Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. METHODS: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. RESULTS: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. DISCUSSION: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Predictors of falls in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy: a retrospective study.

INTRODUCTION: Recurrent falling is a major clinical milestone in Parkinsonian syndromes. It has a detrimental impact on quality of life, further prognosis, and life expectancy. AIM OF THE STUDY: To improve fall management and prevention, we aimed at identifying clinical parameters predicting fall frequency. To this end, we retrospectively analysed records of fall events of patients with Parkinson's disease (PD), or progressive supranuclear palsy (PSP), or multiple system atrophy (MSA), during their two-week inpatient stay at the Parkinson-Klinik Ortenau, Wolfach, Germany. This data served as an objective proxy for patients' fall frequency and allowed us to estimate the impact of several demographic and clinical variables on the occurrence of falling. MATERIAL AND METHODS: Of 2,111 patients admitted to our hospital, 1,810 presented with PD, 191 with PSP, and 110 with MSA. We employed a multiple (quasi-) poisson regression analysis to model the fall frequency as a function of various demographic variables (age at diagnosis, gender) and clinical variables (disease duration and sub-type, motor and cognitive impairment, autonomic dysfunction). RESULTS: Statistically significant predictors for falls in PD were cognitive impairment, motor impairment, and autonomic dysfunction. In PSP, significant predictors for falls were motor and autonomic dysfunction, while in MSA only disease duration predicted falls, but with only marginal statistical significance. CONCLUSIONS: Our results stress the importance of different factors in predicting falls in the different types of Parkinsonian syndrome. Preventive interventions should address these disease-specific targets for optimal success.

Life style and Parkinson's disease.

The question whether life style may impair the advent or course of the disease in patients with Parkinsonism is of great importance for patients and physicians alike. We present here comprehensive information on the influence of the environment, diet (especially caffeine, nicotine, alcohol, chocolate and dairy products), physical activity and sleep on risk and course of Parkinson's disease.

The final diagnoses of patients with clinically suspected atypical parkinsonian syndromes.

We report on 189 patients who were evaluated for APS. Final diagnoses included 77 cases of PSP, 32 patients with MSA and 11 patients with CBS. 35 patients were diagnosed or confirmed with iPD, while in 26 cases a differentiation between iPD and APS could not be definitely made.

[Recommendation for the differentiated use of nuclear medical diagnostic for parkinsonian syndromes]. / Empfehlung zum differenzierten Einsatz nuklearmedizinischer Diagnostik bei Parkinson-Syndromen.

The present work provides an overview of the various nuclear medicine methods in the diagnosis of neurodegenerative parkinsonian syndromes and their respective evidence and is intended to enable practical decision-making aids in the application and interpretation of the methods and findings. The value of the procedures differs considerably in relation to the two relevant diagnostic questions. On the one hand, it is the question of whether there is a neurodegenerative parkinsonian syndrome at all, and on the other hand the question of which one. While the DAT-SPECT is undisputedly the method of choice for answering the first question (taking certain parameters into account), this method is not suitable for answering the second question. To categorise parkinsonian syndromes into idiopathic (i. e. Parkinson´s disease) or atypical, various procedures are used in everyday clinical practice including MIBG scintigraphy, and FDG-PET. We explain why FDG-PET currently is not only the most suitable of these methods to differentiate an idiopathic parkinsonian syndrome, from an atypical Parkinson's syndrome, but also enables sufficiently valid to distinguish the various atypical neurodegenerative Parkinson's syndromes (i. e. MSA, PSP and CBD) from each other and therefore should be reimbursed by health insurances.

Management of delirium in Parkinson's disease.

Delirium is an acute and fluctuating disturbance of attention and awareness. Pre-existing cognitive disturbances or dementia are the most significant risk factors for developing delirium and precipitating factors such as drug treatment, infections, trauma, or surgery may trigger delirium. Patients with Parkinson's disease (PD) are at an increased risk for delirium which may be underdiagnosed due to phenomenological overlap between delirium and chronic neuropsychiatric features of PD or side effects of dopaminergic medication. Prognosis of delirium is detrimental in many cases including permanent cognitive decline, motor impairment, and increased mortality. Management of delirium comprises of pharmacological and non-pharmacological measures. Pharmacotherapy is aimed at treating medical precipitating factors such as infections, pain, and sleep deprivation. Adjustments of anti-parkinsonian medication are recommended to prevent or treat delirium, but no hard evidence in this respect is available from controlled studies. Administration of neuroleptics and other psychoactive drugs in the treatment of delirium is controversially discussed and should be reserved for patients with severe agitation or distressing psychosis. Non-pharmacological interventions to prevent or palliate delirium are based on withdrawing precipitating or distressing factors, and to provide sensory, emotional and environmental support. Appropriate instruments to detect and assess delirium in PD are needed, and efforts are warranted to improve understanding and treatment of this severe and common disorder.

[Dementia with Lewy bodies]. / Demenz mit Lewy-Körpern.

Dementia with Lewy bodies is characterized histopathologically by the deposition of α-synuclein in inclusion bodies. Clinical diagnosis is based on progressive cognitive deficits, cognitive fluctuations, early visual hallucinations, REM sleep disorders and symptoms of Parkinsonism. On the basis of the new criteria published in 2017, better differentiation from other neurodegenerative diseases with dementia should be possible. Therapy concepts include treatment of loss of motor and cognitive performance as well as psychological and behavioral symptoms. At present, only a few studies are available on this clinical picture so that evidence-based therapy approaches are only possible to a limited extent.

Nonmotor fluctuations: phenotypes, pathophysiology, management, and open issues.

Parkinson's disease (PD) is a neurodegenerative multisystem disorder characterized by progressive motor symptoms such as bradykinesia, tremor and muscle rigidity. Over the course of the disease, numerous non-motor symptoms, sometimes preceding the onset of motor symptoms, significantly impair patients' quality of life. The significance of non-motor symptoms may outweigh the burden through progressive motor incapacity, especially in later stages of the disease. The advanced stage of the disease is characterized by motor complications such as fluctuations and dyskinesias induced by the long-term application of levodopa therapy. In recent years, it became evident that various non-motor symptoms such as psychiatric symptoms, fatigue and pain also show fluctuations after chronic levodopa therapy (named non-motor fluctuations or NMFs). Although NMFs have moved into the focus of interest, current national guidelines on the treatment of PD may refer to non-motor symptoms and their management, but do not mention NMF, and do not contain recommendations on their management. The present article summarizes major issues related to NMF including clinical phenomenology and pathophysiology, and outlines a number of open issues and topics for future research.

Gene expression of NMDA receptor subunits in the cerebellum of elderly patients with schizophrenia.

To determine if NMDA receptor alterations are present in the cerebellum in schizophrenia, we measured NMDA receptor binding and gene expression of the NMDA receptor subunits in a post-mortem study of elderly patients with schizophrenia and non-affected subjects. Furthermore, we assessed influence of genetic variation in the candidate gene neuregulin-1 (NRG1) on the expression of the NMDA receptor in an exploratory study. Post-mortem samples from the cerebellar cortex of ten schizophrenic patients were compared with nine normal subjects. We investigated NMDA receptor binding by receptor autoradiography and gene expression of the NMDA receptor subunits NR1, NR2A, NR2B, NR2C and NR2D by in situ hybridization. For the genetic study, we genotyped the NRG1 polymorphism rs35753505 (SNP8NRG221533). Additionally, we treated rats with the antipsychotics haloperidol or clozapine and assessed cerebellar NMDA receptor binding and gene expression of subunits to examine the effects of antipsychotic treatment. Gene expression of the NR2D subunit was increased in the right cerebellum of schizophrenic patients compared to controls. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of the NR2C subunit in the right cerebellum, compared to individuals homozygous for the T allele. Correlation with medication parameters and the animal model revealed no treatment effects. In conclusion, increased NR2D expression results in a hyperexcitable NMDA receptor suggesting an adaptive effect due to receptor hypofunction. The decreased NR2C expression in NRG1 risk variant may cause a deficit in NMDA receptor function. This supports the hypothesis of an abnormal glutamatergic neurotransmission in the right cerebellum in the pathophysiology of schizophrenia.