This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances.

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MDS clinical diagnostic criteria for Parkinson's disease

Interpretation of clinical trials comparing different drug regimens for Parkinson's disease (PD) is complicated by the different dose intensities used: higher doses of levodopa and, possibly, other drugs produce better symptomatic control but more late complications. To address this problem, conversion factors have been calculated for antiparkinsonian drugs that yield a total daily levodopa equivalent dose (LED). LED estimates vary, so we undertook a systematic review of studies reporting LEDs to provide standardized formulae. Electronic database and hand searching of references identified 56 primary reports of LED estimates. Data were extracted and the mean and modal LEDs calculated. This yielded a standardized LED for each drug, providing a useful tool to express dose intensity of different antiparkinsonian drug regimens on a single scale. Using these conversion formulae to report LEDs would improve the consistency of reporting and assist the interpretation of clinical trials comparing different PD medications.

Systematic review of levodopa dose equivalency reporting in Parkinson's disease

Background: A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging studies have advanced the field, requiring a fresh evaluation of diagnostic criteria. We held a second consensus conference in 2007 and present the results here.Methods: Experts in the clinical, neuropathologic, and imaging aspects of MSA were invited to participate in a 2-day consensus conference. Participants were divided into five groups, consisting of specialists in the parkinsonian, cerebellar, autonomic, neuropathologic, and imaging aspects of the disorder. Each group independently wrote diagnostic criteria for its area of expertise in advance of the meeting. These criteria were discussed and reconciled during the meeting using consensus methodology.Results: The new criteria retain the diagnostic categories of MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia to designate the predominant motor features and also retain the designations of definite, probable, and possible MSA. Definite MSA requires neuropathologic demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least one feature suggesting autonomic dysfunction plus one other feature that may be a clinical or a neuroimaging abnormality.Conclusions: These new criteria have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease.

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Second consensus statement on the diagnosis of multiple system atrophy

Mini Mental State

ContextPostmenopausal women have a greater risk than men of developing Alzheimer
disease, but studies of the effects of estrogen therapy on Alzheimer disease
have been inconsistent. On July 8, 2002, the study drugs, estrogen plus progestin,
in the Women's Health Initiative (WHI) trial were discontinued because of
certain increased health risks in women receiving combined hormone therapy.ObjectiveTo evaluate the effect of estrogen plus progestin on the incidence of
dementia and mild cognitive impairment compared with placebo.Design, Setting, and ParticipantsThe Women's Health Initiative Memory Study (WHIMS), a randomized, double-blind,
placebo-controlled clinical trial, began enrolling participants from the Women's
Health Initiative (WHI) estrogen plus progestin trial in May 1996. Of the
4894 eligible participants of the WHI study, 4532 (92.6%) postmenopausal women
free of probable dementia, aged 65 years or older, and recruited from 39 of
40 WHI clinical centers were enrolled in the WHIMS.InterventionParticipants received either 1 daily tablet of 0.625 mg of conjugated
equine estrogen plus 2.5 mg of medroxyprogesterone acetate (n = 2229), or
a matching placebo (n = 2303).Main Outcome MeasuresIncidence of probable dementia (primary outcome) and mild cognitive
impairment (secondary outcome) were identified through a structured clinical
assessment.ResultsThe mean (SD) time between the date of randomization into WHI and the
last Modified Mini-Mental State Examination (3MSE) for all WHIMS participants
was 4.05 (1.19) years. Overall, 61 women were diagnosed with probable dementia,
40 (66%) in the estrogen plus progestin group compared with 21 (34%) in the
placebo group. The hazard ratio (HR) for probable dementia was 2.05 (95% confidence
interval [CI], 1.21-3.48; 45 vs 22 per 10 000 person-years; P = .01). This increased risk would result in an additional 23 cases
of dementia per 10 000 women per year. Alzheimer disease was the most
common classification of dementia in both study groups. Treatment effects
on mild cognitive impairment did not differ between groups (HR, 1.07; 95%
CI, 0.74-1.55; 63 vs 59 cases per 10 000 person-years; P = .72).ConclusionsEstrogen plus progestin therapy increased the risk for probable dementia
in postmenopausal women aged 65 years or older. In addition, estrogen plus
progestin therapy did not prevent mild cognitive impairment in these women.
These findings, coupled with previously reported WHI data, support the conclusion
that the risks of estrogen plus progestin outweigh the benefits.

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Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial.

Menstrual-cycle–related aggravations of parkinsonism resulting from a transient loss of dopaminergic responsiveness in premenopausal women have occasionally been reported in Parkinson’s disease (PD). Thus far, underlying mechanisms remain unclear and treatment options are not well established. We present 2 cases of premenopausal sisters with early-onset PD and severe menstrual-cycle–related reduced responsiveness to medication. A 45-year-old woman diagnosed with early-onset PD at the age of 34 presented with akinetic-rigid right-sided parkinsonism. Initially, she was treated with pramipexole 0.35 mg three times daily (TID), which was increased in the first 4 years to 0.7 mg once-daily (QID) and later switched to ropinirole 5 mg QID. During the switch, the patient felt optimally controlled when she was on pramipexole 0.7 mg twice-daily (BID) and ropinirole 5 mg BID and subsequently refused to complete the switch to ropinirole monotherapy. Over the following 2 years on double-agonist therapy, the patient began to notice mild wearing-off fluctuations approximately 3 hours after each dose. Total daily OFF-time was <25% (according to a score of 1 in the International Parkinson and Movement Disorder Society [MDS]-UPDRS part IV, item 3) and disability during OFFs was mild (according to a score of 2 in the MDS-UPDRS part IV, item 4). At the age of 39, after 5 years of agonist treatment, she began to experience marked reductions of drug response up to 5 days before, during, and 3 days after menstruation. Because of worsening of parkinsonism around period times (MDSUPDRS part III sum score = 25 points) the dose of ropinirole was increased to 5 mg QID and pramipexole 0.7 mg BID was continued. Because of consistent premenstrual aggravation of parkinsonism, the patient was eventually put on gestagen supplementation with dienogest-ethinylestradiol (75 lg) for continuous use. This resulted in a marked improvement of control of parkinsonism also perimenstrually (see Fig. 1). Though she rated herself OFF for at least 75% of the day (according to a score of 4 in the MDS-UPDRS part IV, item 3) preceding gestagen supplementation, this changed to <25% per day (according to a score of 1 in the MDS-UPDRS part IV, item 3) after hormone replacement. A 46-year-old woman, the sister of case 1, was diagnosed with early-onset PD at the age of 37. She presented with mild bradykinesia and left-accentuated mild postural and action tremor. Treatment was initiated with pramipexole 0.35 mg TID, which was increased to 0.7 mg TID within 2 years. One year later, levodopa/benserazide 100/25 mg QID was added because of insufficient motor control. Within 4 weeks after initiation of L-dopa, the patient developed disabling peak-dose dyskinesia (according to 2 points in the MDS-UPDRS part IV, item 1, and to 4 points in the MDSUPDRS part IV, item 2) and mild wearing-off motor fluctuations with a daily off-time <25% (according to a score of 1 in the MDS-UPDRS part IV, item 3). The addition of amantadine 100 mg QID led to satisfactory improvement of dyskinesias, but wearing-off fluctuations remained troublesome. The patient was eventually reasonably well controlled after switching to L-dopa/carbidopa/ entacapone 100/25/200 mg QID and after exchanging pramipexole immediate release with pramipexole extended release 2.1 mg QID. After 6 years of antiparkinsonian treatment, the patient began to experience perimenstrual episodes of pronounced deterioration of motor symptoms (especially tremor) with motor OFFtime occupying more than 75% of waking day (according to a score of 4 in the MDS-UPDRS part IV, item 3, and to an OFF-sum-score of 35 in the MDS-UPDRS part III), accompanied by depressive symptoms with suicidal thoughts and panic attacks. These deteriorations, which started approximately 2 days before menstruation and lasted up to 2 days after menstruation, caused regular consultations of our outpatient clinic. This patient was eventually put on gestagen supplementation with dienogest-ethinylestradiol (75 lg) for continuous use, resulting in a reduction of perimenstrual OFF-time from approximately 75% per day (according to a score of 4 in the MDS-UPDRS part IV, item 3) to <25% per day (according to a score of 1 in the MDS-UPDRS part IV, item 3) without any

Perimenstrual Fluctuations in Two Siblings With Early‐Onset Parkinson's Disease

The footprint of orthostatic hypotension in parkinsonian syndromes.

In clinical practice, conventional magnetic resonance imaging (cMRI) with visual assessment of T2and T1-weighted imaging is a well-established method for the exclusion of other causes of parkinsonism including atypical parkinsonism and symptomatic parkinsonism due to other pathologies. By using magnetically labeled arterial blood water as an endogenous tracer to provide quantitative cerebral blood flow (CBF) measurements, perfusion imaging with arterial spin labeling (ASL) contrast represents a noninvasive MRI perfusion method that quantitatively measures CBF per unit tissue mass. In this study, the authors measured cerebral gray matter perfusion using pseudo-continuous ASL in 61 subjects with Parkinson’s disease (PD) compared with 29 ageand sexmatched controls. Motor impairment was assessed with part III of the Unified Parkinson’s Disease Rating Scale (UPDRS part III) and global cognitive status with the Mini– Mental State Examination and the Montreal Cognitive Assessment (MoCA). PD patients were classified as cognitively normal (n 1⁄4 34), with mild cognitive impairment (n 1⁄4 16), or with dementia (n 1⁄4 11). The authors identified a PD-related perfusion network by principal component analysis (ie, a data-driven technique that enables the unbiased detection of spatial covariance patterns) of ASL-MRI via logistic regression. The ROI analysis of the absolute perfusion values of this PD-related pattern revealed decreased perfusion in many cortical areas, most prominently in the posterior parieto-occipital cortex, precuneus, and cuneus and in middle frontal gyri, whereas perfusion was preserved in the globus pallidus, putamen, anterior cingulate, and postand precentral gyri. Furthermore, both motor (UPDRS-III) and cognitive (MoCA) functions were significant factors related to network score. Cognitively impaired patients and those with greater motor disability expressed the PD-related network more strongly, having increased network scores. On the other hand, although global gray matter perfusion was significantly reduced in the PD group, it performed less well as a classifier than the PD-related network, and it showed no significant relationship with either cognitive or motor status in the PD group. This study established a characteristic PD-related perfusion network via ASL, which was characterized by decreased cortical and preserved subcortical and sensorimotor cortical perfusion. Overall, the authors of this study suggest that ASL-derived perfusion network imaging may provide a readily accessible neuroimaging method to characterize and track progression of both motor and cognitive status in PD. Because both motor status and cognitive status were associated with the expression of the PD-related network in this cross-sectional study, further work using this imaging technique, especially with longitudinal designs, is needed to further clarify its value.

The role of arterial spin labeling, a noninvasive MRI perfusion method, in identifying an abnormal cerebral perfusion pattern in Parkinson's disease

Towards subgroup-specific risk estimates: A meta-analysis of longitudinal studies on olfactory dysfunction and risk of Parkinson's disease

Institute of Medical Education and Research, Chandigarh, India, Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh, India, Pediatric Critical Care Unit, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and Pediatric Biochemistry, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India

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Klaus Seppi

Papers

Perimenstrual Fluctuations in Two Siblings With Early‐Onset Parkinson's Disease

The footprint of orthostatic hypotension in parkinsonian syndromes.

The role of arterial spin labeling, a noninvasive MRI perfusion method, in identifying an abnormal cerebral perfusion pattern in Parkinson's disease

Towards subgroup-specific risk estimates: A meta-analysis of longitudinal studies on olfactory dysfunction and risk of Parkinson's disease

Family History for Neurodegeneration in Multiple System Atrophy: Does it Indicate Susceptibility?