The clinical diagnosis of Parkinson's disease / O diagnóstico clínico da doença de Parkinson

Abstract After more than 200 years since its initial description, the clinical diagnosis of Parkinson's disease (PD) remains an often-challenging endeavor, with broad implications that are fundamental for clinical management. Despite major developments in understanding it's pathogenesis, pathological landmarks, non-motor features and potential paraclinical clues, the most accepted diagnostic criteria remain solidly based on a combination of clinical signs. Here, we review this process, discussing its history, clinical criteria, differential diagnoses, ancillary diagnostic testing, and the role of non-motor and pre-motor signs and symptoms.

Resumo Passados mais de 200 anos desde a sua descrição inicial, o diagnóstico clínico da doença de Parkinson (DP) continua a ser um processo muitas vezes desafiante, com amplas implicações que são fundamentais para o manejo clínico. Apesar dos grandes desenvolvimentos na compreensão da sua patogénese, marcadores patológicos, características não motoras e potenciais pistas paraclínicas, os critérios diagnósticos mais aceitos permanecem solidamente baseados numa combinação de sinais clínicos motores. Aqui, revisamos esse processo, discutindo sua história, critérios clínicos, diagnósticos diferenciais, testes diagnósticos complementares e o papel dos sinais e sintomas não motores e pré-motores.

Initiating dopamine agonists rather than levodopa in early Parkinson's disease does not delay the need for deep brain stimulation.

BACKGROUND AND PURPOSE: While levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), its use is associated with an increased risk of motor complications (MCs) in the first 5 years of treatment compared to dopamine agonist (DA) first therapy. It is not known whether this translates into true benefit later in the disease. We aimed to determine whether there is a difference in the time between initial levodopa versus DA treatment and the development of disabling MCs prompting deep brain stimulation (DBS) consideration. METHODS: This was a retrospective cohort study of patients with PD attending the DBS Clinic at Toronto Western Hospital, Canada between March 2004 and February 2022, who underwent globus pallidus interna (GPI) or subthalamic nucleus (STN) DBS in 2005 or later for disabling MCs. RESULTS: Of the 438 patients included in the study, 352 underwent STN DBS and 86 underwent GPi DBS. The median (range) disease duration was 9 (2-30) years. The majority of patients (n = 312) received levodopa first and 126 received a DA. There was no significant difference in disease duration or amantadine use between the two groups. The duration from the first treatment to assesment for DBS (levodopa: median 8 years, interquartile range [IQ] 4 years; DA: median 9, IQR 4 years) or DBS surgery (levodopa: median 10 years, IIQR 5 years; DA: median 10 years, IQR 5 years) did not differ. CONCLUSION: To our knowledge, this is the only study to date to evaluate the duration between levodopa/DA-first treatment and the development of MCs of sufficient severity to warrant consideration of DBS. No association was found. The results suggest that the development of disabling MCs warranting DBS is independent of the type of first dopaminergic treatment.

Inherited metabolic diseases mimicking hereditary spastic paraplegia (HSP): a chance for treatment.

The syndromic group of hereditary spastic paraplegias has a heterogeneous clinical profile and a broad differential diagnosis, including neurometabolic disorders that are potentially treatable. This group includes 5,10-methylenetetrahydrofolate reductase deficiency, cobalamin C deficiency disease, dopamine responsive dystonia, cerebrotendinous xanthomatosis, biotinidase deficiency, GLUT1 deficiency syndrome, delta-e-pyrroline-carboxylase-synthetase deficiency, hyperonithinemia-hyperammonemia-homocitrullinuria syndrome, arginase deficiency, multiple carboxylase deficiency, and X-linked adrenoleukodystrophy. This review describes these diseases in detail, highlighting the importance of early diagnosis and effective treatment aiming at preserving functionality and quality of life in these patients. For the purpose of this study, we carried a non-systematic review on PUBMED, finding an initial sample of 122 papers; upon refining, 41 articles were found relevant to this review. Subsequently, we added review articles and works with historical relevance, totalizing 76 references. An adequate diagnostic workup in patients presenting with spastic paraplegia phenotype should include screening for these rare conditions, followed by parsimonious ancillary investigation.

Multicenter Validation of Individual Preoperative Motor Outcome Prediction for Deep Brain Stimulation in Parkinson's Disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN DBS) is an established therapy for Parkinson's disease (PD) patients suffering from motor response fluctuations despite optimal medical treatment, or severe dopaminergic side effects. Despite careful clinical selection and surgical procedures, some patients do not benefit from STN DBS. Preoperative prediction models are suggested to better predict individual motor response after STN DBS. We validate a preregistered model, DBS-PREDICT, in an external multicenter validation cohort. METHODS: DBS-PREDICT considered eleven, solely preoperative, clinical characteristics and applied a logistic regression to differentiate between weak and strong motor responders. Weak motor response was defined as no clinically relevant improvement on the Unified Parkinson's Disease Rating Scale (UPDRS) II, III, or IV, 1 year after surgery, defined as, respectively, 3, 5, and 3 points or more. Lower UPDRS III and IV scores and higher age at disease onset contributed most to weak response predictions. Individual predictions were compared with actual clinical outcomes. RESULTS: 322 PD patients treated with STN DBS from 6 different centers were included. DBS-PREDICT differentiated between weak and strong motor responders with an area under the receiver operator curve of 0.76 and an accuracy up to 77%. CONCLUSION: Proving generalizability and feasibility of preoperative STN DBS outcome prediction in an external multicenter cohort is an important step in creating clinical impact in DBS with data-driven tools. Future prospective studies are required to overcome several inherent practical and statistical limitations of including clinical decision support systems in DBS care.

Self-adjustment of deep brain stimulation delays optimization in Parkinson's disease.

BACKGROUND: Parkinson's Disease patients undergo time-consuming programming to refine stimulation parameters after deep brain stimulation surgery. OBJECTIVE: To assess whether the use of the advanced functions of a patient's programmer would facilitate programming of deep brain stimulation. METHODS: Thirty patients were randomly allocated to the use of advanced versus simple mode of the patient programmer in this single-centre, prospective, randomized, controlled study. Primary outcome was the number of days required to optimize the stimulation settings. RESULTS: The number of days required to optimize stimulation was significantly lower in the simple mode (88.5 ± 33.1 vs. 142.1 ± 67.4, p = 0.01). In addition, the advanced mode group had a higher number of side effects (5.4 ± 3.1 vs. 2.6 ± 1.9, p = 0.0055). CONCLUSIONS: The use of the advanced functions of patient programmer delays programming optimization and it is associated with a higher number of side effects. These findings highlight the need for other methods for faster and safer stimulation programming.

Long term follow-up results of deep brain stimulation of the Globus pallidus interna in pediatric patients with DYT1-positive dystonia.

OBJECTIVES: Primary generalized dystonia (PGD) due to heterozygous torsin 1A (TOR1A) gene mutation (DYT1) is a childhood onset dystonia with rapid deterioration of symptoms, leading to severe disability in adolescence. Globus pallidus interna deep brain stimulation (GPi-DBS) has been shown to provide significant improvement in these cases. METHODS: This was a retrospective study of TOR1A mutation positive dystonia patients, conducted at a university hospital from 2006 to 2018. Burke-Fahn-Marsden Dystonia Rating Scale (BFM-DRS) was used to evaluate dystonia severity before and after surgery. Emergence of postsurgical parkinsonian symptoms was evaluated using the Unified Parkinson Disease Rating Scale (UPDRS) part III. Montreal Cognitive Assessment (MOCA) was applied to assess cognitive dysfunction. SPSS version 18 was used for data analysis. RESULTS: Eleven patients entered for analysis with an average age of 22.36 (±3.35) years (range: 18-28). Seven patients (63.6 %) were female. Mean follow-up period was 8.72 (±0.87). Difference between baseline and most recent BFM scores was significant (disability: 10.5 ±4.52 versus 2.09 (±3.20), P: 0.001; severity: 48.45 (±17.88) versus 9.36 (±10.47), P<0.001). The mean MOCA and UPDRS III scores after 7-9 years of DBS were 27.18 (±2.99), and 6.09 (±4.15), respectively. CONCLUSION: Our experience confirms that GPi-DBS in pediatric patients with DYT1 dystonia is overall successful, with significant and long-lasting positive effects on motor and cognitive functions. There was no prominent side effect in long-term follow up.

Levodopa Versus Dopamine Agonist after Subthalamic Stimulation in Parkinson's Disease.

BACKGROUND: No clinical trials have been specifically designed to compare medical treatments after surgery in Parkinson's disease (PD). OBJECTIVE: Study's objective was to compare the efficacy and safety of levodopa versus dopamine agonist monotherapy after deep brain stimulation (DBS) in PD. METHODS: Thirty-five surgical candidates were randomly assigned to receive postoperative monotherapy with either levodopa or dopamine agonist in a randomized, single-blind study. All patients were reevaluated in short- (3 months), mid- (6 months), and long-term (2.5 years) follow-up after surgery. The primary outcome measure was the change in the Non-Motor Symptoms Scale (NMSS) 3 months after surgery. Secondary outcome measures were the percentage of patients maintaining monotherapy, change in motor symptoms, and specific non-motor symptoms (NMS). Analysis was performed primarily in the intention-to-treat population. RESULTS: Randomization did not significantly affect the primary outcome (difference in NMSS between treatment groups was 4.88 [95% confidence interval: -11.78-21.53, P = 0.566]). In short- and mid-term follow-up, monotherapy was safe and feasible in more than half of patients (60% in short- and 51.5% in mid-term follow-up), but it was more often possible for patients on levodopa. The ability to maintain dopamine agonist monotherapy was related to optimal contact location. In the long term, levodopa monotherapy was feasible only in a minority of patients (34.2%), whereas dopamine agonist monotherapy was not tolerated due to worsening of motor conditions or occurrence of impulse control disorders. CONCLUSIONS: This trial provides evidence for simplifying pharmacological treatment after functional neurosurgery for PD. The reduction in dopamine receptor agonists should be attempted while monitoring for occurrence of NMSs, such as apathy and sleep disturbances. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Follow-Up of Advanced Parkinson's Disease Patients after Clinical or Surgical Emergencies: A Practical Approach.

BACKGROUND: Patients with advanced stage Parkinson's disease (PD) typically present with a myriad of motor and nonmotor symptoms in addition to comorbidities and, as a consequence, polypharmacy. OBJECTIVE: To analyze a series of cases of advanced PD in which a clinical or surgical emergency played a trigger role in the irreversible progression of landmarks of the course of the disease. METHODS: Data were collected during a 13-month observational period of a cohort of 230 PD patients, in 751 medical appointments. We included a total of 13 (5.65% of the total number) patients with advanced PD defined by Hoehn & Yahr (H&Y) stage ≥3 who presented with various clinical and surgical complications which, with the contribution of drug interventions, led to significant worsening of patients' overall clinical condition. RESULTS: Hip fractures and infections were the most common complications identified. As part of this scenario, most patients presented with delirium, often requiring treatment with dopamine receptor blocking agents and/or had dopaminergic treatment withdrawn. Upon reassessment after 3 months, all patients remained bed or wheel chair bound (H&Y 5) and presented significant worsening of their UPDRS part III score of at least 10 points (mean 51.5 ± 3.3; paired t-test two-tailed p < 0.0001 compared to baseline). The mean dose of levodopa at baseline was 907.7 ± 149.8 mg (600-1200) and significantly higher (paired t-test two-tailed p < 0.0001) on follow-up, 1061.5 ± 175.8 mg (700-1300). CONCLUSION: Clinical and surgical emergencies are major determinants for a progression of PD to more advanced stages.

Benign versus malignant Parkinson disease: the unexpected silver lining of motor complications.

OBJECTIVE: We sought to evaluate demographic, clinical, and habits/occupational variables between phenotypic extremes in Parkinson's disease (PD). METHODS: Databases from nine movement disorders centers across seven countries were retrospectively searched for subjects meeting criteria for very slowly progressive, benign, PD (bPD) and rapidly progressive, malignant, PD (mPD). bPD was defined as Hoehn and Yahr (H&Y) stage ≤ 3, normal cognitive function, and Schwab and England (S&E) score ≥ 70 after ≥ 20 years of PD (≥ 10 years if older than 60 at PD onset); mPD as H&Y > 3, S&E score < 70, and cognitive impairment within 10 years from PD onset. We performed between-group analysis of demographic, habits/occupational, and clinical features at baseline and follow-up and unsupervised data-driven analysis of the clinical homogeneity of bPD and mPD. RESULTS: At onset, bPD subjects (n = 210) were younger, had a single limb affected, lower severity and greater asymmetry of symptoms, and lower prevalence of depression than mPD (n = 155). bPD was associated with active smoking and physical activity, mPD with agricultural occupation. At follow-up, mPD showed higher prevalence of depression, hallucinations, dysautonomia, and REM behaviour disorder. Interestingly, the odds of mPD were significantly reduced by the presence of dyskinesia and wearing-off. Data-driven analysis confirmed the independent clustering of bPD and mPD, with age at onset emerging as a critical discriminant between the two groups (< 46-year-old vs. > 68-year-old). CONCLUSIONS: Phenotypic PD extremes showed distinct demographic, clinical, and habits/occupational factors. Motor complications may be conceived as markers of therapeutic success given their attenuating effects on the odds of mPD.

Yawning in neurology: a review.

Yawning is a stereotyped physiological behavior that can represent a sign or symptom of several conditions, such as stroke, parakinesia brachialis oscitans, parkinsonism, Parkinson's disease and epilepsy. More rarely, it can occur in patients with intracranial hypertension, brain tumor, multiple sclerosis, migraine, Chiari malformation type I, and amyotrophic lateral sclerosis. Drug-induced yawning is an uncommon clinical condition and yawning in patients with autism or schizophrenia is very rare. The aim of this review is to describe in detail the occurrence of the phenomenon in such conditions, and its' phenomenology and pathophysiology.

Yawning in neurology: a review / Bocejo em neurologia: uma revisão

ABSTRACT Yawning is a stereotyped physiological behavior that can represent a sign or symptom of several conditions, such as stroke, parakinesia brachialis oscitans, parkinsonism, Parkinson's disease and epilepsy. More rarely, it can occur in patients with intracranial hypertension, brain tumor, multiple sclerosis, migraine, Chiari malformation type I, and amyotrophic lateral sclerosis. Drug-induced yawning is an uncommon clinical condition and yawning in patients with autism or schizophrenia is very rare. The aim of this review is to describe in detail the occurrence of the phenomenon in such conditions, and its' phenomenology and pathophysiology.

RESUMO Bocejo é um comportamento estereotipado fisiológico, o qual, contudo, pode representar um sinal ou sintoma de várias condições neurológicas, tais como, acidente vascular encefálico, incluindo a parakinesia brachial oscitans, parkinsonismo, doença de Parkinson, e epilepsia. Mais raramente, o bocejo pode ocorrer em pacientes com hipertensão intra-craniana, tumor cerebral, esclerose múltipla, migrânea, malformação de Chiari tipo I, e esclerose lateral amiotrófica. Bocejo-induzido por drogas representa outra condição clínica pouco comum. De outro modo, bocejo é muito raro em pacientes com autismo e esquizofrenia. O objetivo desta revisão foi descrever em detalhes a ocorrência deste fenômeno em tais condições, sua fenomenologia e fisiopatologia.

Decisions about deep brain stimulation therapy in Parkinson's disease / Decisões a respeito da terapia com estimulação cerebral profunda na doença de Parkinson

ABSTRACT Parkinson's disease can be treated surgically in patients who present with motor complications such as fluctuations and dyskinesias, or medically-refractory disabling tremor. In this review, a group of specialists formulated suggestions for a preoperative evaluation protocol after reviewing the literature published up to October 2017. In this protocol, eligibility and ineligibility criteria for surgical treatment were suggested, as well as procedures that should be carried out before the multidisciplinary therapeutic decisions. The review emphasizes the need to establish "DBS teams", with professionals dedicated specifically to this area. Finally, surgical target selection (subthalamic nucleus or globus pallidus internus) is discussed briefly, weighing the pros and cons of each target.

RESUMO A doença de Parkinson pode ser tratada cirurgicamente em pacientes que desenvolveram complicações motoras, como flutuações e discinesias, ou tremores refratários ao uso de medicação. Nesta revisão, um grupo de especialistas formulou sugestões para um protocolo de avaliação pré-operatória, depois de revisar a literatura publicada até outubro de 2017. Neste protocolo, são sugeridos critérios de elegibilidade e inadmissibilidade para tratamento cirúrgico, bem como procedimentos que devem ser realizados antes das decisões terapêuticas multidisciplinares. A revisão enfatiza a necessidade de estabelecer "equipes de DBS", com profissionais dedicados especialmente a esta área. Ao final, a seleção do alvo cirúrgico (núcleo subtalâmico ou globo pálido interno) é discutida brevemente, ponderando prós e contras de cada escolha.

Botulinum toxin for hereditary spastic paraplegia: effects on motor and non-motor manifestations / Toxina botulínica nas paraplegias espásticas hereditárias: efeitos nas manifestações motoras e não-motoras

ABSTRACT Motor and non-motor manifestations are common and disabling features of hereditary spastic paraplegia (HSP). Botulinum toxin type A (Btx-A) is considered effective for spasticity and may improve gait in these patients. Little is known about the effects of Btx-A on non-motor symptoms in HSP patients. Objective To assess the efficacy of Btx-A on motor and non-motor manifestations in HSP patients. Methods Thirty-three adult patients with a clinical and molecular diagnosis of HSP were evaluated before and after Btx-A injections. Results Mean age was 41.7 ± 13.6 years and there were 18 women. Most patients had a pure phenotype and SPG4 was the most frequent genotype. The Btx-A injections resulted in a decrease in spasticity at the adductor muscles, and no other motor measure was significantly modified. In contrast, fatigue scores were significantly reduced after Btx-A injections. Conclusion Btx-A injections resulted in no significant functional motor improvement for HSP, but fatigue improved after treatment.

RESUMO Manifestações motoras e não motoras são comuns e incapacitantes nas paraparesias espásticas hereditárias (PEH). Toxina botulínica do tipo A (TB-A) é considerada eficaz no tratamento da espasticidade e pode melhorar a marcha nesses pacientes. Pouco se sabe sobre os efeitos da TB-A sobre sintomas não-motores. Objetivo avaliar a eficácia da TB-A sobre manifestações motoras e não-motoras nas PEH. Método trinta e três pacientes adultos com PEH foram avaliados antes e depois das aplicações de TB-A. Resultados A média de idade foi 41,7 ± 13,6 anos e havia 18 mulheres. A maioria dos pacientes portava a forma pura e o genótipo mais comum foi SPG4. Houve diminuição da espasticidade dos músculos adutores da coxa sem melhora da marcha. A pontuação da fadiga reduziu após as injeções. Conclusão As aplicações de TB-A não melhoraram a marcha nos pacientes mas a redução da fadiga foi significativa após o tratamento.

Predictors of deep brain stimulation outcome in tremor patients.

BACKGROUND: Deep brain stimulation of the ventro-intermedius nucleus of the thalamus is an established treatment for tremor of differing etiologies but factors that may predict the short- and especially long-term outcome of surgery are still largely unknown. METHODS: We retrospectively investigated the clinical, pharmacological, electrophysiological and anatomical features that might predict the initial response and preservation of benefit in all patients who underwent deep brain stimulation for tremor. Data were collected at the following time points: baseline (preoperative), one-year post-surgery, and most recent visit. Tremor severity was recorded using the Fahn-Tolosa-Marin Tremor Rating Scale and/or the Unified Parkinson's Disease Rating Scale. RESULTS: A total of 52 patients were included in the final analysis: 31 with essential tremor, 15 with cerebellar tremor of different etiologies, and 6 with Parkinson's disease. Long-term success (mean follow-up duration 34.7 months, range 1.7-121.1 months) was reported in 63.5%. Predictors of long-term benefit were: underlying tremor etiology (best outcome in Parkinson's disease, worst outcome in cerebellar tremor); age at surgery (the older the better); baseline tremor severity (the greater the better); lack of response to benzodiazepines; a more anterior electrode placement and single-unit beta power (the greater the better). CONCLUSIONS: Specific patients' features (including single unit beta activity) and electrode locations may predict the short- and long-term benefit of thalamic stimulation for tremor. Future prospective studies enrolling a much larger sample of patients are needed to substantiate the associations detected by this retrospective study.