews on the PPN focused on its neurochemical organization and connectivity, physiology, involvement in parkinsonian syndromes, and as a target for DBS.

Pathological gambling in Parkinson's disease. A comprehensive review

Parkinsonism Relat Disord. 2013 Mar 11. pii: S1353-8020(13)00074-6. doi: 10.1016/j.parkreldis.2013.02.007. [Epub ahead of print]

Santangelo G, Barone P, Trojano L, Vitale C.

Source

Neuropsychology Laboratory, Department of Psychology, Second University of Naples, Caserta, Italy; Institute of Diagnosis and Care "Hermitage-Capodimonte", Naples, Italy.

Abstract

Pathological gambling (PG) and other Impulse Control Disorders (ICDs), such as hypersexuality, compulsive eating and buying, are often reported in Parkinson's disease (PD). The prevalence of PG is 2.2%-7% in treated PD patients, which is higher than the background population rate. As other non motor symptoms in PD, PG is frequently under-reported by patients and caregivers and may be under-recognized by the treating physicians. Factors associated with PG include male sex, younger age or younger age at PD onset, personal or family history of substance abuse or ICD, a personality profile characterized by impulsiveness, and treatment with dopamine agonists (DA) more than with levodopa (l-dopa). The DA effect seems to be a class effect and not specific for any DA. Neurofunctional studies suggest that medication-induced downregulation of frontostriatal connections and upregulation of striatum might combine to induce impulsive behavior. A dysfunction of fronto-subcortical circuits in PD patients with PG is also supported by neuropsychological findings of impaired executive control and monitoring abilities. Management of ICDs in PD is complex, and until now only discontinuation and/or tapering of DA treatment seem to be an effective management strategy for ICDs in PD. There is no empirical evidence supporting the use of psychiatric drugs for PG such as antipsychotics and antidepressants. Data regarding the effect of deep brain stimulation (DBS), particularly of subthalamic nucleus, on PG and ICDs in PD are still limited and sometimes conflicting since improvement of PG or new onset of PG after surgery have been reported.

Parkin Disease: A Clinicopathologic Entity?

JAMA Neurol. 2013 Mar 4:1-9. doi: 10.1001/jamaneurol.2013.172. [Epub ahead of print]

Doherty KM, Silveira-Moriyama L, Parkkinen L, Healy DG, Farrell M, Mencacci NE, Ahmed Z, Brett FM, Hardy J, Quinn N, Counihan TJ, Lynch T, Fox ZV, Revesz T, Lees AJ, Holton JL.

Abstract

IMPORTANCE Mutations in the gene encoding parkin (PARK2) are the most common cause of autosomal recessive juvenile-onset and young-onset parkinsonism. The few available detailed neuropathologic reports suggest that homozygous and compound heterozygous parkin mutations are characterized by severe substantia nigra pars compacta neuronal loss. OBJECTIVE To investigate whether parkin -linked parkinsonism is a different clinicopathologic entity to Parkinson disease (PD). DESIGN, SETTING, AND PARTICIPANTS We describe the clinical, genetic, and neuropathologic findings of 5 unrelated cases of parkin disease and compare them with 5 pathologically confirmed PD cases and 4 control subjects. The PD control cases and normal control subjects were matched first for age at death then disease duration (PD only) for comparison. RESULTS Presenting signs in the parkin disease cases were hand or leg tremor often combined with dystonia. Mean age at onset was 34 years; all cases were compound heterozygous for mutations of parkin. Freezing of gait, postural deformity, and motor fluctuations were common late features. No patients had any evidence of cognitive impairment or dementia. Neuronal counts in the substantia nigra pars compacta revealed that neuronal loss in the parkin cases was as severe as that seen in PD, but relative preservation of the dorsal tier was seen in comparison with PD (P = .04). Mild neuronal loss was identified in the locus coeruleus and dorsal motor nucleus of the vagus, but not in the nucleus basalis of Meynert, raphe nucleus, or other brain regions. Sparse Lewy bodies were identified in 2 cases (brainstem and cortex). CONCLUSIONS AND RELEVANCE These findings support the notion that parkin disease is characterized by a more restricted morphologic abnormality than is found in PD, with predominantly ventral nigral degeneration and absent or rare Lewy bodies.

Peripheral neuropathy in Parkinson's disease: Levodopa exposure and implications for duodenal delivery

Parkinsonism Relat Disord. 2013 Feb 27. pii: S1353-8020(13)00073-4. doi: 10.1016/j.parkreldis.2013.02.006. [Epub ahead of print]

Müller T, Laar TV, Cornblath DR, Odin P, Klostermann F, Grandas FJ, Ebersbach G, Urban PP, Valldeoriola F, Antonini A.

Source

Department of Neurology, St. Joseph Krankenhaus Berlin-Weißensee, Gartenstr. 1, 13088 Berlin, Germany.

Abstract

In advanced Parkinson's disease (PD) patients, continuous intra-duodenal infusion of levodopa/carbidopa intestinal gel (LCIG) is an established approach in the management of motor complications that cannot be further improved by conventional oral therapy. In general, tolerability of LCIG has resembled that of oral dopaminergic therapy; however, cases of symptomatic peripheral neuropathy (PN), sometimes severe, have been reported in patients receiving LCIG. Cases are generally a sensorimotor polyneuropathy with both subacute and chronic onsets, often associated with vitamin B12 and/or B6 deficiency. Rare cases clinically resemble Guillain-Barré syndrome. In the absence of prospectively collected data on possible associations between LCIG and PN, it is prudent to explore potential mechanisms that may explain a possible relationship. The PN may be linked to use of high-dose levodopa, promoting high levels of homocysteine and methylmalonic acid or reduced absorption of vitamins essential for homocysteine metabolism. Cases of LCIG-associated PN often have responded to vitamin supplementation without need for LCIG cessation, although LCIG cessation is sometimes necessary. It may be advisable to monitor vitamin B12/B6 status before and after patients start LCIG and be vigilant for signs of PN. Prospective, large-scale, long-term studies are needed to clarify whether vitamin supplementation and routine use of a catechol-O-methyltransferase inhibitor may help prevent PN in LCIG recipients and whether these measures should be routine practice in patients with PD on high-dose oral levodopa.

Promotion of physical activity and fitness in sedentary patients with Parkinson's disease: randomised controlled trial

BMJ. 2013 Mar 1;346:f576. doi: 10.1136/bmj.f576.

van Nimwegen M, Speelman AD, Overeem S, van de Warrenburg BP, Smulders K, Dontje ML, Borm GF, Backx FJ, Bloem BR, Munneke M; ParkFit Study Group.

Source

Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Evidence Based Practice, Nijmegen, Netherlands.

Abstract

OBJECTIVE:

To evaluate whether a multifaceted behavioural change programme increases physical activities in patients with Parkinson's disease.

DESIGN:

Multicentre randomised controlled trial.

SETTING:

32 community hospitals in the Netherlands, collaborating in a nationwide network (ParkinsonNet).

PARTICIPANTS:

586 sedentary patients with idiopathic Parkinson's disease aged between 40 and 75 years with mild to moderate disease severity (Hoehn and Yahr stage ≤3).

INTERVENTION:

Patients were randomly assigned to the ParkFit programme or a matched general physiotherapy intervention. ParkFit is a multifaceted behavioural change programme, designed specifically to achieve an enduring increase in the level of physical activity (coaches using motivational strategies; ambulatory feedback).

MAIN OUTCOME MEASURES:

The primary endpoint was the level of physical activity, measured every six months with a standardised seven day recall (LASA physical activity questionnaire-LAPAQ). Secondary endpoints included two other measures of physical activity (activity diary and ambulatory activity monitor), quality of life (Parkinson's disease questionnaire-PDQ-39), and fitness (six minute walk test).

RESULTS:

540 (92.2%) patients completed the primary outcome. During follow-up, overall time spent on physical activities (LAPAQ) was comparable between the groups (adjusted group difference 7%, 95% confidence interval -3 to 17%; P=0.19). Analyses of three secondary outcomes indicated increased physical activity in ParkFit patients, as suggested by the activity diary (difference 30%; P<0.001), the activity monitor (difference 12%; P<0.001), and the six minute walk test (difference 4.8 m; P=0.05). PDQ-39 did not differ between ParkFit patients and controls (difference -0.9 points; P=0.14). The number of fallers was comparable between ParkFit patients (184/299; 62%) and controls (191/287; 67%).

CONCLUSIONS:

The ParkFit behavioural change programme did not increase overall physical activity, as measured with the LAPAQ. The analysis of the secondary endpoints justifies further work into the possible merits of behavioural change programmes to increase physical activities in daily life in Parkinson's disease.

TRIAL REGISTRATION:

Clinical trials NCT00748488.

Rapid eye movement sleep behavior disorder in Parkinson's disease: Magnetic resonance imaging study

Mov Disord. 2013 Feb 28. doi: 10.1002/mds.25367. [Epub ahead of print]

Ford AH, Duncan GW, Firbank MJ, Yarnall AJ, Khoo TK, Burn DJ, O'Brien JT.

Source

Western Australian Centre for Health and Ageing, Centre for Medical Research and School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Western Australia, Australia.

Abstract

BACKGROUND:

Rapid eye movement sleep behavior disorder has poor prognostic implications for Parkinson's disease. The authors recruited 124 patients with early Parkinson's disease to compare clinical and neuroimaging findings based on the presence of this sleep disorder.

METHODS:

The presence of rapid eye movement sleep behavior disorder was assessed with the Mayo Sleep Questionnaire. Magnetic resonance imaging sequences were obtained for voxel-based morphometry and diffusion tensor imaging.

RESULTS:

Patients with sleep disorder had more advanced disease, but groups had similar clinical characteristics and cognitive performance. Those with sleep disorder had areas of reduced cortical grey matter volume and white matter changes compared with those who did not have sleep disorder. However, differences were slight and were not significant when the analyses were adjusted for multiple comparisons.

CONCLUSIONS:

Rapid eye movement sleep behavior disorder was associated with subtle changes in white matter integrity and grey matter volume in patients with early Parkinson's disease.

Short latency afferent inhibition: A biomarker for mild cognitive impairment in Parkinson's disease?

Mov Disord. 2013 Feb 28. doi: 10.1002/mds.25360. [Epub ahead of print]

Yarnall AJ, Rochester L, Baker MR, David R, Khoo TK, Duncan GW, Galna B, Burn DJ.

Source

Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.

Abstract

BACKGROUND:

Mild cognitive impairment in Parkinson's disease (PD) is common and predicts those at risk of dementia. Cholinergic dysfunction may contribute to its pathophysiology and can be assessed using short latency afferent inhibition.

METHODS:

Twenty-two patients with PD (11 cognitively normal; 11 with mild cognitive impairment) and 22 controls participated. Short latency afferent inhibition was measured by conditioning motor evoked potentials, which were elicited by transcranial magnetic stimulation of the motor cortex with electrical stimuli delivered to the contralateral median nerve at varying interstimulus intervals.

RESULTS:

There was no significant difference between cognitively normal PD and controls for short latency afferent inhibition (62.8±30.3% vs. 55.7±21.7%; P=0.447). The PD-mild cognitive impairment group had significantly less inhibition (88.4±25.8%) than both cognitively normal PD (P=0.021) and controls (P=0.01).

CONCLUSIONS:

Cholinergic dysfunction occurs early in those with PD -mild cognitive impairment. Short latency afferent inhibition may be a useful biomarker of increased risk of dementia in PD patients.

Olfactory dysfunction: common in later life and early warning of neurodegenerative disease

Dtsch Arztebl Int. 2013 Jan;110(1-2):1-7. doi: 10.3238/arztebl.2013.0001. Epub 2013 Jan 7.

Hüttenbrink KB, Hummel T, Berg D, Gasser T, Hähner A.

Source

Clinic of Otorhinolaryngology, Head and Neck Surgery, University of Cologne.

Abstract

BACKGROUND:

Disturbances of smell and taste are common. About 5% of the general population have anosmia (absence of the sense of smell). Olfactory dysfunction can markedly impair the quality of life.

METHODS:

Review of pertinent literature retrieved by a selective search.

RESULTS:

In recent years, simple and reliable tests of the sense of smell have been introduced in otorhinolaryngology. Olfactory testing has become a new focus of attention in neurology as well, mainly because many patients with neurodegenerative diseases-including the majority of those with Parkinson's or Alzheimer's disease-have olfactory loss early on in the course of their disorder. Olfactory dysfunction is thus regarded as an early sign of neurodegenerative disease that may allow a tentative diagnosis to be made years before the motor or cognitive disturbances become evident. As for the treatment of olfactory loss, anti-inflammatory drugs and surgery can help in some cases, and olfactory training can lead to significant improvement of post-viral olfactory deficits.

CONCLUSION:

Olfactory dysfunction is common and becomes more common with advancing age. It is increasingly receiving attention as an important sign for the early diagnosis and the differential diagnosis of neurodegenerative disorders.