Chronic Enterovirus Meningoencephalitis in Prolonged B-Cell Depletion After Rituximab Therapy: Case Report.

OBJECTIVES: Persistent impaired immunity is possible even years after B-cell depleting therapies. This may favor the occurrence of infections, including infectious meningitis and encephalitis. In this study, we report a case of chronic enterovirus meningoencephalitis in prolonged B-cell depletion years after rituximab therapy. METHODS: This is a case report from a German academic hospital. In addition to repeated clinical examinations, repeated brain MRI and extended CSF and laboratory diagnostics were performed. We used the CARE checklist when writing our report. RESULTS: A 38-year-old man presented with high fever (>40°C), severe headache, and progressive neurologic and cognitive deficits. As result of previous lymphoma therapy with rituximab years ago, prolonged B-cell aplasia was detected. To restore humoral immunity, the patient received repeated infusions of immunoglobulins. In the end, a complete restitution of the physical and mental condition was achieved with the established therapy. DISCUSSION: This case report should emphasize the importance of assessing humoral immunity even years after B-cell depletion therapy, especially in case of opportunistic infections.

[The exposome in the context of preventive measures for Alzheimer's and Parkinson's diseases]. / Das Exposom im Fokus präventiver Maßnahmen für die Alzheimer- und Parkinson-Erkrankung.

BACKGROUND: Preventive measures addressing the exposome can counteract neurodegenerative diseases. OBJECTIVE: This article gives an overview on the influence of general and individual exogenous factors (environmental influences and lifestyle changes) as well as endogenous factors (e.g. metabolic alterations) on the development and progression of Alzheimer's disease (AD) and Parkinson's disease (PD). METHODS: Summary and evaluation of current scientific studies and evidence regarding the exposome and prevention of AD and PD. RESULTS: Numerous studies could demonstrate a potential influence of environmental influences associated with industrialization (general exogenous factors), such as pesticides, solvents or air pollution on the development of AD and PD. Additionally, individually addressable changes of lifestyle (individual exogenous factors, e.g. physical activity, cognitive stimulation, nutrition and sleep) contribute to disease protection and modification and are becoming increasingly more important in light of still limited therapeutic interventions. Moreover, other exogenous factors (medication, noise pollution, head trauma and heavy metals) are discussed as risk factors for AD and/or PD. Endogenous factors (e.g., changes of the enteral microbiome, systemic inflammation and neuroinflammation, metabolic changes) can contribute to disease development by a higher potential for interacting with exogenous factors. CONCLUSION: Despite the comprehensive scientific evidence confirming the significance of the exposome for the pathogenesis of AD and PD, the great potential of preventive measures has not yet been exploited. A clarification of the high potential of lifestyle changes should be a therapeutic standard not only for individuals with manifest PD/AD but also for individuals with a risk profile or with suspected prodromal disease. Further investigations on the influence of environmental factors and the implementation of preventive strategies to avoid exposure should be the focus of international efforts.

Validity and Prognostic Value of a Polygenic Risk Score for Parkinson's Disease.

Idiopathic Parkinson's disease (PD) is a complex multifactorial disorder caused by the interplay of both genetic and non-genetic risk factors. Polygenic risk scores (PRSs) are one way to aggregate the effects of a large number of genetic variants upon the risk for a disease like PD in a single quantity. However, reassessment of the performance of a given PRS in independent data sets is a precondition for establishing the PRS as a valid tool to this end. We studied a previously proposed PRS for PD in a separate genetic data set, comprising 1914 PD cases and 4464 controls, and were able to replicate its ability to differentiate between cases and controls. We also assessed theoretically the prognostic value of the PD-PRS, i.e., its ability to predict the development of PD in later life for healthy individuals. As it turned out, the PD-PRS alone can be expected to perform poorly in this regard. Therefore, we conclude that the PD-PRS could serve as an important research tool, but that meaningful PRS-based prognosis of PD at an individual level is not feasible.

Moral distress among residents in neurology: a pilot study.

BACKGROUND: Medical progress, economization of healthcare systems, and scarcity of resources raise fundamental ethical issues. Physicians are exposed to increasing moral conflict situations, which may cause Moral Distress (MD). MD occurs when someone thinks he or she might know the morally correct action but cannot act upon this knowledge because of in- or external constraints. Correlations of MD among residents to job changes and burn-out have been shown previously. There are, however, hardly any quantitative studies about MD among physicians in Germany. The aim of this study was to investigate the frequency of occurrence, the level of disturbance, and reasons for MD among neurological residents in German hospitals. METHODS: 1st qualitative phase: Open interviews on workload and ethical conflicts in everyday clinical practice were conducted with five neurological residents. Ethical principles of medical action and potential constraints that could cause MD were identified and a questionnaire designed. 2nd quantitative phase: A preliminary questionnaire was tested and evaluated by five further neurological residents. The final questionnaire consisted of 12 items and was conducted online and anonymously via e-mail or on-site as part of an unrelated resident training event at 56 sites. RESULTS: One hundred seven neurological residents from 56 university/acute care and rehabilitation hospitals throughout Germany were examined (response rate of those requesting the questionnaire: 75.1%). 96.3% of the participants had experienced MD weekly (3.86, SD 1.02), because they were unable to invest the necessary time in a patient or relative consultation. Errors in medical care, which could not be communicated adequately with patients or relatives, were rated as most distressing. The most common reasons for MD were the growing numbers of patients, expectations of patient relatives, fears of legal consequences, incentives of the DRG-system, and the increasing bureaucratization requirement. 43.0% of participants mentioned they considered leaving the field of inpatient-care. 65.4% stated they would like more support in conflict situations. CONCLUSION: MD plays an important role for neurological residents in German hospitals and has an impact on participants' consideration of changing the workplace. Important aspects are rationing (time/beds) and incentives for overdiagnosis as well as lack of internal communication culture and mentoring.

Transcranial Sonography Findings in Alzheimer's Disease: A New Imaging Biomarker.

OBJECTIVE: To validate transcranial sonography (TCS) as a novel imaging tool for the assessment of medial temporal lobe (MTL) atrophy (MTA). MATERIALS AND METHODS: Participants with Alzheimer's disease (AD, n = 30) and age-sex-matched controls (n = 30) underwent TCS and MRI. On TCS, MTL structures (choroidal fissure (CF) and temporal horn (TH)) were measured and combined to create an MTA score in sonography (MTA-S). Furthermore, both THs and the third ventricle were combined to form the ventricle enlargement score in sonography (VES-S). On MRI, the MTL was evaluated by linear measurements, MTA scale and hippocampal volumetry. Validation was performed by comparing imaging methods and the patient group. RESULTS: Intraclass correlations for CF and TH showed substantial intra/inter-rater reliability (> 0.80). TCS and MRI showed strong to moderate correlation regarding TH (right = 0.88, left = 0.89) and CF (right = 0.70, left = 0.47). MTA-S correlated significantly with the hippocampal volume (right = -0.51, left = -0.47), predicted group membership in logistic regression (Exp(B) right = 3.0, left = 2.7), and could separate AD patients from controls (AUC = 0.93). An MTA-S of 6 mm and 10 mm discriminated MRI MTA scores 0-1 (from 2-4) and MTA score 4 (from 0-3) with 100 % specificity, respectively. VES-S also showed a moderate correlation with the hippocampal volume (r = -0.66) and could differentiate AD patients from controls (AUC = 0.93). CONCLUSION: Our results suggest that TCS may be an alternative imaging tool for the assessment of MTL atrophy and ventricular enlargement for patients in whom MRI scanning is not possible. Additionally, TCS offers a practical, patient-friendly and inexpensive option for the screening and follow-up of individuals with AD.

Executive Function Is Related to the Urinary Urgency in Non-demented Patients With Parkinson's Disease.

Introduction: Evidence suggests urinary urgency is associated with cognitive impairment in a subtype of Parkinson's disease (PD) patients. This study investigates if cognitive impairment independently predicts the presence of urinary dysfunction. Methods: We report data of 189 idiopathic PD patients, excluding those with concomitant diseases or medication interacting with bladder function. A standardized questionnaire was used to define the presence of urinary urgency. All patients underwent a comprehensive motor, cognitive non-motor and health-related quality of life (HRQoL) assessment. Multivariable linear regression analysis was performed to identify independent variables characterizing urinary urgency in PD (PD-UU), which were assigned as discriminant features to estimate their individual contribution to the phenotype of the PD-UU group. Results: Of 189 PD patients, 115 (60.8%) reported PD-UU. The linear regression analysis showed that among cognitive domains, executive function (EF; p = 0.04) had a significant negative association with PD-UU. In a second model, scores of the Montreal Cognitive Assessment (MoCA) significantly differentiated between study groups (p = 0.007) and also non-motor symptom (NMS) burden (p < 0.001). The third model consisted of reports of HRQoL, of which stigma was the only subscale of the Parkinson's Disease Questionnaire (PDQ-39) differentiating between patients with and without PD-UU (p = 0.02). The linear discriminant analysis provided evidence that the combination of EF, NMS burden, nocturia, and stigma discriminated between groups with 72.4% accuracy. Conclusion: In our large, non-demented PD cohort, urinary urgency was associated with executive dysfunction (EF), supporting a possible causative link between both symptoms. A combination of neuropsychological and non-motor aspects identified patients with PD-UU with high discriminative accuracy.

Nerve Ultrasonography as an Additive Tool to Clinical Examination and Electrodiagnostics in Sporadic Mononeuritis - Imaging is the Key.

PURPOSE: Sporadic mononeuropathies without trauma or compression are challenging to diagnose. Nerve ultrasound has recently proven its usefulness in the diagnosis of traumatic neuropathies, tumors and polyneuropathies. However, its role in mononeuropathies currently remains unclear. We describe ultrasonography follow-up results in 12 patients with suggested spontaneous, monophasic mononeuritis without signs of generalization. MATERIALS AND METHODS: Nerve conduction studies (NCS), ultrasonography of the affected nerves and the contralateral side, laboratory analysis, and if possible magnetic resonance imaging (MRI) of the affected nerves were established in all patients at onset. In one patient, additive nerve biopsy was performed. In all patients, ultrasonography was repeated after immunotherapy. RESULTS: An infectious pathogen of neuritis was not found in any patient. All but one patient showed predominant axonal nerve damage in NCS, whereas ultrasonography and MRI revealed fascicular and/or overall cross-sectional area (CSA) enlargement or T2 hyperintensity of the affected nerve segments, suggesting an inflammatory background of the neuropathy. Most patients showed significant clinical amelioration of symptoms under treatment (75.0 %) and consequently a decrease in CSA/fascicle enlargement over time (77.8 %). CONCLUSION: Ultrasonography and MRI of the nerves revealed enlargement in patients with mononeuropathy of axonal NCS pattern of unknown origin. Ultrasonography can facilitate the therapeutic decision for immunotherapy. Next to nerve trauma, nerve tumors and nerve entrapments, ultrasonography reliably shows nerve enlargement in the case of inflammation and therefore could further enrich neurophysiology. Nerve imaging might serve as a follow-up tool by observing a decrease in nerve enlargement and improved function.

Role of ANO3 mutations in dystonia: A large-scale mutational screening study.

BACKGROUND: The role of ANO3 variants as a monogenic cause of dystonia is still under debate because of its relatively high frequency also in controls. OBJECTIVE: To screen >1000 patients with movement disorders for rare ANO3 variants. METHODS: We searched for rare ANO3 variants in 729 dystonia and 294 Parkinson's disease (PD) patients using a gene panel. Variants were validated by Sanger sequencing. For one variant carrier, family members were available for segregation analysis. RESULTS: Nine carriers (seven with dystonia [1.0%], two with PD [0.7%]) of seven different rare, protein-changing variants were identified. None of these variants has been previously reported in dystonia patients. Two of the variants in dystonia patients were found recurrently: p.Arg328Cys was detected in two Korean and p.Arg969Gln in two German patients. The frequency of these two variants in our sample seemed to be higher as in ethnically matched samples from the Genome Aggregation Database (GnomAD). Further, we identified a patient with early-onset, generalized dystonia with a de-novo variant in ANO3 (p.Val561Glu). Of note, she benefitted from deep brain stimulation. CONCLUSION: This study confirms the relatively high frequency of rare, protein-changing ANO3 variants in both dystonia and non-dystonia patients indicating that not all variants contribute to the disease. Thus, disease relevance of novel variants remains difficult to interpret and functional studies are warranted for a better understanding of the role of ANO3 variants in dystonia. In contrast, de-novo variants in childhood-onset, generalized dystonia seem to represent an as yet underestimated phenotypic expression of changes in ANO3.

Progress of Pharmacological Approaches in Parkinson's Disease.

The progressive neurodegenerative process in Parkinson's disease (PD) is not restricted to dopaminergic midbrain neurons but involves the entire nervous system. In this review, we outline established treatment options at different disease stages and address new therapeutic approaches. These include, based on recent advances in the understanding of the pathophysiology of PD, genetic and disease-modifying approaches to reduce abnormal accumulation and aggregation of alpha-synuclein (aSYN), mitochondrial dysfunction, and dysfunction of lysosomal proteins. Moreover, we highlight clinical trials to reduce neuroinflammation and increase neurorestoration.

Polygenic load: Earlier disease onset but similar longitudinal progression in Parkinson's disease.

OBJECTIVES: In order to evaluate the influence of the genetic load of 49 genetic variants known to be associated with PD on the age at onset as well as on clinical outcome parameters. BACKGROUND: PD patients show a large variability in phenotype and progression reflecting interindividual heterogeneity. This might be influenced by a diverse genetic architecture. METHODS: Six hundred seventeen PD patients were included in this study and stratified by their "genetic load," which is based on the weighted odds ratios of 49 genetic variants known to be associated with PD from genome-wide association studies. Clinical parameters (H & Y, UPDRS-III, MMSE, and Beck's Depression Inventory) were evaluated cross-sectionally and in a subgroup longitudinally over 8 years. RESULTS: PD patients with the highest genetic load were younger at disease onset, whereas severity of clinical parameters were similar compared to patients with the lowest genetic load. These findings could be confirmed regarding progression to clinical endpoints in the longitudinal analysis. CONCLUSION: A high genetic load is associated with a younger age at onset, which, in turn, might possibly promote more effective compensatory mechanisms resulting in a similar rate of disease progression. © 2018 International Parkinson and Movement Disorder Society.

Validation of the MDS clinical diagnostic criteria for Parkinson's disease.

BACKGROUND: In 2015, the International Parkinson and Movement Disorder Society published clinical diagnostic criteria for Parkinson's disease. These criteria aimed to codify/reproduce the expert clinical diagnostic process and to help standardize diagnosis in research and clinical settings. Their accuracy compared with expert clinical diagnosis has not been tested. The objectives of this study were to validate the International Parkinson and Movement Disorder Society diagnostic criteria against a gold standard of expert clinical diagnosis, and to compare concordance/accuracy of the International Parkinson and Movement Disorder Society criteria to 1988 United Kingdom Brain Bank criteria. METHODS: From 8 centers, we recruited 626 parkinsonism patients (434 PD, 192 non-PD). An expert neurologist diagnosed each patient as having PD or non-PD, regardless of International Parkinson and Movement Disorder Society criteria (gold standard, clinical diagnosis). Then a second neurologist evaluated the presence/absence of each individual item from the International Parkinson and Movement Disorder Society criteria. The overall accuracy/concordance rate, sensitivity, and specificity of the International Parkinson and Movement Disorder Society criteria compared with the expert gold standard were calculated. RESULTS: Of 434 patients diagnosed with PD, 94.5% met the International Parkinson and Movement Disorder Society criteria for probable PD (5.5% false-negative rate). Of 192 non-PD patients, 88.5% were identified as non-PD by the criteria (11.5% false-positive rate). The overall accuracy for probable PD was 92.6%. In addition, 59.3% of PD patients and only 1.6% of non-PD patients met the International Parkinson and Movement Disorder Society criteria for clinically established PD. In comparison, United Kingdom Brain Bank criteria had lower sensitivity (89.2%, P = 0.008), specificity (79.2%, P = 0.018), and overall accuracy (86.4%, P < 0.001). Diagnostic accuracy did not differ according to age or sex. Specificity improved as disease duration increased. CONCLUSIONS: The International Parkinson and Movement Disorder Society criteria demonstrated high sensitivity and specificity compared with the gold standard, expert diagnosis, with sensitivity and specificity both higher than United Kingdom Brain Bank criteria. © 2018 International Parkinson and Movement Disorder Society.

Movement disorder society criteria for clinically established early Parkinson's disease.

BACKGROUND: In 2015, the International Parkinson and Movement Disorder Society published clinical diagnostic criteria for Parkinson's disease (PD). Although recent validation studies suggest high accuracy, one unmet need is for highly specific criteria for clinical trials in early/de novo PD. OBJECTIVES: The objective of this study was to generate and test a PD diagnostic criteria termed "clinically established early PD." METHODS: We modified the Movement Disorder Society criteria to increase specificity for early PD by removing all disease duration components and changing red flags to absolute exclusions. We then estimated the sensitivity/specificity of clinically established early PD criteria in patients with disease duration <5 years, selected from a 626-patient validation study. RESULTS: After documentation of parkinsonism, 18 individual exclusion criteria are assessed that preclude the diagnosis of "clinically established early PD." Among 212 PD and 152 non-PD patients, the estimated specificity was 95.4%, with 69.8% sensitivity. CONCLUSIONS: We describe high-specificity criteria for de novo PD, which are freely available for use in clinical trials. © 2018 International Parkinson and Movement Disorder Society.

Psychometric Properties of an Abbreviated Version of the Apathy Evaluation Scale for Parkinson Disease (AES-12PD).

BACKGROUND: Apathy is a frequent symptom in Parkinson's disease (PD), substantially aggravating the course of PD. Regarding the accumulating evidence of the key role of apathy in PD, time-efficient assessments are useful for fostering progress in research and treatment. The Apathy Evaluation Scale (AES) is widely used for the assessment of apathy across different nosologies. OBJECTIVE: To facilitate the application of the AES in PD, we reduced the AES to two-thirds its length and validated this abbreviated version. DESIGN: Data sets of 339 PD patients of the DEMPARK/LANDSCAPE study without dementia and depression were randomly split into two samples. Data of sample 1 were used to develop a brief version of the AES (AES-12PD). A cross-validation was conducted in sample 2 and in a subsample of 42 PD patients with comorbid dementia and depressive symptomatology. Receiver operating characteristic analysis was applied to determine the optimal cutoff of the AES-12PD as an indicator of apathy. RESULTS: The AES-12PD featured high internal consistency that was better compared to the AES. The abbreviated scale was well differentiated from motor impairment and cognitive deficits. The AES-12PD cutoff of 27/28 was the optimal cutoff for apathy in PD patients without dementia and depression. The cutoff of 25/26 indicated apathy in PD patients with comorbid dementia and depression. CONCLUSION: Results confirm a high internal consistency and good discriminant validity of the AES-12PD. The AES-12PD represents a reliable tool for the efficient assessment of apathy that can be applied in PD patients with and without dementia and depression.

Brain-Area Specific White Matter Hyperintensities: Associations to Falls in Parkinson's Disease.

BACKGROUND: Falls are common among people with idiopathic Parkinson's disease (IPD) and are suggested to be associated with white matter hyperintensities (WMH) of the brain. OBJECTIVE: To investigate the contribution of brain area-specific WMH to the risk of falls in IPD. METHODS: In fifty participants with IPD, occurrence and severity of WMH in specific brain areas were determined using Scheltens (without lateralization) and Age-related white matter changes (ARWMC) (with lateralization) scores. Falls were evaluated with the fall item of the Unified PD Rating Scale (UPDRS). Correlations between area-specific WMH and falls were tested with stepwise backward regression and multivariate regression analyses. RESULTS: In this cohort of participants with IPD, left temporal WMH were associated with occurrence of falls. Frontal WMH of both hemispheres showed tendencies towards significance for the association with falls. CONCLUSION: According to our study, WMH in the left temporal area are significantly associated with falls in IPD. Potential reasons for this association could be deficits in memory, navigation, orientation, auditory processing, and fear conditioning, which are all associated with pathologies of the left temporal lobe.

Cognitive changes in prodromal Parkinson's disease: A review.

Although other nonmotor phenomena representing possible prodromal symptoms of Parkinson's disease have been described in some detail, the occurrence and characteristics of cognitive decline in this early phase of the disease are less well understood. The aim of this review is to summarize the current state of research on cognitive changes in prodromal PD. Only a small number of longitudinal studies have been conducted that examined cognitive function in individuals with a subsequent PD diagnosis. However, when we consider data from at-risk groups, the evidence suggests that cognitive decline may occur in a substantial number of individuals who have the potential for developing PD. In terms of specific cognitive domains, executive function in particular and, less frequently, memory scores are reduced. Prospective longitudinal studies are thus needed to clarify whether cognitive, and specifically executive, decline might be added to the prodromal nonmotor symptom complex that may precede motor manifestations of PD by years and may help to update the risk scores used for early identification of PD. © 2017 International Parkinson and Movement Disorder Society.

Psychometric properties of the apathy evaluation scale in patients with Parkinson's disease.

Parkinson's disease (PD) frequently entails non-motor symptoms, worsening the course of the disease. Apathy is one of the core neuropsychiatric symptoms that has been investigated in recent years; research is however hampered by the limited availability of well-evaluated apathy scales for these patients. We evaluated the psychometric properties of the Apathy Evaluation Scale (AES) in a sample of PD patients. Psychometric properties, convergent and discriminant validity and sensitivity/specificity were evaluated in patients with (n = 582) or without dementia/depression (n = 339). Internal consistency was high in the entire sample as well as in patients without dementia/depression. Correlations were moderate for convergent validity (UPDRS I item 4: motivation). While apathy could be differentiated from cognitive decline, it was related to depression (Geriatric Depression Scale, GDS-15). The overall classification accuracy based on the UPDRS I item 4 was comparable for AES and GDS scores. The AES exhibits good psychometric properties in PD patients with and without dementia and/or depression. Commonly used screenings on the presence of apathy had low detection rates compared to the AES and reflected both apathetic and depressive symptoms. Psychometric evaluation of available instruments will support further research on the clinical relevance of apathy for disease progression and treatment approaches in PD patients.

Ultrasound assessment of peripheral nerve pathology in neurofibromatosis type 1 and 2.

OBJECTIVE: The neurofibromatoses (NF) type 1 and 2 are hereditary tumor predisposition syndromes caused by germline mutations in the NF1 and NF2 tumor suppressor genes. In NF1 and 2, peripheral nerve tumors occur regularly. For further characterizing nerve ultrasound was performed in patients with NF1 and 2. METHODS: Patients with established diagnosis of NF1 (n=27) and NF2 (n=10) were included. Ultrasound of peripheral nerves and cervical roots was performed during routine follow-up visits. Healthy volunteers were studied for comparison. RESULTS: In patients with NF1, median cross-sectional area (CSA) of most nerves was significantly increased compared to controls and to NF2 due to generalized plexiform tumors, which arose out of multiple fascicles in 23 of 27 patients (85%). These were often accompanied by cutaneous or subcutaneous neurofibromas. In NF2, the overall aspect of peripheral nerves consisted of localized schwannomas (80%) and, apart from that, normal nerve segments. CONCLUSION: Nerve ultrasound is able to visualize different nerve pathologies in NF1 and NF2. It is a precise and inexpensive screening method for peripheral nerve manifestation in neurofibromatosis and should be considered as the first choice screening imaging modality for all peripheral nerves within reach of non-invasive ultrasound techniques. SIGNIFICANCE: Ultrasound patterns of peripheral nerve pathologies are described for the first time in a large cohort of patients with NF1 and NF2. It is a suitable screening tool and enables targeted MRI analysis.