The special role of CXCL13 in Lyme neuroborreliosis: a case report

The diagnosis of chronic lyme neuroborreliosis can be a challenge even for experienced neurologists. The clinical picture may be multifaceted, including polyradiculitis to cranial nerve palsies, meningitis, encephalomyelitis, encephalopathy and peripheral neuropathy. We report on a patient presenting with basal leptomeningoencephalitis associated with vasculopathy where the chemokine CXCL13 in cerebrospinal fluid played an important diagnostic role.

Neurological management and work-up of neurotoxicity associated with CAR T cell therapy

Introduction Treatment with CD19 chimeric antigen receptor (CAR) T cells is an innovative therapeutic approach for patients with relapsed/refractory diffuse large B cell lymphoma (r/rDLBCL) and B-lineage acute lymphoblastic leukemia (r/rALL). However, convincing therapeutic response rates can be accompanied by cytokine release syndrome (CRS) and severe neurotoxicity termed immune effector cell-associated neurotoxicity syndrome (ICANS). Methods Single center, prospective observational study of fifteen consecutive r/r DLBCL patients treated with Tisagenlecleucel within 1 year at Hannover Medical School. Extensive neurological work-up prior to CAR T cell infusion included clinical examination, cognitive testing (Montreal-Cognitive-Assessment), brain MRI, electroencephalogram, electroneurography, and analysis of cerebrospinal fluid. After CAR T cell infusion, patients were neurologically examined for 10 consecutive days. Afterwards, all patients were assessed at least once a week. Results ICANS occurred in 4/15 patients (27%) within 6 days (4–6 days) after CAR T cell infusion. Patients with ICANS grade 2 (n = 3) exhibited similar neurological symptoms including apraxia, expressive aphasia, disorientation, and hallucinations, while brain MRI was inconspicuous in either case. Treatment with dexamethasone rapidly resolved the clinical symptoms in all three patients. Regarding baseline parameters prior to CAR T cell treatment, patients with and without ICANS did not differ. Conclusions In our cohort, ICANS occurred in only every fourth patient and rather low grade neurotoxicity was found during daily examination. Our results demonstrate that a structured neurological baseline examination and close monitoring are helpful to detect CAR T cell related neurotoxicity already at an early stage and to potentially prevent higher grade neurotoxicity.

Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders

Background Major efforts have been made in the last decade to develop and improve therapies for proximal spinal muscular atrophy (SMA). The introduction of Nusinersen/Spinraza™ as an antisense oligonucleotide therapy, Onasemnogene abeparvovec/Zolgensma™ as an AAV9-based gene therapy and Risdiplam/Evrysdi™ as a small molecule modifier of pre-mRNA splicing have set new standards for interference with neurodegeneration. Main body Therapies for SMA are designed to interfere with the cellular basis of the disease by modifying pre-mRNA splicing and enhancing expression of the Survival Motor Neuron (SMN) protein, which is only expressed at low levels in this disorder. The corresponding strategies also can be applied to other disease mechanisms caused by loss of function or toxic gain of function mutations. The development of therapies for SMA was based on the use of cell culture systems and mouse models, as well as innovative clinical trials that included readouts that had originally been introduced and optimized in preclinical studies. This is summarized in the first part of this review. The second part discusses current developments and perspectives for amyotrophic lateral sclerosis, muscular dystrophies, Parkinson's and Alzheimer's disease, as well as the obstacles that need to be overcome to introduce RNA-based therapies and gene therapies for these disorders. Conclusion RNA-based therapies offer chances for therapy development of complex neurodegenerative disorders such as amyotrophic lateral sclerosis, muscular dystrophies, Parkinson’s and Alzheimer’s disease. The experiences made with these new drugs for SMA, and also the experiences in AAV gene therapies could help to broaden the spectrum of current approaches to interfere with pathophysiological mechanisms in neurodegeneration.

Impact of the COVID-19 pandemic on emergency admission for patients with stroke: a time series study in Japan

Background Appropriate treatment of stroke immediately after its onset contributes to the improved chances, while delay in hospitalisation affects stroke severity and fatality. This study aimed to determine the impact of the coronavirus disease 2019 (COVID-19) pandemic on emergency hospitalisation of patients with stroke in Japan. Methods This was an observational study that used nationwide administrative data of hospitalised patients diagnosed with stroke. We cross-sectionally observed patients’ background factors during April and May 2020, when the COVID-19 pandemic-related state of emergency was declared; we also observed these factors in the same period in 2019. We also modelled monthly trends in emergency stroke admissions, stroke admissions at each level of the Japan Coma Scale (JCS), fatalities within 24 h, stroke care unit use, intravenous thrombolysis administration, and mechanical thrombectomy implementation using interrupted time series (ITS) regression. Results There was no difference in patients’ pre-hospital baseline characteristics between the pre-pandemic and pandemic periods. However, ITS regression revealed a significant change in the number of emergency stroke admissions after the beginning of the pandemic (slope: risk ratio [RR] = 0.97, 95% confidence interval [CI]: 0.95–0.99, P = 0.027). There was a significant difference in the JCS score for impaired consciousness in emergency stroke, which was more severe during the pandemic than the pre-pandemic (JCS3 in level: RR = 1.75, 95% CI: 1.29–2.33, P < 0.001). There was no change in the total number of fatalities with COVID-19, compared with those without COVID-19, but there were significantly more fatalities within 24 h of admission (fatalities within 24 h: RR = 1.75, 95% CI: 1.29–2.33, P < 0.001). Conclusions The infection prevalence of COVID-19 increased the number of fatalities within 24 h as well as the severity of illness in Japan. However, there was no difference in baseline characteristics, intravenous thrombolysis administration, and mechanical thrombectomy implementation during the COVID-19 pandemic. A decrease in the number of patients and fatalities was observed from the time the state of emergency was declared until August, the period of this study.

Long-term recovery of upper limb motor function and self-reported health: results from a multicenter observational study 1 year after discharge from rehabilitation

Background Impaired motor functions after stroke are common and negatively affect patients' activities of daily living and quality of life. In particular, hand motor function is essential for daily activities, but often returns slowly and incompletely after stroke. However, few data are available on the long-term dynamics of motor recovery and self-reported health status after stroke. The Interdisciplinary Platform for Rehabilitation Research and Innovative Care of Stroke Patients (IMPROVE) project aims to address this knowledge gap by studying the clinical course of recovery after inpatient rehabilitation. Methods In this prospective observational longitudinal multicenter study, patients were included towards the end of inpatient rehabilitation after ischemic or hemorrhagic stroke. Follow-up examination was performed at three, six, and twelve months after enrollment. Motor function was assessed by the Upper Extremity Fugl-Meyer Assessment (FMA), grip and pinch strength, and the nine-hole peg test. In addition, Patient-Reported Outcomes Measurement Information System 10-Question Short Form (PROMIS-10) was included. Linear mixed effect models were fitted to analyze change over time. To study determinants of hand motor function, patients with impaired hand function at baseline were grouped into improvers and non-improvers according to hand motor function after twelve months. Results A total of 176 patients were included in the analysis. Improvement in all motor function scores and PROMIS-10 was shown up to 1 year after inpatient rehabilitation. FMA scores improved by an estimate of 5.0 (3.7–6.4) points per year. In addition, patient-reported outcome measures increased by 2.5 (1.4–3.6) and 2.4 (1.4–3.4) per year in the physical and mental domain of PROMIS-10. In the subgroup analysis non-improvers showed to be more often female (15% vs. 55%, p = 0.0155) and scored lower in the Montreal Cognitive Assessment (25 [23–27] vs. 22 [20.5–24], p = 0.0252). Conclusions Continuous improvement in motor function and self-reported health status is observed up to 1 year after inpatient stroke rehabilitation. Demographic and clinical parameters associated with these improvements need further investigation. These results may contribute to the further development of the post-inpatient phase of stroke rehabilitation. Trial registration: The trial is registered at ClinicalTrials.gov (NCT04119479).

Seizures and epilepsy in patients with ischaemic stroke

Background With the increased efficacy of stroke treatments, diagnosis and specific treatment needs of patients with post-stroke seizures (PSS) and post-stroke epilepsy have become increasingly important. PSS can complicate the diagnosis of a stroke and the treatment of stroke patients, and can worsen post-stroke morbidity. This narrative review considers current treatment guidelines, the specifics of antiseizure treatment in stroke patients as well as the state-of-the-art in clinical and imaging research of post-stroke epilepsy. Treatment of PSS needs to consider indications for antiseizure medication treatment as well as individual clinical and social factors. Furthermore, potential interactions between stroke and antiseizure treatments must be carefully considered. The relationship between acute recanalizing stroke therapy (intravenous thrombolysis and mechanical thrombectomy) and the emergence of PSS is currently the subject of an intensive discussion. In the subacute and chronic post-stroke phases, important specific interactions between necessary antiseizure and stroke treatments (anticoagulation, cardiac medication) need to be considered. Among all forms of prevention, primary prevention is currently the most intensively researched. This includes specifically the repurposing of drugs that were not originally developed for antiseizure properties, such as statins. PSS are presently the subject of extensive basic clinical research. Of specific interest are the role of post-stroke excitotoxicity and blood–brain barrier disruption for the emergence of PSS in the acute symptomatic as well as late (> 1 week after the stroke) periods. Current magnetic resonance imaging research focussing on glutamate excitotoxicity as well as diffusion-based estimation of blood–brain barrier integrity aim to elucidate the pathophysiology of seizures after stroke and the principles of epileptogenesis in structural epilepsy in general. These approaches may also reveal new imaging-based biomarkers for prediction of PSS and post-stroke epilepsy. Conclusion PSS require the performance of individual risk assessments, accounting for the potential effectiveness and side effects of antiseizure therapy. The use of intravenous thrombolysis and mechanical thrombectomy is not associated with an increased risk of PSS. Advances in stroke imaging may reveal biomarkers for PSS.

DIPS (Dystonia Image-based Programming of Stimulation: a prospective, randomized, double-blind crossover trial)

Introduction Deep brain stimulation of the internal globus pallidus is an effective treatment for dystonia. However, there is a large variability in clinical outcome with up to 25% non-responders even in highly selected primary dystonia patients. In a large cohort of patients we recently demonstrated that the variable clinical outcomes of pallidal DBS for dystonia may result to a large degree by the exact location and stimulation volume within the pallidal region. Here we test a novel approach of programing based on these insights: we first defined probabilistic maps of anti-dystonic effects by aggregating individual electrode locations and volumes of tissue activated of > 80 patients collected in a multicentre effort. We subsequently modified the algorithms to be able to test all possible stimulation settings of de novo patients in silico based on the expected clinical outcome and thus potentially predict the best possible stimulation parameters for the individual patients. Methods Within the framework of a BMBF-funded study, this concept of a computer-based prediction of optimal stimulation parameters for patients with dystonia will be tested in a randomized, controlled crossover study. The main parameter for clinical efficacy and primary endpoint is based on the blinded physician rating of dystonia severity reflected by Clinical Dystonia Rating Scales for both interventions (best clinical settings and model predicted settings) after 4 weeks of continuous stimulation. The primary endpoint is defined as “successful treatment with model predicted settings” (yes or no). The value is “yes” if the motor symptoms with model predicted settings are equal or better (tolerance 5% of absolute difference in percentages) to clinical settings. Secondary endpoints will include measures of quality of life, calculated energy consumption of the neurostimulation system and physician time for programming. Perspective We envision, that computer-guided deep brain stimulation programming in silico might provide optimal stimulation settings for patients with dystonia without the burden of months of programming sessions. The study protocol is designed to evaluate which programming method is more effective in controlling motor symptom severity and improving quality of life in dystonia (best clinical settings and model predicted settings). Trial registration Registered with ClinicalTrials.gov on Oct 27, 2021 (NCT05097001).

Thromboses of major arteries and ChAdOx1 nCov-19 vaccination

This correspondence discussed on published article on “thromboses of major arteries and ChAdOx1 nCov-19 vaccination”.

Evidence of extensive cellular immune response after SARS-CoV-2 vaccination in ocrelizumab-treated patients with multiple sclerosis

Background Patients with multiple sclerosis receiving ocrelizumab-treatment are in desperate need of a protection against SARS-CoV-2 infection. Methods In this study, Euroimmun semi-quantitative Anti-SARS-CoV-2 IgG for detection of humoral response and ELISpot assays for detection of SARS-CoV-2-specific T-cell-response were used in 10 ocrelizumab-treated patients with multiple sclerosis twice vaccinated with Comirnaty® mRNA vaccine. This data was compared with a control group of 20 age- and sex-matched healthy volunteers, who had all previously received a full SARS-CoV-2 mRNA vaccination with Comirnaty® or Spikevax®. Results While all subjects in the control group had high humoral response to the vaccination, in B-cell-depleted individuals a significantly reduced antibody response to vaccination against SARS-CoV-2 was observed. SARS-CoV-2 specific T-cell-response, however, did not differ significantly between both cohorts. Conclusions T-cell-mediated response to Comirnaty® vaccination is observable despite attenuated humoral response in B-cell-depleted patients. This might enable partial protection against COVID-19. Trial registration Retrospectively registered.

Performance of ENMC and EULAR/ACR classification systems applied to a single tertiary center cohort of dermatomyositis patients

Background There have been numerous classification systems to diagnose corresponding myositis subtypes and select appropriate therapeutic measures. However, the lack of a broad consensus on diagnostic criteria has led to clinical uncertainties. The objective of this study was to compare two commonly used dermatomyositis-classification systems regarding their clinical practicability and to point out their specific advantages and disadvantages. Methods This study included 30 patients diagnosed with dermatomyositis at the Charité university hospital, Berlin, Germany from 2010 to 2017. Patient files with complete data and defined historical classifications were enrolled and ENMC (2003) and EULAR/ACR (2017) criteria retrospectively applied. Results According to the ENMC approach, 14 patients were classified as "definite" and 12 as "probable" dermatomyositis. One patient exhibited an "amyopathic dermatomyositis" and three a "DM without dermatitis". Regarding the criteria probability of the EULAR/ACR set, 16 patients had a "high", 13 a "medium" and one a "low probability". There was a significant difference (p = 0.004) between the subclasses of the ENMC in relation to the EULAR/ACR score. The agreement between the classification probabilities of "definite/high" (κ = 0.400) and "possible/medium" (κ = 0.324) was fair. Conclusions It is important to find a consensus among the medical disciplines involved and to establish a structured procedure. Future studies with newer approaches are warranted to conclusively decide which system to use for the physician.