Data-driven subtyping of Parkinson's disease: comparison of current methodologies and application to the Bochum PNS cohort.

Considerable efforts have been made to better describe and identify Parkinson's disease (PD) subtypes. Cluster analyses have been proposed as an unbiased development approach for PD subtypes that could facilitate their identification, tracking of progression, and evaluation of therapeutic responses. A data-driven clustering analysis was applied to a PD cohort of 114 subjects enrolled at St. Josef-Hospital of the Ruhr University in Bochum (Germany). A wide spectrum of motor and non-motor scores including polyneuropathy-related measures was included into the analysis. K-means and hierarchical agglomerative clustering were performed to identify PD subtypes. Silhouette and Calinski-Harabasz Score Elbow were then employed as supporting evaluation metrics for determining the optimal number of clusters. Principal Component Analysis (PCA), analysis of variance (ANOVA), and analysis of covariance (ANCOVA) were conducted to determine the relevance of each score for the clusters' definition. Three PD cluster subtypes were identified: early onset mild type, intermediate type, and late-onset severe type. The between-cluster analysis consistently showed highly significant differences (P < 0.01), except for one of the scores measuring polyneuropathy (Neuropathy Disability Score; P = 0.609) and Levodopa dosage (P = 0.226). Parkinson's Disease Questionnaire (PDQ-39), Non-motor Symptom Questionnaire (NMSQuest), and the MDS-UPDRS Part II were found to be crucial factors for PD subtype differentiation. The present analysis identifies a specific set of criteria for PD subtyping based on an extensive panel of clinical and paraclinical scores. This analysis provides a foundation for further development of PD subtyping, including k-means and hierarchical agglomerative clustering.Trial registration: DRKS00020752, February 7, 2020, retrospectively registered.

Emerging Immunotherapies for Parkinson Disease.

Symptomatic treatment options for Parkinson disease have steadily improved, and individualized therapeutic approaches are becoming established for every stage of the disease. However, disease-modifying therapy with a causal approach is still unavailable. The central causative role of alpha-synuclein pathology, including its progressive spread to most areas of the CNS, has been widely recognized, and a strong involvement of immune responses has recently been discovered. New immunologic technologies have been shown to effectively prevent the progression of alpha-synuclein pathology in animal models. These approaches have recently been translated into the first human clinical trials, representing a novel starting point for the causal therapy of Parkinson disease. In this review, the pathomechanistic role of alpha-synuclein and its influence on the surrounding cellular environment are analyzed with a strong focus on immune responses and neuroinflammation. The potential of novel immunotherapeutic approaches that reduce the burden of alpha-synuclein pathology in the CNS is critically evaluated, and currently ongoing human clinical trials are presented. The clinical development of these new immunotherapies is progressing rapidly and gives reason to hope that a causal therapy of Parkinson disease could be possible in the foreseeable future.

Reappraisal of the posterior approach for cervical decompressive herniectomy.

BACKGROUND: Does posterior cervical herniectomy impact on symptoms related to cervical paramedian/lateral soft disc herniation? METHODS: In a patient series over 15 years operated for single level paramedian/lateral soft disc herniation with posterior cervical approach, perceived radicular and cervical pre- and postoperative symptoms were reconstructed and analyzed. RESULTS: Out of 105 patients with these characteristics 75 could be recruited for long-term follow-up. Preoperative symptoms included: radicular motor deficit (81.3%); radicular pain (93.3%); radicular sensory deficit (84%); cervical pain (80%) and disturbance of cervical motility (49.3%). Postoperatively radicular motor score improved in all patients (score 5 in 92% and 4 in 8%); sensory disturbance improved in all and radicular pain disappeared in 90% and improved in the others. Cervical pain disappeared in 78% and improved in other 22%, two had new onset moderate cervical pain. CONCLUSIONS: This series confirms safety and efficacy of the posterior approach in relieving motor and sensory symptoms in patients with symptomatic single level, lateral soft disc herniation.

Successful therapy with rituximab in three patients with probable neurosarcoidosis.

BACKGROUND: Neurosarcoidosis occurs in about 5-15% of patients with sarcoidosis. Therapy with corticosteroids is generally accepted as the first-line medication, followed by various immunomodulating and cytotoxic agents or combined therapy. However, some patients show an unsatisfactory outcome or have adverse events and require novel treatment strategies. METHODS: We describe three patients with systemic sarcoidosis and central nervous system involvement who received CD20-targeted B-cell depletion with rituximab. RESULTS: Treatment with rituximab was well tolerated and followed by marked remission in patients nonresponsive to other immunosuppressive agents. CONCLUSION: Rituximab may be used for patients with neurosarcoidosis who are nonresponsive to established treatment regimes.

Could Spinal Canal Compression be a Cause of Polyneuropathy?

Causality between spinal cord compression and polyneuropathy is difficult to define, especially under the circumstances that polyneuropathy can have many causes. Seven patients with spinal cord compression and electrophysiological signs of polyneuropathy were treated surgically on decompression of their spinal canal stenosis in the time from April 2010 to January 2013. Median follow up time was 9 months (2-23 months). Causes of polyneuropathy were: 1 patient with methotrexate-induced polyneuropathy, 1 endocrine-dysfunction-induced, 2 with diabetic-polyneuropathy, and 3 patients had unknown reasons. The localization of the spinal canal stenosis was also varying: 2 patients suffered of cervical spinal canal stenosis and 5 of lumbar. Decompressive surgery led to pain relieve in all patients initially. Surprisingly, also symptoms of polyneuropathy seemed to regress in all 7 patients for the first 5 months after surgery, and in 5 patients for the time of 9 months after surgery. There are two points we would like to emphasize in this short report. Since 5/7 patients with polyneuropathy and spinal canal stenosis improved clinically after surgery, surgery has a place in the treatment of such a combined pathology. Since it seems to be a possible causality between polyneuropathy of unknown origin and spinal cord stenosis, decompression of the spinal canal could also be a therapeutic step in a specific kind of polyneuropathy. Which patients could possibly have a spinal canal stenosis induced polyneuropathy remains a subject of further studies.

Mitochondrial changes in platelets are not related to those in skeletal muscle during human septic shock.

Platelets can serve as general markers of mitochondrial (dys)function during several human diseases. Whether this holds true even during sepsis is unknown. Using spectrophotometry, we measured mitochondrial respiratory chain biochemistry in platelets and triceps brachii muscle of thirty patients with septic shock (within 24 hours from admission to Intensive Care) and ten surgical controls (during surgery). Results were expressed relative to citrate synthase (CS) activity, a marker of mitochondrial density. Patients with septic shock had lower nicotinamide adenine dinucleotide dehydrogenase (NADH)/CS (p = 0.015), complex I/CS (p = 0.018), complex I and III/CS (p<0.001) and complex IV/CS (p = 0.012) activities in platelets but higher complex I/CS activity (p = 0.021) in triceps brachii muscle than controls. Overall, NADH/CS (r2 = 0.00; p = 0.683) complex I/CS (r(2) = 0.05; p = 0.173), complex I and III/CS (r(2) = 0.01; p = 0.485), succinate dehydrogenase (SDH)/CS (r(2) = 0.00; p = 0.884), complex II and III/CS (r(2) = 0.00; p = 0.927) and complex IV/CS (r(2) = 0.00; p = 0.906) activities in platelets were not associated with those in triceps brachii muscle. In conclusion, several respiratory chain enzymes were variably inhibited in platelets, but not in triceps brachii muscle, of patients with septic shock. Sepsis-induced mitochondrial changes in platelets do not reflect those in other organs.

Venous flow rearrangement after treatment of cerebral arteriovenous malformations: a novel approach to evaluate the risks of treatment.

OBJECTIVE: This study aims to identify the angiographic parameters that could help predict the risks of hyperemic complications (HCs) in the treatment of cerebral arteriovenous malformations (AVMs). METHODS: The charts and the pre- and post-treatment angiographies of 400 consecutively treated patients with cerebral AVMs were retrospectively reviewed. Several parameters were analyzed: grade, size, drainage depth, number of the "recruited veins" (veins coming from the brain and joining the main AVM drainage), and "venous times" (the times of visualization of the nidus and the main drainage, of the "recruited veins," and finally of the normal cerebral veins). On this basis, two groups were identified: group 1, consisting of 309 patients (77.3%) with normal/subnormal venous times, and group 2, consisting of 91 patients (22.7%) with altered venous times and venous engorgement. Finally, the weight of the various parameters was measured by univariate and multivariate analyses. RESULTS: An overall number of 245 patients (61.2%) achieved favorable outcomes. HCs occurred in a total of 28 patients (7%): No patient belonged to group 1, so that these adverse effects were reported in 30.7% of group 2 patients. The presence of deep drainage and the number of recruited veins resulted in statistically significantly different impacts on the risk of the different grades. CONCLUSIONS: The statistical analysis allowed the identification of three different risk scores, which were named Nig-scores (Niguarda scores). Nig-score 0 means no risk of HCs and concerns patients without altered venous times; Nig-score 1 represents patients with intermediate risk, that is, with moderately altered venous times and few recruited veins; Nig-score 2 indicates high risk of HCs and refers to patients with markedly altered venous times.

The tumour is not enough or is it? Problems and new concepts in the surgery of cerebral metastases.

Cerebral metastases are the most frequent cerebral tumours. Surgery of cerebral metastases plays an indispensible role in a multimodal therapy concept. Conventional white-light, microscopy assisted microsurgical and circumferential stripping of cerebral metastases is neurosurgical standard therapy, but is associated with an extraordinarily high recurrence rate of more than 50% without subsequent whole-brain radiotherapy. Therefore, neurosurgical standard therapy fails to achieve local tumour control in many patients. The present conceptual paper focuses on this issue and discusses the possible causes of the high recurrence rates such as intraoperative dissemination of tumour cells or the lack of sharp delimitation of metastases from the surrounding brain tissue resulting in incomplete resections. Adjuvant whole-brain radiotherapy reduces the risk of local and distant recurrences, but is associated with a well-documented impairment of neurocognitive function. New surgical strategies, such as supramarginal or fluorescence-guided resection, address the possibility of infiltrating tumour parts to achieve more complete resection of cerebral metastases. Supramarginal resection was shown to significantly reduce the risk of a local recurrence and prolongs two-year survival rates. Furthermore, radiosurgery in combination with surgery represents a promising approach.

Is it a glioblastoma? In dubio pro 5-ALA!

BACKGROUND: Differential diagnosis of unclear contrast-enhancing cerebral lesions includes cerebral metastases as well as malignant glioma. In the majority of cases, a definite preoperative diagnosis by neuroradiological assessment alone cannot be made. Since the introduction of 5-ALA-induced fluorescence-guided resection in the treatment of glioblastoma (GBM), the preoperative putative diagnosis of metastasis vs. GBM triggers a specific preoperative preparation of the patients. We analyzed the patient population with known cancer outside the central nervous system who underwent surgery for an assumed cerebral metastasis and for whom the intraoperative diagnosis was corrected to a malignant glioma. METHODS: Retrospective analysis of patients with a known primary cancer who were operated on for an assumed cerebral metastasis, which turned out to be a GBM. The patients were treated at our center between January 2008 and June 2011. RESULTS: We identified ten patients who underwent surgery for an assumed cerebral metastasis and for whom the diagnosis was corrected intraoperatively to a malignant glioma by frozen section. The median age was 68 years (41-82 years). The female-to-male ratio was 2:8. In all patients, the final histopathological analysis of the intracerbral tumors revealed a glioblastoma, while the patients suffered from diverse primary carcinomas. CONCLUSION: A malignant glioma should always be considered as a differential diagnosis of an unclear contrast-enhancing cerebral lesion even for patients with a known malignancy. Furthermore, we make the case for a more liberal indication for 5-ALA.

Surgical treatment of CM2 and syringomyelia in a series of 231 myelomeningocele patients.

A series of 231 consecutive patients with myelomeningocele was reviewed for what concerns the Chiari II malformation. This was present in 228 subjects (98.8%), but was symptomatic in 74 patients (31.5%) and required surgery just in 26 cases (11.4%). First treatment was addressed to hydrocephalus which was always associated. Shunting reverted the symptoms in 12 patients, but failed in 14 who required craniocervical decompression. Mortality consisted of two cases (one early and one delayed). All the remaining patients achieved satisfactory results.