Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Charcot: Past and present.

Jean-Martin Charcot (1825-1893) was the preeminent neurologist of the nineteenth century. Several of his major contributions remain fully relevant to contemporary neurology, and this essay highlights three areas of particular importance to the modern neurologist: the anatomo-clinical method that Charcot developed as the anchor of neurological study; the integration of new scientific discoveries from other fields as a core strategy for neurological advancement; and the role of heredity as the fundamental etiological focus to the understanding of the pathogenesis of primary neurological disorders. Further, Charcot left a strong tradition of visual skills as the core requirement for accurate neurological diagnosis and emphasized scientific humility in the face of difficult diseases. In spite of vast advances in neuroscience over the 20th and 21st centuries, the challenges faced by Charcot remain largely the same for the contemporary neurologist, and the lessons provided by Charcot retain their power and significance today.

Assessing the non-motor symptoms of Parkinson's disease: MDS-UPDRS and NMS Scale.

BACKGROUND AND PURPOSE: Although Parkinson's disease (PD) is characterized by typical motor manifestations, non-motor symptoms (NMS) are an outstanding part of the disease. At present, several specific instruments for assessment of NMS are available. The objective of our study was to determine the performance of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Part I - Non-Motor Aspects of Experiences of Daily Living (nM-EDL) compared with the Non-Motor Symptoms Scale (NMSS). METHODS: To this purpose, 434 consecutive patients with PD were included in an international, observational, cross-sectional study. The association between scores of both scales was determined by the Spearman rank correlation coefficient. Equations for transformation of total score of a scale to the other were constructed from weighted regression models and both, transformed and observed score, contrasted by means of the Lin's Concordance Correlation Coefficient (LCCC) and Bland-Altman plot. RESULTS: As a whole, the prevalence of the NMS according to each scale was quite similar, and most of the correlations between their corresponding components were high (r(S) > 0.60). The total score correlation of the MDS-UPDRS Part I with the NMSS was high (r(S) = 0.81). Concerning the transformed scores, estimated scores only partially approach the observed ones (sharing about 60-64% of the variance) because residual variance increased with increasing magnitudes of the scores, i.e. the most severe patients (Bland-Altman plot; LCCC < 0.60 for severe patients). CONCLUSIONS: (i) MDS-UPDRS Part I (nM-EDL) and NMSS showed a strong convergent validity; (ii) however, transformed scores using the equations from weighted regression models showed that for patients with the most severe NMS they are not concordant.

Relationship between the MDS-UPDRS domains and the health-related quality of life of Parkinson's disease patients.

BACKGROUND AND PURPOSE: The Movement Disorder Society sponsored version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a comprehensive instrument for assessing Parkinson's disease (PD). The present study was aimed at determining the relationships between MDS-UPDRS components and health-related quality of life (HRQoL) evaluations in PD patients. METHODS: An international, multicenter, cross-sectional study was carried out of 435 PD patients assessed with the MDS-UPDRS, Hoehn and Yahr (HY), Clinical Impression Severity for PD, EQ-5D and PD Questionnaire - eight items (PDQ-8). Spearman's rank correlation coefficients, exploratory factor analysis and multiple linear regression models (dependent variables EQ-5D and PDQ-8) were performed. RESULTS: The participants' age was 66.71 ± 10.32 years (51.5% men). PD duration was 8.52 ± 6.14, and median HY was 2 (range 1-5). The correlation between the EQ-5D index and the MDS-UPDRS ranged from -0.46 (Part IV) to -0.72 (Part II) and for the PDQ-8 index from 0.47 (Part III) to 0.74 (Part II). In multiple regression models with the MDS-UPDRS domains as independent variables, the main determinant for both the EQ-5D index and the PDQ-8 was Part II followed by Part I. After factorial grouping of the cardinal PD manifestations embedded in the MDS-UPDRS Parts III and IV for inclusion into multiple regression models, a factor formed by M-EDL, nM-EDL and fluctuations was the main determinant for both the EQ-5D and PDQ-8 indexes. CONCLUSIONS: The MDS-UPDRS component most tightly related with the HRQoL measures was a combination of motor and non-motor experiences of daily living.

What's new? Clinical progression and staging of Parkinson's disease.

Several new advances facilitate current understanding of the progression of Parkinson's disease. The application of statistical modeling techniques has helped to estimate rates of clinical decline in the context of symptomatic interventions. These approaches may allow a new means for testing neuroprotection effects even when patients are on dopaminergic treatment. Further, the development of new rating scales, specifically the Movement Disorder Society-initiated revision of the Unified Parkinson's Disease Rating Scale has capitalized on a greater clinical appreciation of non-motor elements of Parkinson's disease. Finally, adaptations of new technologies that are computer-based and enable data transmission from at-home environments allow researchers to capture disease impairment and disability with potentially greater precision and much more frequently than permissible in a hospital clinic or practice setting.

Charcot, hysteria, and simulated disorders.

Jean-Martin Charcot (1825-1893) was the 19th-century's premier international neurologist. One of his areas of focused interest was the neurologic disorder, hysteria, a condition with distinctive neurologic signs, but no established structural lesions identified at autopsy. Charcot considered hysteria as a physiologic disorder that affected specific neuroanatomic areas of the brain comparable to the same areas that were damaged by structural neurologic disorders provoking the same or similar signs. He considered hysteria primarily a hereditary disorder, but environmental factors including physical and emotional stress served as provoking factors. Charcot drew the strict distinction between hysteria and consciously simulated neurologic disorders, although he was keenly aware that the two disorders could occur in the same patients or be difficult to distinguish at times. He developed specific experimental techniques to separate hysteria from simulation. His studies of hysteria and simulation offer a basis for studies of functional neurologic disorders applicable to the 21st century.

Relationship of aluminum to neurocognitive dysfunction in chronic dialysis patients.

Aluminum has been proposed as the causative agent in dialysis encephalopathy syndrome. We prospectively assessed whether other, less severe, neuropsychologic abnormalities were also associated with aluminum. A total of 16 patients receiving chronic dialytic therapy were studied. The deferoxamine infusion test (DIT) was used to assess total body aluminum burden. Neurologic function was evaluated by quantitative measures of asterixis, myoclonus, motor strength, and sensation. Cognitive function was assessed by measures of dementia, memory, language, and depression. There were four patients with a positive DIT (greater than 125 micrograms/L increment in serum aluminum) that was associated with an increase in the number of neurologic abnormalities observed, as well as an increase in severity of myoclonus, asterixis, and lower extremity weakness. Patients with a positive DIT also showed significant impairment in memory; however, no differences were noted on tests of dementia, depression, or language. There was no significant correlation between sex, age, presence of diabetes, mode of dialysis, years of chronic renal failure, years of dialysis or years of aluminum ingestion and any neurologic or neurobehavioral measurement, serum aluminum level, or DIT. These changes may represent early aluminum-associated neurologic dysfunction.

Tardive dyskinesia: review and update.

Tardive dyskinesia is an extrapyramidal syndrome associated with the chronic administration of major neuroleptic agents. The pathogenesis of the disorder appears to relate to chronic striatal dopaminergic receptor site blockade; the pathophysiology of tardive dyskinesia appears to relate to the resultant denervation hypersensitivity. Agents that deplete the brain of dopamine are the mainstay of therapy for tardive dyskinesia. Cholinergic agents that potentially modulate the balance between dopamine and acetycholine in the striatum offer possible additional therapeutic options. Clearly, resumption of neuroleptic therapy is treatment with the presumed pathogenic agent and is to be avoided whenever possible.

Pharmacology of hallucinations induced by long-term drug therapy.

The authors studied 20 patients with Parkinson's disease and prominent hallucinations related to dopaminergic or anticholinergic therapy. The character of the hallucinations appeared distinct from the classic description of either acute anticholinergic or acute aminergic hallucinatory states. Manipulation of either kind of drug could precipitate or relieve hallucinations in a given patient, which suggests that the dopaminergic/cholinergic systems are reciprocally active in the pathophysiology of long-term drug-induced hallucinatory states in this population.

Visual art in the neurologic career of Jean-Martin Charcot.

Jean-Martin Charcot, the world's first chaired professor of neurology, incorporated visual art into his daily practice of neurology. Art served as scientific documentation and was a pivotal tool in the development and dissemination of Charcot's clinicoanatomic method. Although Charcot drew extensively in clinical and laboratory studies, very few of these visual documents have ever been published or are currently available for public study. Charcot was central to the incorporation of medical photographs into the study of neurologic disease and relied heavily on visual material in his capacity as an international teacher. Art also misguided Charcot's career when he relied heavily on artwork in his attempt to convince critics that disorders seen at the Salpêtrière Hospital, Paris, France, were independent of his suggestive influence.

Shakespeare in Charcot's neurologic teaching.

Charcot frequently used Shakespearean references in his neurologic teaching sessions. With these citations, he emphatically stressed how objective observation and an attention to detail were essential to expert clinical diagnosis. At the same time, Charcot presented his personal credentials as a cultured man. Charcot's interest in Shakespeare permeated many aspects of his professional work, and also his private and family life.

The Salpêtrière in the wake of Charcot's death.

After Charcot died in 1893, the students of his immediate circle did not fare well academically in the French medical system. Fatigue and bitterness toward the authoritarian Charcot may have contributed to the change in the scientific and social ambience of the Salpêtrière of Paris in the generation after Charcot died. Clearly, however, the faculty were not invested in energetically overturning the system that Charcot had established, and their choice of Fulgence Raymond as Charcot's successor was an effective means of permitting a passive waning in the Salpêtrière's magnetic influence in world neurology.

Pergolide in Parkinson's disease.

Twenty-two patients received pergolide mesylate for Parkinson's disease for one year. Improvement was maximal at six months, but average functional scores were still better at 12 months than at pretreatment evaluation. On-off fluctuations were reduced in severity, and two of 18 patients experienced full resolution. Pergolide is an effective and safe ongoing medication for Parkinson's disease.

Acute orthostatic hypotension when starting dopamine agonists in Parkinson's disease.

OBJECTIVE: To study the frequency and severity of acute orthostatic hypotension (OH) in patients with Parkinson's disease who are starting dopamine agonist therapy. PATIENTS AND METHODS: In the context of an outpatient clinical practice, 29 consecutive patients with Parkinson's disease who were starting dopamine agonist therapy were brought into the clinic for their first dose of agonist. After a baseline supine and standing blood pressure assessment, patients were given a test dose of either pergolide mesylate (0.025, 0.05, 0. 125, or 0.25 mg), pramipexole dihydrochloride (0.125 mg), or ropinirole hydrochloride (0.125 or 0.25 mg). At 3 selected times, blood pressure readings were repeated in the supine and standing positions. MAIN OUTCOME MEASURE: Orthostatic hypotension was defined as a drop in either systolic blood pressure of more than 25 mm Hg or diastolic pressure of more than 10 mm Hg. Patients with OH before the administration of the dopamine agonist were excluded. RESULTS: Ten subjects (34%) met the criteria for acute OH. There was no evidence that OH was related to the use of a specific dopamine agonist or the concurrent use of levodopa. Of the patients who met the criteria for OH, only 3 (30%) had symptoms of OH, such as lightheadedness or general malaise. CONCLUSIONS: Acute OH occurs frequently when starting dopamine agonist therapy in Parkinson's disease, but is frequently not appreciated by patients. Knowledge of acute blood pressure responses may be useful when making decisions regarding agonist titration schedules in clinical practice. Arch Neurol. 2000;57:1461-1463

Speech abnormalities in tardive dyskinesia.

Twelve outpatients with tardive dyskinesia underwent speech evaluation by trained listeners who analyzed oral reading and vowel production for deviation in multiple speech dimensions. In the six patients with speech abnormalities, temporal organization and voice production dimensions were the most severely deviant and were highly related to the overall intelligibility and bizarre quality of speech. Deviations in articulation were less prominent. Abnormal involuntary movement scale ratings of the trunk in these patients were significantly greater than in the patients without speech impairment, although the lingual-facial-buccal and total body scores were similar between the two groups.

Fluphenazine and multifocal tic disorders.

In a five-year study, 21 patients with multiple tic disorder intolerant of haloperidol therapy were treated with fluphenazine hydrochloride. Sixteen of these patients had fewer side effects with fluphenazine and had either equivalent (five patients) or better (11 patients) tic control. Fluphenazine can be an effective treatment for multiple tics in patients with dose-limiting side effects related to haloperidol.

Pharmacological therapy in progressive supranuclear palsy.

BACKGROUND: To our knowledge, previous reports on drug treatment in progressive supranuclear palsy have not evaluated autopsy-confirmed cases. OBJECTIVE: To evaluate pharmacological treatment responses from detailed clinical records in patients with autopsy-confirmed progressive supranuclear palsy. SUBJECTS AND METHODS: We reviewed medical records for clinical presentation and pharmacological response in 12 patients with autopsy-confirmed progressive supranuclear palsy diagnosed using the National Institute of Neurological Disorders and Stroke pathologic criteria. For each drug class, exposure, global positive response, and specific positive response (parkinsonism, other movement disorders, or gaze dysfunction) were recorded. RESULTS: Drug classes examined were dopaminergics (all patients), tricyclics (3 patients), methysergide maleate (3 patients), 5-hydroxytryptophan (2 patients), and anticholinergics and selective serotonin inhibitors (1 patient). Positive clinical response was detected in 7 of the patients receiving dopaminergic drugs and in 1 patient each receiving tricyclics, methysergide, and 5-hydroxytryptophan, respectively. None of the patients responded markedly however, and there was no persistent beneficial effect. Use of dopaminergic drugs most frequently improved parkinsonian features, but disabling adverse effects included orthostatic hypotension (6 patients), hallucinations and delusions (3 patients), gastrointestinal complaints (3 patients), and dizziness (1 patient). Only 1 patient developed dyskinesia. CONCLUSION: Use of antiparkinsonian medications and other neurotransmitter replacement therapies was largely ineffective and caused frequent adverse effects in this series of patients with autopsy-confirmed with progressive supranuclear palsy.

A pure parkinsonian syndrome following acute carbon monoxide intoxication.

A 50-year-old woman with carbon monoxide (CO)-induced parkinsonism was found to have bilateral lucencies of the globus pallidus on computed tomographic (CT) scan consistent with old necrotic lesions. She showed no clinical response to levodopa therapy, although she did improve with anticholinergic therapy. It is suggested that the parkinsonism in this patient is due to the pallidal lesions demonstrated on CT scan, and that such pallidal-related parkinsonism may not respond to dopaminergic therapy.