Fatigue and associated factors in myasthenia gravis: a nationwide registry study.

Fatigue is commonly associated with myasthenia gravis (MG), but factors contributing to fatigue development in MG are incompletely understood. This nationwide cross-sectional registry study included 1464 patients diagnosed with autoimmune MG, recruited between February 2019 and April 2023. Frequency and severity of fatigue was assessed at study inclusion using the patient-reported Chalder Fatigue Questionnaire (CFQ). Frequency of fatigue was 59%. Fatigue severity strongly correlated with both patient-reported and physician-assessed MG outcome measures (MG-ADL, MG-QoL15, QMG and MGFA classes) and was associated with a history of myasthenic exacerbation and/or myasthenic crises and a delay in diagnosis of more than 1 year after symptom onset. Fatigue was more prevalent in women and coincided with symptoms of depression, anxiety, and sleep dissatisfaction. Differences in fatigue severity were observed between antibody (ab) subgroups, with highest fatigue severity in LRP4-ab-positive patients and lowest fatigue severity in AChR-ab-positive patients. Fatigue is a frequent and clinically highly relevant symptom of MG. Early diagnosis and prevention of MG crises may limit the long-term burden of fatigue in patients with MG.

Cell-mediated cytotoxicity within CSF and brain parenchyma in spinal muscular atrophy unaltered by nusinersen treatment.

5q-associated spinal muscular atrophy (SMA) is a motoneuron disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Adaptive immunity may contribute to SMA as described in other motoneuron diseases, yet mechanisms remain elusive. Nusinersen, an antisense treatment, enhances SMN2 expression, benefiting SMA patients. Here we have longitudinally investigated SMA and nusinersen effects on local immune responses in the cerebrospinal fluid (CSF) - a surrogate of central nervous system parenchyma. Single-cell transcriptomics (SMA: N = 9 versus Control: N = 9) reveal NK cell and CD8+ T cell expansions in untreated SMA CSF, exhibiting activation and degranulation markers. Spatial transcriptomics coupled with multiplex immunohistochemistry elucidate cytotoxicity near chromatolytic motoneurons (N = 4). Post-nusinersen treatment, CSF shows unaltered protein/transcriptional profiles. These findings underscore cytotoxicity's role in SMA pathogenesis and propose it as a therapeutic target. Our study illuminates cell-mediated cytotoxicity as shared features across motoneuron diseases, suggesting broader implications.

Efgartigimod and Ravulizumab for Treating Acetylcholine Receptor Auto-antibody-Positive (AChR-Ab+) Generalized Myasthenia Gravis: Indirect Treatment Comparison.

INTRODUCTION: Efgartigimod and ravulizumab, both approved for treating acetylcholine receptor auto-antibody-positive (AChR-Ab+) generalized myasthenia gravis (gMG), have not been directly compared. This paper assessed comparative effects of efgartigimod vs. ravulizumab for treating adults with AChR-Ab+ gMG using indirect treatment comparison methods. METHODS: The matching-adjusted indirect comparison used data from two randomized trials of adult men and women. The ADAPT (efgartigimod vs. placebo; individual patient data available) population was reweighted to match the CHAMPION (ravulizumab vs. placebo; index study; aggregate data available) population. The relative effect of efgartigimod versus placebo was estimated in this reweighted population and compared with the observed ravulizumab versus placebo effect to estimate the efgartigimod versus ravulizumab effect. The outcomes were Myasthenia Gravis Activities of Daily Living (MG-ADL), Quantitative Myasthenia Gravis (QMG), and Myasthenia Gravis Quality of Life 15-item-revised scale (MG-QoL15r) assessed as cumulative effect (area under the curve; AUC) over 26 weeks (primary) and change from baseline at 4 weeks and time of best response (week 4 for efgartigimod; week 26 for ravulizumab). RESULTS: For MG-QoL15r, efgartigimod had a statistically significant improvement compared with ravulizumab over 26 weeks [mean difference (95% confidence interval): - 52.6 (- 103.0, - 2.3)], at week 4 [- 4.0 (- 6.6, - 1.4)], and at time of best response [- 3.9 (- 6.5, - 1.3)]. Efgartigimod had a statistically significant improvement over ravulizumab in MG-ADL at week 4 [- 1.9 (- 3.3, - 0.5)] and at time of best response [- 1.4 (- 2.8, 0.0)] and in QMG at week 4 [- 3.2 (- 5.2, - 1.2)] and at time of best response [- 3.0 (- 5.0, - 1.0)]. For AUC over 26 weeks, improvements were not significantly different between efgartigimod and ravulizumab for MG-ADL [- 8.7 (- 36.1, 18.8)] and QMG [- 13.7 (- 50.3, 22.9)]. CONCLUSION: Efgartigimod may provide a faster and greater improvement over 26 weeks in quality of life than ravulizumab in adults with AChR-Ab+ gMG. Efgartigimod showed faster improvements in MG-ADL and QMG than ravulizumab.

Alteration of LARGE1 abundance in patients and a mouse model of 5q-associated spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by recessive pathogenic variants affecting the survival of motor neuron (SMN1) gene (localized on 5q). In consequence, cells lack expression of the corresponding protein. This pathophysiological condition is clinically associated with motor neuron (MN) degeneration leading to severe muscular atrophy. Additionally, vulnerability of other cellular populations and tissues including skeletal muscle has been demonstrated. Although the therapeutic options for SMA have considerably changed, treatment responses may differ thus underlining the persistent need for validated biomarkers. To address this need and to identify novel marker proteins for SMA, we performed unbiased proteomic profiling on cerebrospinal fluid derived (CSF) from genetically proven SMA type 1-3 cases and afterwards performed ELISA studies on CSF and serum samples to validate the potential of a novel biomarker candidates in both body fluids. To further decipher the pathophysiological impact of this biomarker, immunofluorescence studies were carried out on spinal cord and skeletal muscle derived from a 5q-SMA mouse model. Proteomics revealed increase of LARGE1 in CSF derived from adult patients showing a clinical response upon treatment with nusinersen. Moreover, LARGE1 levels were validated in CSF samples of further SMA patients (type 1-3) by ELISA. These studies also unveiled a distinguishment between groups in improvement of motor skills: adult patients do present with lowered level per se at baseline visit while no elevation upon treatment in the pediatric cohort can be observed. ELISA-based studies of serum samples showed no changes in the pediatric cohort but unraveled elevated level in adult patients responding to future intervention with nusinersen, while non-responders did not show a significant increase. Additional immunofluorescence studies of LARGE1 in MN and skeletal muscle of a SMA type 3 mouse model revealed an increase of LARGE1 during disease progression. Our combined data unraveled LARGE1 as a protein dysregulated in serum and CSF of SMA-patients (and in MN and skeletal muscle of SMA mice) holding the potential to serve as a disease marker for SMA and enabling to differentiate between patients responding and non-responding to therapy with nusinersen.

Daratumumab in first-line treatment of patients with light chain amyloidosis and Mayo stage IIIb improves treatment response and overall survival.

Treatment of patients with Mayo stage IIIb light chain (AL) amyloidosis is still challenging, and the prognosis remains very poor. Mayo stage IIIb patients were excluded from the pivotal trial leading to the approval of daratumumab in combination with bortezomib-cyclophosphamide-dexamethasone. This retrospective, multicenter study evaluates the addition of daratumumab to first-line therapy in patients with newly diagnosed stage IIIb AL amyloidosis. In total, data from 119 consecutive patients were analyzed, 27 patients received an upfront treatment including daratumumab, 63 a bortezomibbased regimen without daratumumab, eight received therapies other than daratumumab or bortezomib and 21 pretreated patients or deceased prior to treatment were excluded. In the daratumumab group, median overall survival was not reached after a median follow-up time of 14.5 months, while it was significantly worse in the bortezomib- and the otherwise treated group (6.6 and 2.2 months, respectively) (P=0.002). Overall hematologic response rate at 2 and 6 months was better in the daratumumab group compared to the bortezomib group (59% vs. 37%, P=0.12, 67% vs. 41%, P=0.04, respectively). Landmark survival analyses revealed a significantly improved overall survival in patients with partial hematologic response or better, compared to non-responders. Cardiac response at 6 months was 46%, 21%, 0% in the daratumumab-, bortezomib- and otherwise treated groups, respectively (P=0.04). A landmark survival analysis revealed markedly improved overall survival in patients with cardiac very good partial response vs. cardiac non-responders (P=0.002). This study demonstrates for the first time the superiority of an upfront treatment with daratumumab over standard-of-care in stage IIIb AL amyloidosis.

Guideline for the management of myasthenic syndromes.

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline 'Diagnostics and therapy of myasthenic syndromes' has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.

Benign peripheral nerve sheath tumors: an interdisciplinary diagnostic and therapeutic challenge.

A benign peripheral nerve sheath tumor (bPNST) is a rare lesion associated with peripheral nerval structures. Symptoms may be heterogeneous, complicating diagnosis finding. Additionally, management concepts of bPNST may vary. In some cases, initial misdiagnosis leads to mistreatment resulting in severe functional deficits and chronic pain syndromes. Therefore, we analyzed patients treated for bPNST in our specialized institution with a primary focus on prior misdiagnosis and possible mistreatment. Patients with bPNSTs (schwannomas, neurofibromas, hybrid nerve sheath tumors, and perineuriomas) treated at the Neurosurgical Department between January 1, 2015, and July 31, 2021, were included. Assessment of demographics, tumor entity, tumor location, symptoms, the interval between the onset of symptoms and surgery, involved medical specialties, and outpatients' treatment, with particular focus on initial misdiagnosis and inappropriate medical treatment, was performed. Eighty-five patients were included in the final analysis with schwannoma being the most prevalent histopathological diagnosis (schwannoma (75.3%, n=64), neurofibroma (12.9%, n=11), hybrid nerve sheath tumor (5.9%, n=5), and perineurioma (5.9%, n=5)). An incorrect primary diagnosis was detected in 44.7% (n=38), leading to suboptimal or insufficient treatment in these cases. Of those, 28.9% (n=11/38) were treated suboptimal, while 18.5% (n=7/38) underwent unnecessary invasive diagnostics. Inappropriate surgery based on prior misdiagnosis, which led to severe neurological deficits in all these cases, was reported in 26.3% (n=10/38). For the first time, our data shows the quantity and impact of incorrect initial diagnosis in bPNST causing a delay in causative treatment or resulting in unnecessary or potentially harmful treatment.

Brainstem Infarction in Immunodeficiency Identified as Adenosine Deaminase 2 Deficiency: Case Report.

PURPOSE: We present the case of a 24-year-old male with CNS granulomatosis due to an immunodeficiency syndrome which was identified as deficiency of adenosine deaminase 2 (DADA2) as a cause of brainstem infarction. METHODS: Case report and detailed description of the clinical course of diagnosis and treatment. CASE: The patient's medical history consisted of an unknown immunodeficiency syndrome. Based on former findings, common variable immunodeficiency (CVID) was diagnosed. The patient suffered from three consecutive brainstem strokes of unknown etiology within 3 years. An MRI scan detected gadolinium-enhancing, granulomatous-suspect lesions in the interpeduncular cistern, temporal lobe, and tegmentum. Laboratory analysis was compatible with CVID, with leukopenia and immunoglobulin deficiency. Because granulomatous CNS inflammation was suspected, the patient received methylprednisolone immunosuppressive therapy, which led to partially regressive MRI lesions. However, in contrast to imaging, the patient showed a progressive cerebellar syndrome, indicating plasma exchange therapy and immunoglobulin treatment, which led to rapid symptom amelioration. After a relapse and a further stroke, expanded analysis confirmed DADA2 (and not CVID) as the inflammatory cause for recurrent stroke. After starting the therapy with immunoglobulins and adalimumab, no further strokes occurred. CONCLUSION: We present the case of a young adult with diagnosis of DADA2 as a cause for recurrent strokes due to vasculitis. This stroke etiology is rare but should be considered as a cause of recurrent stroke of unknown origin in young patients to avoid a disabling disease course by disease-specific treatment options.

Corneal confocal microscopy identifies corneal nerve loss and increased Langerhans cells in presymptomatic carriers and patients with hereditary transthyretin amyloidosis.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a rare, but life-threatening protein misfolding disorder due to TTR gene mutations. Cardiomyopathy (ATTRv-CM) and polyneuropathy (ATTRv-PN) with early small nerve fibre involvement are the most common manifestations. Timely diagnosis and treatment initiation are key to limiting progression of disease. Corneal confocal microscopy (CCM) is a non-invasive method to quantify corneal small nerve fibres and immune cell infiltrates in vivo. METHODS: This cross-sectional study investigated the utility of CCM in 20 patients with ATTRv amyloidosis (ATTRv-CM, n = 6; ATTRv-PN, n = 14) and presymptomatic carriers (n = 5) compared to 20 age- and sex-matched healthy controls. Corneal nerve fibre density, corneal nerve fibre length, corneal nerve branch density, and cell infiltrates were assessed. RESULTS: Corneal nerve fibre density and nerve fibre length were significantly lower in patients with ATTRv amyloidosis compared to healthy controls regardless of the clinical phenotype (ATTRv-CM, ATTRv-PN) and corneal nerve fibre density was significantly lower in presymptomatic carriers. Immune cell infiltrates were only evident in patients with ATTRv amyloidosis, which correlated with reduced corneal nerve fibre density. CONCLUSIONS: CCM identifies small nerve fibre damage in presymptomatic carriers and symptomatic patients with ATTRv amyloidosis and may serve as a predictive surrogate marker to identify individuals at risk of developing symptomatic amyloidosis. Furthermore, increased corneal cell infiltration suggests an immune-mediated mechanism in the pathogenesis of amyloid neuropathy.

Quantitative 99mTc-DPD-SPECT/CT assessment of cardiac amyloidosis.

INTRODUCTION: Transthyretin (ATTR) amyloidosis is responsible for the majority of cardiac amyloidosis (CA) cases and can be reliably diagnosed with bone scintigraphy and the visual Perugini score. We aimed to implement a quantification method of cardiac amyloid deposits in patients with suspected cardiac amyloidosis and to compare performance to visual scoring. METHODS AND MATERIALS: 136 patients received 99mTc-DPD-bone scintigraphy including SPECT/CT of the thorax in case of suspicion of cardiac amyloidosis. Imaging phantom studies were performed to determine the scaling factor for standardized uptake value (SUV) quantification from SPECT/CT. Myocardial tracer uptake was quantified in a whole heart volume of interest. RESULTS: Forty-five patients were diagnosed with CA. A strong relationship between cardiac SUVmax and Perugini score was found (Spearman r 0.75, p < 0.0001). Additionally, tracer uptake in bone decreased with increasing cardiac SUVmax and Perugini score (p < 0.0001). ROC analysis revealed good performance of the SUVmax for the detection of ATTR-CA with AUC of 0.96 ± 0.02 (p < 0.0001) with sensitivity 98.7% and specificity 87.2%. CONCLUSION: We demonstrate an accessible and accurate quantitative SPECT approach in CA. Quantitative assessment of the cardiac tracer uptake may improve diagnostic accuracy and risk classification. This method may enable monitoring and assessment of therapy response in patients with ATTR amyloidosis.

Risk and course of COVID-19 in immunosuppressed patients with myasthenia gravis.

BACKGROUND: Patients with myasthenia gravis (MG) are potentially prone for a severe COVID-19 course, but there are limited real-world data available on the risk associated with COVID-19 for patients with MG. Here, we investigate whether current immunosuppressive therapy (IST) influences the risk of SARS-CoV-2 infection and COVID-19 severity. METHODS: Data from the German myasthenia gravis registry were analyzed from May 2020 until June 2021 and included patient demographics, MG disease duration, comorbidities, current IST use, COVID-19 characteristics, and outcomes. Propensity score matching was employed to match MG patients with IST to those without, and multivariable binary logistic regression models were used to determine associations between IST with (1) symptomatic SARS-CoV-2 infection and (2) severe COVID-19 course, as measured by hospitalization or death. RESULTS: Of 1379 patients with MG, 95 (7%) patients (mean age 58 (standard deviation [SD] 18) presented with COVID-19, of which 76 (80%) received IST at time of infection. 32 patients (34%) were hospitalized due to COVID-19; a total of 11 patients (12%) died. IST was a risk factor for hospitalization or death in the group of COVID-19-affected MG patients (odds ratio [OR] 3.04, 95% confidence interval [CI] = 1.02-9.06, p = 0.046), but current IST was not associated with a higher risk for SARS-CoV-2 infection itself. DISCUSSION: In this national MG cohort study, current IST use was a risk factor for a severe disease course of COVID-19 but not for SARS-CoV-2 infection itself. These data support the consequent implementation of effective strategies to prevent COVID-19 in this high-risk group. TRIAL REGISTRATION INFORMATION: German clinical trial registry ( https://www.drks.de ), DRKS00024099, first patient enrolled: February 4th, 2019.

Radiation dose and fluoroscopy time of aneurysm coiling in patients with unruptured and ruptured intracranial aneurysms as a function of aneurysm size, location, and patient age.

PURPOSE: Endovascular treatment of unruptured intracranial aneurysms (UIAs) requires a risk-benefit analysis and adherence to diagnostic reference levels (DRLs). The national DRL (250 Gy·cm2) is only determined for intracranial aneurysm coiling in general, including ruptured intracranial aneurysms (RIAs). This study aims to investigate the dose in the treatment of UIAs and RIAs separately. METHODS: In a retrospective study design, dose area product (DAP) and fluoroscopy time (FT) were assessed for all patients undergoing intracranial aneurysm coiling between 2010 and 2021. DRL was set as the 75th percentile of the dose distribution. A multivariable linear regression analysis was performed to investigate DAP and FT for the two groups, UIA and RIA adjusted for patient age, aneurysm size, and location. RESULTS: 583 (414 females, mean age 56.5 years, 311 UIAs) are included. In the overall population, DAP (median (IQR)) is 157 Gy·cm2 (108-217) with a median FT of 32.7 min (IQR 24.0-47.0). Local DRL is 183 Gy·cm2 for UIAs and 246 Gy·cm2 for RIAs. After adjustment for the other variables, the UIA and RIA groups have a significant effect on both DAP (p < 0.001; 95% CI - 68.432 - - 38.040) and FT (p < 0.001; 95% CI - 628.279 - - 291.254). In general, both DAP and FT increase significantly with patient age and aneurysm size, whereas the location of the aneurysm did not significantly change neither DAP (p = 0.171; 95% CI - 5.537-31.065) nor FT (p = 0.136; 95% CI - 357.391-48.508). CONCLUSION: Both aneurysm size and patient age were associated with increased DAP, whereas aneurysm location did not significantly change DAP or FT. The increased dose in patients with RIAs is likely equivalent to additional diagnostic cerebral four-vessel angiography performed in this group.

[Essen transition model for neuromuscular diseases]. / "Essener Transitionsmodell" bei neuromuskulären Erkrankungen.

BACKGROUND: Advances in healthcare systems with new therapeutic options improve the life expectancy of patients with neuromuscular diseases. With this, a shift in the phenotype of the diseases from the neuromuscular system towards other organs is more frequently observed, requiring closer interdisciplinary cooperation in caring for these young adults. Therefore, the transition to the adult caring system is nowadays a multilayered transfer with the need for complex care of these patients. OBJECTIVE: How can the transitional process be efficiently structured to combine the therapeutic effort of each specialist discipline involved and improve the healthcare process and quality of life in young adults with neuromuscular diseases? MATERIAL AND METHOD: The Departments of Neuropediatrics and Neurology of the University Medicine Essen established the Essen transition model for a structured transitional process. A concept of care was developed for the late onset Pompe's disease, Duchenne muscular dystrophy and juvenile myasthenia gravis representatively for neuromuscular diseases. It consists of four components: 1) In a standardized operational procedure (SOP), general processes, clinical diagnostic steps and guidance of treatment between the two departments are harmonized and specified. 2) The young adults and their relatives are seen in a joint consultation of both disciplines allowing a comprehensive handover for healthcare professionals. 3) In a quarterly meeting, transition conference representatives from the different specialized disciplines from pediatric and adult medicine get together for a case-related interdisciplinary exchange. 4) An interdepartmental transitional database was created to integrate all diagnostic results and parameters as a common information platform and data basis. CONCLUSION: The Essen transition model aims to close a gap in the transition of patients with neuromuscular diseases and improve healthcare in these patients with their complex needs.

A novel TTR mutation (p.Ala65Val) underlying late-onset hereditary transthyretin (ATTRv) amyloidosis with mixed cardiac and neuropathic phenotype: a case report.

BACKGROUND: Hereditary transthyretin (ATTRv) amyloidosis is a rare, genetically heterogeneous and phenotypically variable systemic disease characterized by deposition of misfolded transthyretin fibrils in various tissues. ATTRv cardiomyopathy and progressive axonal polyneuropathy are the most common manifestations, leading to severe disability and ultimately death within approximately ten years. As disease-modifying treatment options evolve, timely diagnosis and treatment initiation are crucial to prevent rapid disease progression. CASE PRESENTATION: Here, we report on a 73-year old patient initially diagnosed with cardiac wild-type ATTR (ATTRwt) amyloidosis by endomyocardial biopsy. Molecular genetic analysis revealed a novel TTR sequence variant (p.Ala65Val) that is highly likely to be amyloidogenic in light of previously reported TTR mutations and the patient's clinical presentation and family history. CONCLUSIONS: Our findings expand the spectrum of known pathogenic TTR mutations and underline the importance of a thorough diagnostic workup in amyloidosis patients including careful genetic testing to avoid misdiagnosis and missing of treatment opportunities and to enable cascade testing and tracking of carriers.

Dataset of a retrospective multicenter cohort study on characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis.

Over the past decade, cancer immunotherapy with immune checkpoint inhibitors (ICIs) has significantly improved the outcome of many malignancies. However, with the broad use of ICIs, neurological immune related adverse events (irAE) are increasingly recognized. ICI-induced encephalitis (ICI-iE) is a particularly severe irAE, often leading to treatment termination, long-term sequalae or death. Despite its high morbidity and mortality, data on clinical features and diagnostic criteria are limited. We aimed to define clinical, radiologic and laboratory characteristics of ICI-iE and identify factors that discriminate it from anti-leucine-rich glioma-inactivated (anti-LGI)-1 encephalitis and herpes simplex virus (HSV)-1 encephalitis - two alternative causes of encephalitis - to increase the awareness of ICI-iE and improve its diagnosis and management. To that end, we retrospectively collected 30 cases of ICI-iE that were reported to the Side Effect Registry Immuno-Oncology (SERIO) and 46 cases of anti-LGI1 encephalitis or herpes simplex virus (HSV)-1 encephalitis that presented to a large German neurological referral center (Charité Universitätsmedizin Berlin) between January 2015 and September 2021. Signs and symptoms, imaging and electroencephalogram features, laboratory findings and outcome measures were assessed using standardized case report forms as well as patients' medical records and compared between the groups. The data reported here represents the largest primary cohort of patients with ICI-iE to date and the first comparison with other types of encephalitis. As all three disorders - ICI-iE, HSV-1 encephalitis and anti-LGI1 encephalitis - are rare neurological entities, this dataset can be used as a reference in future clinical studies on ICI-induced neurotoxicity, neurological autoimmune disorders, and central nervous system infections.

Characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis: A retrospective multicentre cohort study.

AIM: Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis. METHODS: In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre. RESULTS: Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43). CONCLUSIONS: ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death.

Prevalence of Anti-Adeno-Associated Virus Serotype 9 Antibodies in Adult Patients with Spinal Muscular Atrophy.

5q-associated spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that leads to progressive muscle atrophy and weakness. The disease is caused by a homozygous deletion or mutation in the survival of motor neuron 1 (SMN1) gene, resulting in insufficient levels of SMN protein. Onasemnogene abeparvovec-xioi (OA) is a nonreplicating vector based on adeno-associated virus serotype 9 (AAV9) that contains the full-length human SMN1 gene. Recently, OA was approved for the treatment of SMA by the U.S. Food and Drug Administration and the European Medicines Agency. Because the presence of neutralizing antibodies caused by previous natural exposure to wild-type adeno-associated viruses (AAVs) may impair the efficiency of AAV-mediated gene transfer and thus reduce the therapeutic benefit of the gene therapy, an AAV9-binding antibody titer of >1:50 was defined as a surrogate exclusion criterion in pivotal OA clinical trials. However, these studies were exclusively conducted in infants and children. Because data on anti-AAV9 antibody titers in adults are generally sparse and not available for adult patients with SMA, we determined the prevalence of anti-AAV9 antibodies in sera of adult individuals with SMA to evaluate the feasibility of AAV9-mediated gene therapy in this cohort. In our study population of 69 adult patients with SMA type 2 and type 3 from four German academic sites, only 3 patients (4.3%) had an elevated anti-AAV9 antibody titer of >1:50. The prevalence of anti-AAV9 antibodies did not increase with age. The low and age-independent prevalence of anti-AAV9 antibodies in our cohort provides evidence that gene therapy with intravenous administered recombinant AAV9 vectors (rAAV9) might be feasible in adult patients with SMA, regardless of the patients' sex, SMA type, walking ability, or ventilatory status. This could also apply to the treatment of other inherited neurological diseases with rAAV9.

Prevalence and predictors of neurological manifestations in systemic AL amyloidosis.

INTRODUCTION: Immunoglobulin light chain (AL) amyloidosis is a life-threatening systemic disease due to plasma cell dyscrasias, which is characterized by amyloid deposition in various tissues. Neurological manifestations, in particular peripheral nervous system involvement, play a major role for quality of life and treatment decisions as frequently potentially neurotoxic drugs are used. METHODS: We retrospectively investigated the prevalence of neurological manifestations, its risk factors and prognostic value in 155 consecutive patients with AL amyloidosis in a single German tertiary center between 2010 and 2021. Multiple logistic regression was performed to identify predictors of amyloid neuropathy and the impact of peripheral neuropathy on patient survival was assessed by Cox proportional hazard regression analysis. RESULTS: Nearly half of patients showed at least one of four neurological manifestations of AL amyloidosis which were frequent in our study: peripheral neuropathy (36.8%), carpal tunnel syndrome (12.9%), lumbar spinal stenosis (7.1%), and amyloid myopathy (3.9%). Male sex (OR 2.943, CI 1.152-8.139, p = 0.029) and cardiac involvement (OR 6.186, CI 1.449-43.38, p = 0.028) were independent predictors of peripheral neuropathy which was closely related to autonomic dysfunction in patients with AL amyloidosis. Peripheral neuropathy had no impact on survival (HR 0.952, CI 0.517-1.754, p = 0.876). CONCLUSIONS: Neurological involvement is common in systemic AL amyloidosis. Treatment decisions should take into account peripheral neuropathy, in particular in male patients with amyloid cardiomyopathy, but also amyloid myopathy that seems to be not as rare as previously suggested.

Anti-EBNA1 IgG titre is not associated with fatigue in multiple sclerosis patients.

INTRODUCTION: Fatigue is the most frequent symptom in multiple sclerosis (MS), although it is still poorly understood due to its complexity and subjective nature. There is an urgent need to identify reliable biomarkers to improve disease prognosis and therapeutic strategies. Epstein-Barr virus (EBV) is the major environmental risk factor associated with MS aetiology, and trials with EBV-targeted T cell therapies have reduced fatigue severity in MS patients. AIM OF THE STUDY: We investigated whether the serum amount of immunoglobulin (Ig)G-specific for EBV antigens could be a suitable prognostic marker for the assessment of MS-related fatigue. MATERIAL AND METHODS: A total of 194 MS patients were enrolled. We quantified EBV nuclear antigen 1 (EBNA1) and EBV viral capsid antigen (VCA) immunoglobulin (Ig) G levels and B cell-activating factor of the tumour necrosis factor family (BAFF) concentration in the serum of patients with relapsing-remitting MS (RRMS) and chronic progressive MS (CPMS), and we analysed their correlation with aspects of fatigue and other clinical disease parameters. RESULTS: A complete EBV seropositivity could be detected in our cohort. After adjusting for confounding variables and covariates, neither EBNA1 nor VCA antibody titres were associated with levels of fatigue, sleepiness, depression, or with any of the clinical values such as expanded disability status scale, lesion count, annual relapse rate, or disease duration. However, patients with RRMS had significantly higher EBNA1 IgG titre than those with CPMS, whereas this was not the case under therapies targeting CD20+ cells. BAFF levels in serum were inversely proportional to anti-EBNA1 IgG. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our results show that EBNA1 IgG titre is not associated with the presence or level of fatigue. Whether the increased EBNA1 titre in RRMS plays a direct role in disease progression, or is only a consequence of excessive B cell activation, remains to be answered in future studies.

Corneal confocal microscopy to detect early immune-mediated small nerve fibre loss in AL amyloidosis.

OBJECTIVE: Light chain (AL) amyloidosis is a life-threatening disorder characterised by extracellular deposition of amyloid leading to dysfunction of multiple organs. Peripheral nerve involvement, particularly small fibre neuropathy, may be associated with poorer survival. Corneal confocal microscopy (CCM) is a rapid and non-invasive imaging technique to quantify corneal small nerve fibres and immune cells in vivo. We aimed to evaluate CCM as a tool for early diagnosis of peripheral nerve involvement in AL amyloidosis. METHODS: CCM and nerve conduction studies (NCS) were undertaken in 21 newly diagnosed, treatment-naïve AL amyloidosis patients and 21 age- and sex-matched healthy controls. Corneal nerve fibre density (CNFD), corneal nerve branch density and fibre length, and cell infiltrates were quantified in the sub-basal layer of the cornea. RESULTS: There was a significant reduction in CNFD and nerve fibre length, even without large fibre affection and an increase in cell density, particularly around corneal nerve fibres in patients with AL amyloidosis compared to controls. Additionally, cell infiltration correlated with reduced nerve fibre density in patients with AL amyloidosis, but reduced CNFD did not correlate with laboratory parameters of organ dysfunction. INTERPRETATION: Our study is the first to show that CCM allows rapid non-invasive identification of early small nerve fibre damage associated with immune cell infiltration in patients with AL amyloidosis. CCM detects peripheral nerve involvement more sensitively than NCS.