Vorkommen und Wertigkeit von Oberfrequenzen in der 24-Stunden-Elektromyographie und Accelerometrie bei Parkinson und Essentiellem Tremor

EMG und ACC stellen die gängigsten Verfahren dar, Tremores zu objektivieren und quantifizieren. Die ACC ermöglicht Aussagen über Frequenz und Amplitude, das EMG über Muskelaktivität. Zur Differentialdiagnose der Tremorformen ist die Analyse komplexerer Parameter notwendig. Untersucht wurden 56 Patienten (PT 43/ ET 13) mithilfe des 24-h-TREMOR$\textit {analysers}$, der auf einem Oberflächen-EMG (M. ext. carpi radialis / M. flexor carpi ulnaris) basiert. Parallel wurde der Tremor per ACC aufgezeichnet (je 5 min Ruhe- / Haltebedingungen). In den Frequenzspektren der ACC vom PT finden sich im Vergleich zum ET signifikant mehr Oberfrequenzen (OF). Erstmals konnten im EMG OF nachgewiesen werden. Bezogen auf die Co-Existenz von OF korreliert in der Gruppe der Parkinson Patienten das Auftreten von Harmonischen in der ACC mit dem Vorkommen von OF im 24-h-EMG. Frequenzen des PT liegen häufig außerhalb des Frequenzbandes 3-10 Hz, also unterhalb der bisher allgemein akzeptierten Definition der PT-Untergrenze

Positive effect of immunomodulatory therapies on disease progression in Huntington’s disease?

$\bf Background:$ The role of neuroinflammation and autoimmune processes in neurodegenerative diseases is not fully understood. Activation of microglia with expression of proinflammatory cytokines supports the hypothesis that immune processes may play an important role in the pathophysiology of Huntington’s disease (HD) and thus, immunomodulating therapies might have potential neuroprotective properties. Until now, no disease-modifying therapy (DMT) is available for HD. $\bf Objective:$ The aim of this research was to characterize a cohort of patients suffering from both HD and autoimmune demyelinating diseases of the central nervous system (classified as G35-37 in ICD-10; ADD-CNS) in comparison to HD cases without ADD-CNS. In particular, we were interested to investigate potential modulating effects on disease manifestation and progression of HD over time of prescribed immunomodulating medications (DMT). $\bf Methods:$ We analyzed the course of HD regarding motoric, functional, and cognitive aspects, using longitudinal data of up to 2 years from the worldwide registry study ENROLL-HD. Additional cross-sectional data in the largest cohort worldwide of HD patients was analyzed using demographic and molecular genetic parameters. Data were analyzed using analysis of variance (ANOVA) for cross-sectional and repeated-measures ANOVA for longitudinal parameters in IBM SPSS Statistics V.27. $\bf Results:$ Within the ENROLL-HD database, we investigated $\it N$ = 21,116 participants and identified $\it n$ = 60 participants suffering from ADD-CNS. Molecular, genetic, and demographic data did not differ between groups. The subgroup of $\it n$ = 32 participants with motor-manifest HD revealed better cognitive performance in five out of eight cognitive tests at baseline with less progression over time in two tests (all $\it p$ < 0.05). Differentiation between DMT-treated and untreated patients revealed better cognitive and motor performance in the DMT group; those patients, however, tended to be younger. Pre-manifest HD patients simultaneously diagnosed with ADD-CNS ($\it n$ = 12) showed lower functional scores and more decline over time when compared with other pre-manifest HD ($\it p$ < 0.05). $\bf Conclusion:$ Patients suffering from motor-manifest HD and simultaneously from ADD-CNS have better cognitive capacities compared with other motor-manifest HD patients. Moreover, DMTs might have beneficial effects on progression of neurodegeneration including the motor phenotype. However, this effect might have been biased by younger age in DMT-treated patients. Pre-manifest HD patients showed more functional impairment as expected due to their additional ADD-CNS disease

Brainstem encephalitis with low-titer acetylcholine receptor antibodies mimicking myasthenia gravis

$\textbf {Objective:}$ To report a rare case of brainstem encephalitis with low-titer acetylcholine receptor antibodies mimicking myasthenia gravis. $\textbf {Methods:}$ The patient was investigated with repeated brain MRI, CSF examination, repetitive nerve stimulation, thoracic CT, and serologic screening. Our patient passed away and finally autopsy revealed a definitive diagnosis. Written informed consent was obtained from the relatives of the patient for access to clinical files for research purposes and publication. $\textbf {Results:}$ We present a young woman with a subacute bulbar syndrome, who was initially diagnosed with myasthenia gravis based on clinical finding and elevated acetylcholine receptor antibodies. Episodes of numbness in the pharynx and tongue and moderate saccadic horizontal and vertical pursuits were atypical. Despite initial stabilization with intravenous immunoglobulins she developed acute asphyxia after regurgitation of food and had to be resuscitated with ultimately lethal outcome. Autopsy revealed an autoimmune T-cell mediated brainstem encephalitis. Serological screening revealed positive GAD and Ma2 autoantibodies, indicating its probable paraneoplastic nature. $\textbf {Conclusions:}$ Brainstem encephalitis is an important differential diagnosis even in seropositive bulbar myasthenia gravis, as several autoimmune processes often co-occur. Sudden unexpected death must be taken into account in brainstem encephalitis, requiring prolonged monitoring of the patients

Insight into metabolic 1 ^{1}H-MRS changes in natalizumab induced progressive multifocal leukoencephalopathy brain lesions

$\textbf {Background:}$ Progressive multifocal leukoencephalopathy (PML) is a severe complication of immunosuppressive therapies, especially of natalizumab in relapsing–remitting multiple sclerosis (MS). Metabolic changes within PML lesions have not yet been described in natalizumab-associated PML in MS patients. $\textbf {Objective:}$ To study metabolic profiles in natalizumab-associated PML lesions of MS patients by $^{1}$H magnetic resonance spectroscopy ($^{1}$H-MRS) at different stages during the PML course. To assess changes associated with the occurrence of the immune reconstitution inflammatory syndrome (IRIS). $\textbf {Methods:}$ 20 patients received $^{1}$H-MRS and imaging at 3 T either in the pre-IRIS, IRIS, early-post-PML, or late post-PML setting. Five of these patients received individual follow-up examinations, including the pre-IRIS or IRIS phase. Clinical worsening was described by changes in the Karnofsky Performance Scale (KPS) and the expanded disability status scale (EDSS) 1 year before PML and scoring at the time of $^{1}$H-MRS. $\textbf {Results:}$ In PML lesions, increased levels of the Lip/Cr ratio, driven by rising of lipid and reduction of Creatine, were found before the occurrence of IRIS ($\it p$ = 0.014) with a maximum in the PML–IRIS group ($\it p$ = 0.004). By contrast, marked rises of Cho/Cr in PML lesions were detected exclusively during the IRIS phase ($\it p$ = 0.003). The Lip/Cr ratio decreased to above-normal levels in early-post-PML ($\it p$ = 0.007, compared to normal appearing white matter (NAWM)) and to normal levels in the late-post-PML group. NAA/Cho was reduced compared to NAWM in the pre-IRIS, IRIS, and early-post-PML group. In NAA/Cr, the same effect was seen in the pre-IRIS and early-post-PML group. These cross-sectional results were confirmed by the individual follow-up examinations of four patients. NAA/Cho, Cho/Cr, and the lipid rise relative to NAWM in PML lesions were significantly correlated with the residual clinical worsening (KPS change) in post-PML patients (Spearman correlations $\it p$ = 0.481, $\it p$ = 0.018; $\it p$ = −0.505, $\it p$ = 0.014; and $\it p$ = −0.488, $\it p$ = 0.020). $\textbf {Conclusion:}$ $^{1}$H-MRS detected clinically significant dynamic changes of metabolic patterns in PML lesions during the course of natalizumab-associated PML in MS patients. Lip/Cr and Cho/Cr may provide additional information for detecting the onset of the IRIS phase in the course of the PML disease

Germany-wide evaluation of residency in neurological intensive care medicine

$\bf Background:$ Neurointensive medicine is an important subspecialization of neurology. Its growing importance can be attributed to factors such as demographic change and the establishment of new therapeutic options. Part of the neurological residency in Germany is a six-month rotation on an intensive care unit (ICU), which has not yet been evaluated nationwide. The aim of this study was to evaluate kind and feasibility of neurointensive care training in Germany and to discover particularly successful training concepts. $\bf Methods:$ In a preliminary study, ten residents and ten instructors were interviewed. Using content analysis, two questionnaires were created, which contained questions about specific teaching methods as well as individual satisfaction. The questionnaires were sent to 187 neurological clinics in Germany, and residents and instructors were asked to participate in the study. The data analysis was performed using SPSS and content analysis for the free-text data. $\bf Results:$ Seventy of the 187 clinics contacted did not offer ICU-rotation. At 59,8% ($\it n$ = 70) of the remaining hospitals, a total of 154 participants (84 residents, 70 educators) could be recruited. General satisfaction with the neurointensive medical training is high in both groups (residents: 3.34 $\pm$ 0.54; instructors: 3.79 $\pm$ 0.41, evaluated on the basis of a Likert scale from 1 = "not satisfied" to 5 = "fully satisfied"). Specific teaching methods (e.g. simulation trainings, feedback sessions) are perceived as very useful by residents, but rarely take place. Instructors are interested in educational opportunities such as didactic courses. $\bf Conclusion:$ This study provides an overview of the ICU-rotation as part of the five-year neurological residency. Neurointensive care rotations usually take place at maximum care hospitals and last at least seven months. Despite frequent time and personnel restrictions, motivation of trainers and residents is high. Nevertheless, teaching methods as simulation training and educational opportunities for instructors must be expanded

Metabolic profiles by 1^{1}H-magnetic resonance spectroscopy in natalizumab-associated post-PML lesions of multiple sclerosis patients who survived progressive multifocal leukoencephalopathy (PML)

$\bf Purpose$ Early diagnosis and treatment of multiple sclerosis-related progressive multifocal leukoencephalopathy (PML) significantly improve clinical outcomes. However, there is a lack of information regarding the restart of immunomodulatory therapy in the post-PML setting, when multiple sclerosis activity reappears. We aimed at the examination of metabolic differences using $^{1}$H-magnetic resonance spectroscopy ($^{1}$H-MRS) in multiple sclerosis patients at various post-PML stages and at the exploration of differences according to their disease and JC virus (JCV) status. $\bf Methods$ $^{1}$H-MRS of PML lesions was carried out on 15 relapsing-remitting multiple sclerosis patients with natalizumab-associated PML. Patients were grouped according to their stage after PML infection as early post-PML, less than 19 months after PML onset ($\it n$ = 5), or late post-PML group, more than 23 months after PML onset ($\it n$ = 10). The latter group was further categorized according to persisting JCV load in the cerebrospinal fluid. $\bf Results$ Early post-PML patients showed significantly higher Lipid/Creatine ratios within PML lesions than late post-PML ($\it p$ = 0.036). Furthermore, N-Acetyl-Aspartate/Creatine and N-Acetyl-Aspartate/Choline were significantly reduced in early post-PML and late post-PML lesions relative to normal-appearing white matter. In late post-PML, virus-positive patients showed significantly higher ratios of Choline/Creatine ($\it p$ = 0.019) and consequently a reduced N-Acetyl-Aspartate/Choline ratio ($\it p$ = 0.010) in contrast to virus-negative patients. In late post-PML patients with persisting viral load, an elevated Choline/Creatine ratio correlated significantly with higher disability. $\bf Conclusions$ $^{1}$H-MRS may provide additional information related to underlying PML disease activity in various post-PML stages. In particular, Choline/Creatine levels, Lipid levels, and N-Acetyl-Aspartate/Choline are relevant markers in the post-PML setting, taking also the JCV status into account

Novel variants in a patient with late-onset hyperprolinemia type II

$\bf Background$ Hyperprolinemia type 2 (HPII) is a rare autosomal recessive disorder of the proline metabolism, that affects the ALDH4A1 gene. So far only four different pathogenic mutations are known. The manifestation is mostly in neonatal age, in early infancy or early childhood. $\bf Case presentation$ The 64-years female patient had a long history of abdominal pain, and episode of an acute neuritis. Ten years later she was admitted into the neurological intensive-care-unit with acute abdominal pain, multiple generalized epileptic seizures, a vertical gaze palsy accompanied by extensive lactic acidosis in serum 26.0 mmol/l (reference: 0.55–2.2 mmol/l) and CSF 12.01 mmol/l (reference: 1.12–2.47 mmol/l). Due to repeated epileptic seizures and secondary complications a long-term sedation with a ventilation therapy over 20 days was administered. A diagnostic work-up revealed up to 400-times increased prolin-level in urine CSF and blood. Furthermore, a low vitamin-B$_6$ serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The $\it ALDH4A1$ gene sequencing confirmed two previously unknown compound heterozygous variants ($\it ALDH4A1$ gene (NM_003748.3) Intron 1: c.62 + 1G > A - heterozygous and $\it ALDH4A1$ gene (NM_003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B$_6$ therapy no further seizures occurred. $\bf Conclusion$ We describe two novel $\it ALDH4A1$-variants in an adult patient with hyperprolinemia type II causing secondary pyridoxine deficiency and seizures. Severe and potentially life-threatening course of this treatable disease emphasizes the importance of diagnostic vigilance and thorough laboratory work-up including gene analysis even in cases with atypical late manifestation

Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Huntington's disease

Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disease. The exact sequel of events finally resulting in neurodegeneration is only partially understood and there is no established protective treatment so far. Some lines of evidence speak for the contribution of oxidative stress to neuronal tissue damage. The fumaric acid ester dimethylfumarate (DMF) is a new disease modifying therapy currently in phase III studies for relapsing-remitting multiple sclerosis. DMF potentially exerts neuroprotective effects via induction of the transcription factor "nuclear factor E2-related factor 2" (Nrf2) and detoxification pathways. Thus, we investigated here the therapeutic efficacy of DMF in R6/2 and YAC128 HD transgenic mice which mimic many aspects of HD and are characterized by an enhanced generation of free radicals in neurons. Treatment with DMF significantly prevented weight loss in R6/2 mice between postnatal days 80–90. At the same time, DMF treatment led to an attenuated motor impairment as measured by the clasping score. Average survival in the DMF group was 100.5 days vs. 94.0 days in the placebo group. In the histological analysis on day 80, DMF treatment resulted in a significant preservation of morphologically intact neurons in the striatum as well as in the motor cortex. DMF treatment resulted in an increased Nrf2 immunoreactivity in neuronal subpopulations, but not in astrocytes. These beneficial effects were corroborated in YAC128 mice which, after one year of DMF treatment, also displayed reduced dyskinesia as well as a preservation of neurons. In conclusion, DMF may exert beneficial effects in mouse models of HD. Given its excellent side effect profile, further studies with DMF as new therapeutic approach in HD and other neurodegenerative diseases are warranted

Diagnostic value of the impairment of olfaction in Parkinson's disease

$\it Background$ Olfactory impairment is increasingly recognized as an early symptom in the development of Parkinson's disease. Testing olfactory function is a non-invasive method but can be time-consuming which restricts its application in clinical settings and epidemiological studies. Here, we investigate odor identification as a supportive diagnostic tool for Parkinson's disease and estimate the performance of odor subsets to allow a more rapid testing of olfactory impairment. $\textit {Methodology/Principal Findings}$ Odor identification was assessed with 16 Sniffin' sticks in 148 Parkinson patients and 148 healthy controls. Risks of olfactory impairment were estimated with proportional odds models. Random forests were applied to classify Parkinson and non-Parkinson patients. Parkinson patients were rarely normosmic (identification of more than 12 odors; 16.8%) and identified on average seven odors whereas the reference group identified 12 odors and showed a higher prevalence of normosmy (31.1%). Parkinson patients with rigidity dominance had a twofold greater prevalence of olfactory impairment. Disease severity was associated with impairment of odor identification (per score point of the Hoehn and Yahr rating OR 1.87, 95% CI 1.26–2.77). Age-related impairment of olfaction showed a steeper gradient in Parkinson patients. $\textit {Coffee, peppermint}$, and $\it anise$ showed the largest difference in odor identification between Parkinson patients and controls. Random forests estimated a misclassification rate of 22.4% when comparing Parkinson patients with healthy controls using all 16 odors. A similar rate (23.8%) was observed when only the three aforementioned odors were applied. $\textit {Conclusions/Significance}$ Our findings indicate that testing odor identification can be a supportive diagnostic tool for Parkinson's disease. The application of only three odors performed well in discriminating Parkinson patients from controls, which can facilitate a wider application of this method as a point-of-care test

NEMO reshapes the α\alpha-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62

NEMO is a ubiquitin-binding protein which regulates canonical NF-$\kappa$B pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-$\kappa$B-independent function of NEMO in proteostasis regulation by promoting autophagosomal clearance of protein aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress and are vulnerable to proteostasis challenges. Moreover, a patient with a mutation in the NEMO-encoding $\it IKBKG$ gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including $\alpha$-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at $\alpha$-synuclein aggregates and promotes the local concentration of p62 into foci. In vitro, NEMO lowers the threshold concentrations required for ubiquitin-dependent phase transition of p62. In summary, NEMO reshapes the aggregate surface for efficient autophagosomal clearance by providing a mobile phase at the aggregate interphase favoring co-condensation with p62