Objective: Parkinson’s disease (PD) is a progressive neurological disorder characterised by a large number of motor and non-motor features that can impact on function to a variable degree. This review describes the clinical characteristics of PD with emphasis on those features that differentiate the disease from other parkinsonian disorders. Methods: A MedLine search was performed to identify studies that assess the clinical characteristics of PD. Search terms included “Parkinson’s disease”, “diagnosis” and “signs and symptoms”. Results: Because there is no definitive test for the diagnosis of PD, the disease must be diagnosed based on clinical criteria. Rest tremor, bradykinesia, rigidity and loss of postural reflexes are generally considered the cardinal signs of PD. The presence and specific presentation of these features are used to differentiate PD from related parkinsonian disorders. Other clinical features include secondary motor symptoms (eg, hypomimia, dysarthria, dysphagia, sialorrhoea, micrographia, shuffling gait, festination, freezing, dystonia, glabellar reflexes), non-motor symptoms (eg, autonomic dysfunction, cognitive/neurobehavioral abnormalities, sleep disorders and sensory abnormalities such as anosmia, paresthesias and pain). Absence of rest tremor, early occurrence of gait difficulty, postural instability, dementia, hallucinations, and the presence of dysautonomia, ophthalmoparesis, ataxia and other atypical features, coupled with poor or no response to levodopa, suggest diagnoses other than PD. Conclusions: A thorough understanding of the broad spectrum of clinical manifestations of PD is essential to the proper diagnosis of the disease. Genetic mutations or variants, neuroimaging abnormalities and other tests are potential biomarkers that may improve diagnosis and allow the identification of persons at risk.

https://jnnp.bmj.com/content/jnnp/79/4/368.full.pdf

Parkinson’s disease: clinical features and diagnosis

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.

/pdf/mds-clinical-diagnostic-criteria-for-parkinson-s-disease-74dzuucoq6.pdf

MDS clinical diagnostic criteria for Parkinson's disease

BACKGROUND: Neurostimulation of the subthalamic nucleus reduces levodopa-related motor complications in advanced Parkinson's disease. We compared this treatment plus medication with medical management. METHODS: In this randomized-pairs trial, we enrolled 156 patients with advanced Parkinson's disease and severe motor symptoms. The primary end points were the changes from baseline to six months in the quality of life, as assessed by the Parkinson's Disease Questionnaire (PDQ-39), and the severity of symptoms without medication, according to the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III). RESULTS: Pairwise comparisons showed that neurostimulation, as compared with medication alone, caused greater improvements from baseline to six months in the PDQ-39 (50 of 78 pairs, P=0.02) and the UPDRS-III (55 of 78, P<0.001), with mean improvements of 9.5 and 19.6 points, respectively. Neurostimulation resulted in improvements of 24 to 38 percent in the PDQ-39 subscales for mobility, activities of daily living, emotional well-being, stigma, and bodily discomfort. Serious adverse events were more common with neurostimulation than with medication alone (13 percent vs. 4 percent, P<0.04) and included a fatal intracerebral hemorrhage. The overall frequency of adverse events was higher in the medication group (64 percent vs. 50 percent, P=0.08). CONCLUSIONS: In this six-month study of patients under 75 years of age with severe motor complications of Parkinson's disease, neurostimulation of the subthalamic nucleus was more effective than medical management alone. (ClinicalTrials.gov number, NCT00196911 [ClinicalTrials.gov].).

/pdf/a-randomized-trial-of-deep-brain-stimulation-for-parkinson-s-40jf18b006.pdf

A Randomized Trial of Deep-Brain Stimulation for Parkinson's Disease

Measuring Health: A Guide to Rating Scales and Questionnaires

The clinical diagnosis of Parkinson's disease rests on the identification of the characteristics related to dopamine deficiency that are a consequence of degeneration of the substantia nigra pars compacta. However, non-dopaminergic and non-motor symptoms are sometimes present before diagnosis and almost inevitably emerge with disease progression. Indeed, non-motor symptoms dominate the clinical picture of advanced Parkinson's disease and contribute to severe disability, impaired quality of life, and shortened life expectancy. By contrast with the dopaminergic symptoms of the disease, for which treatment is available, non-motor symptoms are often poorly recognised and inadequately treated. However, attention is now being focused on the recognition and quantitation of non-motor symptoms, which will form the basis of improved treatments. Some non-motor symptoms, including depression, constipation, pain, genitourinary problems, and sleep disorders, can be improved with available treatments. Other non-motor symptoms can be more refractory and need the introduction of novel non-dopaminergic drugs. Inevitably, the development of treatments that can slow or prevent the progression of Parkinson's disease and its multicentric neurodegeneration provides the best hope of curing non-motor symptoms.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(06)70373-8.pdf

Non-motor symptoms of Parkinson's disease: diagnosis and management

OBJECTIVE To examine changes in quality of life (QOL) and global clinical status after 30 days of adjunctive treatment with tolcapone, a revers-ible inhibitor of catechol-O-methyltransferase, in patients with fluctuating Parkinson's disease. METHODS This 30-day, multicenter, open-label, community-based study enrolled fluctuating Parkinson's disease patients to receive tolcapone 100 mg TID as an adjunct to levodopa/carbidopa. The primary end point was QOL change assessed using the Parkinson's Disease Questionnaire (PDQ)-8. Clinical change was assessed using the investigator-rated Clinical Global Impression of Improvement Scale (CGI-I). RESULTS Fifty-six physicians enrolled 202 patients; 138 (68%) were > or = 65 years of age and 116 (57%) had Parkinson's disease for > or = 5 years. The mean PDQ-8 total score improved from 42.1 to 34.8 after 30 days of tolcapone (P<.0001). Sixty-nine percent of patients improved on the CGI-I. Physicians planned to continue tolcapone beyond the 30 days in 72%, most commonly because of positive changes in motor function and overall general improvement. No patient discontinued because of liver adverse events. CONCLUSIONS Adjunctive tolcapone treatment was associated with statistically significant improvement in QOL in fluctuating Parkinson's disease patients. A majority of patients experienced clinical benefits and continued treatment beyond the end of this study. No liver-related adverse events were reported.

Quality of life in Parkinson's disease patients following adjunctive tolcapone therapy: results of an open-label, multicenter, community-based trial.

Anticholinergic drugs were the mainstay of symptomatic therapy in Parkinson disease until 1967. That year, George Cotzias reported dramatic improvement of motor symptoms with a dopamine precursor (levodopa). Other drugs followed and have enhanced the quality of life of patients suffering from Parkinson’s disease (PD). However, the underlying disease continues to progress with the emergence of a variety of medication resistant motor and nonmotor problems. The lack of a definite neuroprotective therapy that slows or stops the progression of PD is a major unmet need in the field. The DATATOP study, using selegiline and vitamin E, was the first large-scale effort to conduct a neuroprotective clinical trial [1]. Although there have been several candidate drugs that seemed to work in the laboratory setting, they have failed in the clinical trials. A variety of reasons for this failure exist; however, a major limiting factor is the ability to dissociate symptomatic effects of the drug from its putative neuroprotective effect. The delayed-start design was developed to address this specific concern where one group receives the active drug and the other group receives placebo for the first phase of the study, then in the second phase both groups receive the active drug. Any difference in the two groups at the end of phase 2 can be interpreted as a disease-modifying effect of the drug (all else being equal) as both groups receive active drug in the second phase. In the Olanow et al. publication, the authors test rasagiline, a second-generation monoamine oxidase inhibitor type B, in a delayed-start paradigm to examine its potential disease-modifying effects in PD.

Does rasagiline have a disease-modifying effect on Parkinson's disease?

Mechanical compression of the extracranial vertebral artery during neck rotation. Authors' reply

A 52-year-old man with a history of cerebrovascular disease presented with a 3-year history of paroxysmal hemidystonia precipitated by assuming an upright position after sitting or lying down. MRA showed occlusion of the contralateral internal carotid artery (ICA) and near-total occlusion of the ipsilateral ICA. Subtraction single proton emission computed tomography demonstrated decreased perfusion in the contralateral frontoparietal cortex during the typical dystonic spell. We have coined the term "orthostatic paroxysmal dystonia" for this phenomenon.

Orthostatic paroxysmal dystonia.

Summary

Background: People with idiopathic Parkinson’s disease (PD) develop postural instability in the later stages of the ailment. Postural instability has traditionally been quantified with the Pull test even though its face validity is limited. We previously established cut-off scores for a three-part rapid assessment of postural instability (RAPID) questionnaire as a non-physical complement to the physical test. In the current study, the questionnaire was administered to a new group of PD subjects to evaluate the diagnostic value of the instrument.



Methods:  Sensitivity and specificity values were calculated for single and combined sections of the questionnaire by using the Pull test as the gold standard for assessing the presence of postural instability.



Results:  The questionnaire when used in its entirety gave the highest sensitivity (.71), whereas specificity was highest in the activities of daily living (.74) and fear of falling sections (.74). Net specificity decreased to .44 when the scores from the three sections of the questionnaire were combined.



Conclusions:  The high sensitivity of the RAPID questionnaire suggests that it may be used as an adjunct to the Pull test or solely if it is not convenient or contraindicated. The questionnaire may also be adapted for use via the telephone or internet. The limitation of the Pull test in revealing postural instability may explain the low specificity of the questionnaire, i.e. the questionnaire correctly identifies patients as unstable when the Pull test indicates normal postural control. It is hoped that the rapid identification of postural instability in PD may lead to increased awareness of the disease progression and fewer falls.

Kapil D. Sethi

Papers

Quality of life in Parkinson's disease patients following adjunctive tolcapone therapy: results of an open-label, multicenter, community-based trial.

Does rasagiline have a disease-modifying effect on Parkinson's disease?

Mechanical compression of the extracranial vertebral artery during neck rotation. Authors' reply

Orthostatic paroxysmal dystonia.

Diagnostic value of the rapid assessment of postural instability in parkinson’s disease (RAPID) questionnaire