Cindy Zadikoff

A comparison of the mini mental state exam to the Montreal cognitive assessment in identifying cognitive deficits in Parkinson's disease.

Dementia is an important and increasingly recognized problem in Parkinsons disease (PD). The mini‐mental state examination (MMSE) often fails to detect early cognitive decline. The Montreal cognitive assessment (MoCA) is a brief tool developed to detect mild cognitive impairment that assesses a broader range of domains frequently affected in PD. The scores on the MMSE and the MoCA were compared in 88 patients with PD. A pronounced ceiling effect was observed with the MMSE but not with the MoCA. The range and standard deviation of scores was larger with the MoCA(7–30, 4.26) than with the MMSE(16–30, 2.55). The percentage of subjects scoring below a cutoff of 26/30 (used by others to detect mild cognitive impairment) was higher on the MoCA (32%) than on the MMSE (11%)(P < 0.000002). Compared to the MMSE, the MoCA may be a more sensitive tool to identify early cognitive impairment in PD.

Circadian Melatonin Rhythm and Excessive Daytime Sleepiness in Parkinson Disease

IMPORTANCE Diurnal fluctuations of motor and nonmotor symptoms and a high prevalence of sleep-wake disturbances in Parkinson disease (PD) suggest a role of the circadian system in the modulation of these symptoms. However, surprisingly little is known regarding circadian function in PD and whether circadian dysfunction is involved in the development of sleep-wake disturbances in PD. OBJECTIVE To determine the relationship between the timing and amplitude of the 24-hour melatonin rhythm, a marker of endogenous circadian rhythmicity, with self-reported sleep quality, the severity of daytime sleepiness, and disease metrics. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study from January 1, 2009, through December 31, 2012, of 20 patients with PD receiving stable dopaminergic therapy and 15 age-matched control participants. Both groups underwent blood sampling for the measurement of serum melatonin levels at 30-minute intervals for 24 hours under modified constant routine conditions at the Parkinsons Disease and Movement Disorders Center of Northwestern University. INTERVENTIONS Twenty-four hour monitoring of serum melatonin secretion. MAIN OUTCOMES AND MEASURES Clinical and demographic data, self-reported measures of sleep quality (Pittsburgh Sleep Quality Index) and daytime sleepiness (Epworth Sleepiness Scale), and circadian markers of the melatonin rhythm, including the amplitude, area under the curve (AUC), and phase of the 24-hour rhythm. RESULTS Patients with PD had blunted circadian rhythms of melatonin secretion compared with controls; the amplitude of the melatonin rhythm and the 24-hour AUC for circulating melatonin levels were significantly lower in PD patients (P < .001). Markers of the circadian phase were not significantly different between the 2 groups. Compared with PD patients without excessive daytime sleepiness, patients with excessive daytime sleepiness (Epworth Sleepiness Scale score ≥10) had a significantly lower amplitude of the melatonin rhythm and 24-hour melatonin AUC (P = .001). Disease duration, Unified Parkinsons Disease Rating Scale scores, levodopa equivalent dose, and global Pittsburgh Sleep Quality Index score in the PD group were not significantly related to measures of the melatonin circadian rhythm. CONCLUSIONS AND RELEVANCE Circadian dysfunction may underlie excessive sleepiness in PD. The nature of this association needs to be explored further in longitudinal studies. Approaches aimed to strengthen circadian function, such as timed exposure to bright light and exercise, might serve as complementary therapies for the nonmotor manifestations of PD.

Measuring mild cognitive impairment in patients with Parkinson's disease.

We examined the frequency of Parkinson disease with mild cognitive impairment (PD‐MCI) and its subtypes and the accuracy of 3 cognitive scales for detecting PD‐MCI using the new criteria for PD‐MCI proposed by the Movement Disorders Society. Nondemented patients with Parkinsons disease completed a clinical visit with the 3 screening tests followed 1 to 3 weeks later by neuropsychological testing. Of 139 patients, 46 met Level 2 Task Force criteria for PD‐MCI when impaired performance was based on comparisons with normative scores. Forty‐two patients (93%) had multi‐domain MCI. At the lowest cutoff levels that provided at least 80% sensitivity, specificity was 44% for the Montreal Cognitive Assessment and 33% for the Scales for Outcomes in Parkinsons Disease‐Cognition. The Mini‐Mental State Examination could not achieve 80% sensitivity at any cutoff score. At the highest cutoff levels that provided specificity of at least 80%, sensitivities were low (≤44%) for all tests. When decline from estimated premorbid levels was considered evidence of cognitive impairment, 110 of 139 patients were classified with PD‐MCI, and 103 (94%) had multi‐domain MCI. We observed dramatic differences in the proportion of patients who had PD‐MCI using the new Level 2 criteria, depending on whether or not decline from premorbid level of intellectual function was considered. Recommendations for methods of operationalizing decline from premorbid levels constitute an unmet need. Among the 3 screening tests examined, none of the instruments provided good combined sensitivity and specificity for PD‐MCI. Other tests recommended by the Task Force Level 1 criteria may represent better choices, and these should be the subject of future research.

Movement disorders in patients taking anticonvulsants

Background: A wide variety of movement disorders may occur as a consequence of the administration of antiepileptic drugs (AEDs). Although it has been suggested that the risk of parkinsonism is 10-fold higher in those taking valproate as compared with other AEDs, there have been no large, systematic trials assessing this. Aim: To establish more precisely the prevalence of and risk factors for developing parkinsonism associated with valproate use,and to assess the occurrence of movement disorders with the newer AEDs. Methods: Patients with epilepsy were recruited from the Toronto Western Hospital Epilepsy Clinic (University of Toronto, Toronto, Ontario, Canada). Each patient was examined by a movement disorder specialist who was blinded to the treatment status of the patient. Results: 201 patients were included. Postural tremor was the most common movement disorder (45%), followed by parkinsonism (4.5%). The odds of having parkinsonism were 5 times higher with valproate than with other AEDs. No single factor predicted the presence of parkinsonism; however, many (5/9) of the patients concurrently used other drugs or had comorbidities that could have caused or exacerbated parkinsonism. None of the newer AEDs were clearly associated with the presence of movement disorders; however, the numbers were too small to make a formal analysis. Conclusion: Although the risk of parkinsonism with valproate is higher than with other AEDs, it is lower than originally reported. The cases available were not enough to accurately comment on the prevalence of movement disorders with the newer AEDs.

VITAMINS AND ENTACAPONE IN LEVODOPA-INDUCED HYPERHOMOCYSTEINEMIA: A RANDOMIZED CONTROLLED STUDY

Elevated homocysteine is associated with increased risk of heart disease, stroke, and dementia. Therapy of Parkinson disease (PD) with levodopa elevates homocysteine. The authors conducted a 6-week, multicenter, randomized, double-blind, placebo-controlled trial to test whether folate 1 mg/vitamin B12 500 μg or entacapone reduced serum homocysteine in 35 levodopa-treated PD patients. Levodopa initiation caused a small elevation in homocysteine. Vitamin therapy, but not entacapone, resulted in a decrease in homocysteine compared to placebo.

Tolerability of isradipine in early Parkinson's disease: A pilot dose escalation study†

Recent data suggests that isradipine, a dihydropyridine calcium channel blocker, is neuroprotective in preclinical models of parkinsonism. Isradipine has not been systematically studied in patients with Parkinsons disease (PD). The aim of this study was to evaluate safety and tolerability of isradipine controlled release (CR) in patients with early PD. Qualified subjects (n = 31) received isradipine CR, titrated from 5 to 20 mg daily dose over 8 weeks as tolerated. Eighty‐one percent of subjects completed the study. Tolerability of isradipine CR was dose dependent: 94% for 5 mg dose; 87% for 10 mg; 68% for 15 mg; and 52% for 20 mg. Isradipine had no significant effect on blood pressure or PD motor disability. The two most common reasons for dose reduction were leg edema (7) and dizziness (3). There was no difference in isradipine tolerability between subjects with and without dopaminergic treatment, or with and without hypertension.

Low-frequency repetitive transcranial magnetic stimulation for treatment of levodopa-induced dyskinesias

Levodopa-induced dyskinesia (LID) is a major source of disability in Parkinson disease (PD) and functional imaging studies suggest that it may be related to overactivity of the motor cortex.1 Low- frequency repetitive transcranial magnetic stimulation (rTMS) at about 1 Hz decreases excitability of the stimulated area.2 A single 15-minute session of 1 Hz rTMS to the supplementary motor area reduced LID for up to 15 minutes.3 We hypothesize that longer sessions4 such as a 2-week course of 1 Hz rTMS to primary motor cortex will produce longer lasting reduction of LID. We studied six patients with PD (table E-1 on the Neurology Web site at www.neurology.org). Inclusion criteria were 1) stable medication dose for 4 weeks, and 2) LID >25% of waking hours (item 32 of Unified PD Rating Scale [UPDRS] ≥ 2) and bothersome (item 33 ≥ 2). Exclusion criteria were previous PD surgery and contraindications to rTMS. Patients took regular medications during the study except on days of levodopa challenge test. Informed consent and Ethics Board approval were obtained. Patients received 10 days of …

LOCATION OF ACTIVE CONTACTS IN PATIENTS WITH PRIMARY DYSTONIA TREATED WITH GLOBUS PALLIDUS DEEP BRAIN STIMULATION

OBJECTIVE Deep brain stimulation of the globus pallidus internus has been used for the treatment of various forms of dystonia, but the factors influencing postoperative outcomes remain unknown. We compared the location of the contacts being used for stimulation (active contacts) in patients with cervical dystonia, generalized dystonia, and Parkinsons disease and correlated the results with clinical outcome. METHODS Postoperative magnetic resonance scans of 13 patients with cervical dystonia, six patients with generalized dystonia, and five patients with Parkinsons disease who underwent globus pallidus internus deep brain stimulation were analyzed. We assessed the location of the active contacts relative to the midcommisural point and in relation to the anteroposterior and mediolateral boundaries of the pallidum. Postoperative outcome was measured with the Toronto Western Spasmodic Torticollis Rating Scale (for cervical dystonia) and the Burke-Fahn-Marsden Dystonia Rating Scale (for generalized dystonia) during the last follow-up. RESULTS We found that the location of the active contacts relative to the midcommisural point and the internal boundaries of the pallidum was similar across the groups. In our series, the contacts used for stimulation were clustered in the posterolateral region of the pallidum. Within that region, we found no correlation between the location of the contacts and postoperative outcome. CONCLUSION The location of the active contacts used for globus pallidus internus deep brain stimulation was similar in patients with cervical dystonia, generalized dystonia, and Parkinsons disease.

Implicit Perceptual-Motor Skill Learning in Mild Cognitive Impairment and Parkinson's Disease

OBJECTIVE Implicit skill learning is hypothesized to depend on nondeclarative memory that operates independent of the medial temporal lobe (MTL) memory system and instead depends on cortico striatal circuits between the basal ganglia and cortical areas supporting motor function and planning. Research with the Serial Reaction Time (SRT) task suggests that patients with memory disorders due to MTL damage exhibit normal implicit sequence learning. However, reports of intact learning rely on observations of no group differences, leading to speculation as to whether implicit sequence learning is fully intact in these patients. Patients with Parkinsons disease (PD) often exhibit impaired sequence learning, but this impairment is not universally observed. METHOD Implicit perceptual-motor sequence learning was examined using the Serial Interception Sequence Learning (SISL) task in patients with amnestic Mild Cognitive Impairment (MCI; n = 11) and patients with PD (n = 15). Sequence learning in SISL is resistant to explicit learning and individually adapted task difficulty controls for baseline performance differences. RESULTS Patients with MCI exhibited robust sequence learning, equivalent to healthy older adults (n = 20), supporting the hypothesis that the MTL does not contribute to learning in this task. In contrast, the majority of patients with PD exhibited no sequence-specific learning in spite of matched overall task performance. Two patients with PD exhibited performance indicative of an explicit compensatory strategy suggesting that impaired implicit learning may lead to greater reliance on explicit memory in some individuals. CONCLUSION The differences in learning between patient groups provides strong evidence in favor of implicit sequence learning depending solely on intact basal ganglia function with no contribution from the MTL memory system.

Integrated safety of levodopa-carbidopa intestinal gel from prospective clinical trials

Continuous administration of levodopa‐carbidopa intestinal gel (carbidopa‐levodopa enteral suspension) through a percutaneous endoscopic gastrojejunostomy is a treatment option for advanced Parkinson disease (PD) patients with motor fluctuations resistant to standard oral medications. Safety data from 4 prospective studies were integrated to assess the safety of this therapy.