B.R. Bloem

EFNS/MDS‐ES recommendations for the diagnosis of Parkinson's disease

A Task Force was convened by the EFNS/MDS‐ES Scientist Panel on Parkinsons disease (PD) and other movement disorders to systemically review relevant publications on the diagnosis of PD.

Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson's disease

To summarize the 2010 EFNS/MDS‐ES evidence‐based treatment recommendations for the management of Parkinsons disease (PD). This summary includes the treatment recommendations for early and late PD.

On state freezing of gait in Parkinson disease: a paradoxical levodopa-induced complication.

Objective: To describe the phenotype of levodopa-induced “on” freezing of gait (FOG) in Parkinson disease (PD). Methods: We present a diagnostic approach to separate “on” FOG (deterioration during the “on state”) from other FOG forms. Four patients with PD with suspected “on” FOG were examined in the “off state” (>12 hours after last medication intake), “on state” (peak effect of usual medication), and “supra-on” state (after intake of at least twice the usual dose). Results: Patients showed clear “on” FOG, which worsened in a dose-dependent fashion from the “on” to the “supra-on” state. Two patients also demonstrated FOG during the “off state,” of lesser magnitude than during “on.” In addition, levodopa produced motor blocks in hand and feet movements, while other parkinsonian features improved. None of the patients had cognitive impairment or a predating “off” FOG. Conclusions: True “on” FOG exists as a rare phenotype in PD, unassociated with cognitive impairment or a predating “off” FOG. Distinguishing the different FOG subtypes requires a comprehensive motor assessment in at least 3 medication states.

Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype

Objective: To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements. Methods: Nonmanifesting individuals carrying a single heterozygous Parkin (n = 13) or PINK1 (n = 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous Parkin and PINK1 mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype. Results: Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation. Conclusion: Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a “generic” compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit.

Ten steps to identify atypical parkinsonism

Background: Balance impairment is a frequently encountered problem in patients with Parkinson’s disease. A profound balance disorder, however, is an atypical feature. Methods: Tandem gait performance (10 consecutive tandem steps) was judged in 36 consecutive patients with Parkinson’s disease and 49 consecutive patients with atypical parkinsonism. Results: Only 9 (18%) patients with atypical parkinsonism had a fully normal tandem gait (not a single side step) as opposed to 33 (92%) patients with Parkinson’s disease. Analysis for the subgroup of patients with a disease duration of <3 years yielded the same diagnostic accuracy. Conclusions: Tandem gait performance has a good diagnostic ability to differentiate patients with atypical parkinsonism from those with Parkinson’s disease, and might be used as an additional “red flag” to assist existing clinical tests in identifying atypical parkinsonism.

Management of the hospitalized patient with Parkinson's disease: current state of the field and need for guidelines.

OBJECTIVEnTo review the literature and to identify practice gaps in the management of the hospitalized Parkinsons disease (PD) patient.nnnBACKGROUNDnPatients with PD are admitted to hospitals at higher rates, and frequently have longer hospital stays than the general population. Little is known about outpatient interventions that might reduce the need for hospitalization and also reduce hospital-related complications.nnnMETHODSnA literature review was performed on PubMed about hospitalization and PD between 1970 and 2010. In addition, in press peer-reviewed papers or published abstracts known to the authors were included. Information was reviewed by a National Parkinson Foundation workgroup and a narrative review article was generated.nnnRESULTSnMotor disturbances in PD are believed to be a causal factor in the higher rates of admissions and complications. However, other conditions are commonly recorded as the primary reason for hospitalization including motor complications, reduced mobility, lack of compliance, inappropriate use of neuroleptics, falls, fractures, pneumonia, and other important medical problems. There are many relevant issues related to hospitalization in PD. Medications, dosages and specific dosage schedules are critical. Staff training regarding medications and medication management may help to avoid complications, particularly those related to reduced mobility, and aspiration pneumonia. Treatment of infections and a return to early mobility is also critical to management.nnnCONCLUSIONSnEducational programs, recommendations, and guidelines are needed to better train interdisciplinary teams in the management of the PD patient. These initiatives have the potential for both cost savings and improved outcomes from a preventative and a hospital management standpoint.

CSF analysis differentiates multiple-system atrophy from idiopathic late-onset cerebellar ataxia

Background: Differentiating idiopathic late-onset cerebellar ataxia (ILOCA) from ataxia due to the cerebellar subtype of multiple-system atrophy (MSA-C) can be difficult in the early stages of the disease Methods: The authors analyzed the levels of various CSF biomarkers in 27 patients with MSA-C and 18 patients with ILOCA and obtained cut-off points for each potential biomarker to differentiate MSA-C from ILOCA. Results: Increased levels of neurofilament light chain (NFL) and neurofilament heavy chain (NFHp35) and decreased levels of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindoleaceticacid (5-HIAA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) were observed in MSA-C compared with ILOCA patients. Receiver operating characteristic analysis showed high sensitivity and specificity levels for NFL, NFHp35, and MHPG analysis. At a cut-off of 24.4 ng/L for the NFL analysis, a sensitivity of 79% and a specificity of 94% were obtained for differentiating MSA-C from ILOCA. At a cut-off point for NFHp35 of 129.5 ng/L, sensitivity was 87% and specificity 83%. Analysis of MHPG levels (cut-off 42.5 nM) resulted in a sensitivity of 86% with a specificity of 75%. A multivariate logistic regression model selected NFL, MHPG, and tau as independent predictive biomarkers that separated the MSA-C and ILOCA groups. Conclusions: Increased levels of neurofilament light chain and tau and decreased levels of 3-methoxy-4-hydroxyphenylethyleneglycol were associated with high accuracy levels in differentiating the cerebellar subtype of multiple-system atrophy from idiopathic late-onset cerebellar ataxia (LOCA). CSF analysis may thus serve as a useful tool in early diagnostic differentiation of LOCA.

Accelerometer-based quantitative analysis of axial nocturnal movements differentiates patients with Parkinson's disease, but not high-risk individuals, from controls

Introduction There is a need for prodromal markers to diagnose Parkinson’s disease (PD) as early as possible. Knowing that most patients with overt PD have abnormal nocturnal movement patterns, we hypothesised that such changes might occur already in non-PD individuals with a potentially high risk for future development of the disease. Methods Eleven patients with early PD (Hoehn & Yahr stage ≤2.5), 13 healthy controls and 33 subjects with a high risk of developing PD (HR-PD) were investigated. HR-PD was defined by the occurrence of hyperechogenicity of the substantia nigra in combination with prodromal markers (eg, slight motor signs, olfactory dysfunction). A triaxial accelerometer was used to quantify nocturnal movements during two nights per study participant. Outcome measurements included mean acceleration, and qualitative axial movement parameters, such as duration and speed. Results Mean acceleration of nocturnal movements was lower in patients with PD compared to controls. Frequency and speed of axial movements did not differ between patients with PD and controls, but mean size and duration were lower in PD. The HR-PD group did not significantly differ from the control group in any of the parameters analysed. Conclusions Compared with controls, patients with PD had an overall decreased mean acceleration, as well as smaller and shorter nocturnal axial movements. These changes did not occur in our potential HR-PD individuals, suggesting that relevant axial movement alterations during sleep have either not developed or cannot be detected by the means applied in this at-risk cohort.

Weight-Specific Anticipatory Coding of Grip Force in Human Dorsal Premotor Cortex

The dorsal premotor cortex (PMd) uses prior sensory information for motor preparation. Here, we used a conditioning-and-map approach in 11 healthy male humans (mean age 27 years) to further clarify the role of PMd in anticipatory motor control. We transiently disrupted neuronal processing in PMd, using either continuous theta burst stimulation (cTBS) at 80% (inhibitory cTBS) or 30% (sham cTBS) of active motor threshold. The conditioning effects of cTBS on preparatory brain activity were assessed with functional MRI, while participants lifted a light or heavy weight in response to a go-cue (S2). An additional pre-cue (S1) correctly predicted the weight in 75% of the trials. Participants were asked to use this prior information to prepare for the lift. In the sham condition, grip force showed a consistent undershoot, if the S1 incorrectly prompted the preparation of a light lift. Likewise, an S1 that falsely announced a heavy weight produced a consistent overshoot in grip force. In trials with incorrect S1, preparatory activity in left PMd during the S1–S2 delay period predicted grip force undershoot but not overshoot. Real cTBS selectively abolished this undershoot in grip force. Furthermore, preparatory S1–S2 activity in left PMd no longer predicted the individual undershoot after real cTBS. Our results provide converging evidence for a causal involvement of PMd in anticipatory downscaling but not upscaling of grip force, suggesting an inhibitory role of PMd in anticipatory grip force control during object lifting.

Improving the diagnostic accuracy in parkinsonism: a three-pronged approach

Separating Parkinsons disease from the various causes of atypical parkinsonism (AP) is a common and clinically relevant challenge in clinical practice. Distinguishing between the different causes of AP is even more difficult. Here the authors discuss a systematic, clinically based and three-pronged approach that can assist clinicians in establishing the correct diagnosis in the consulting room. The three consecutive steps include: (1) to verify that the clinical syndrome truly represents parkinsonism (hypokinetic–rigid syndrome); (2) to search systematically for ‘red flags’ (alarm signs that may signal the presence of AP); and (3) to integrate these two steps, as a basis for a narrow differential diagnosis and a guide for further ancillary tests.