Speeding Up and Improving Image Quality in Glioblastoma MRI Protocol by Deep Learning Image Reconstruction.

A fully diagnostic MRI glioma protocol is key to monitoring therapy assessment but is time-consuming and especially challenging in critically ill and uncooperative patients. Artificial intelligence demonstrated promise in reducing scan time and improving image quality simultaneously. The purpose of this study was to investigate the diagnostic performance, the impact on acquisition acceleration, and the image quality of a deep learning optimized glioma protocol of the brain. Thirty-three patients with histologically confirmed glioblastoma underwent standardized brain tumor imaging according to the glioma consensus recommendations on a 3-Tesla MRI scanner. Conventional and deep learning-reconstructed (DLR) fluid-attenuated inversion recovery, and T2- and T1-weighted contrast-enhanced Turbo spin echo images with an improved in-plane resolution, i.e., super-resolution, were acquired. Two experienced neuroradiologists independently evaluated the image datasets for subjective image quality, diagnostic confidence, tumor conspicuity, noise levels, artifacts, and sharpness. In addition, the tumor volume was measured in the image datasets according to Response Assessment in Neuro-Oncology (RANO) 2.0, as well as compared between both imaging techniques, and various clinical-pathological parameters were determined. The average time saving of DLR sequences was 30% per MRI sequence. Simultaneously, DLR sequences showed superior overall image quality (all p < 0.001), improved tumor conspicuity and image sharpness (all p < 0.001, respectively), and less image noise (all p < 0.001), while maintaining diagnostic confidence (all p > 0.05), compared to conventional images. Regarding RANO 2.0, the volume of non-enhancing non-target lesions (p = 0.963), enhancing target lesions (p = 0.993), and enhancing non-target lesions (p = 0.951) did not differ between reconstruction types. The feasibility of the deep learning-optimized glioma protocol was demonstrated with a 30% reduction in acquisition time on average and an increased in-plane resolution. The evaluated DLR sequences improved subjective image quality and maintained diagnostic accuracy in tumor detection and tumor classification according to RANO 2.0.

The Brainstem Cavernoma Case Series: A Formula for Surgery and Surgical Technique.

Background and Objectives: Cavernous malformations (CM) are vascular malformations with low blood flow. The removal of brainstem CMs (BS) is associated with high surgical morbidity, and there is no general consensus on when to treat deep-seated BS CMs. The aim of this study is to compare the surgical outcomes of a series of deep-seated BS CMs with the surgical outcomes of a series of superficially located BS CMs operated on at the Department of Neurosurgery, College of Tuebingen, Germany. Materials and Methods: A retrospective evaluation was performed using patient charts, surgical video recordings, and outpatient examinations. Factors were identified in which surgical intervention was performed in cases of BS CMs. Preoperative radiological examinations included MRI and diffusion tensor imaging (DTI). For deep-seated BS CMs, a voxel-based 3D neuronavigation system and electrophysiological mapping of the brainstem surface were used. Results: A total of 34 consecutive patients with primary superficial (n = 20/58.8%) and deep-seated (n = 14/41.2%) brainstem cavernomas (BS CM) were enrolled in this comparative study. Complete removal was achieved in 31 patients (91.2%). Deep-seated BS CMs: The mean diameter was 14.7 mm (range: 8.3 to 27.7 mm). All but one of these lesions were completely removed. The median follow-up time was 5.8 years. Two patients (5.9%) developed new neurologic deficits after surgery. Superficial BS CMs: The median diameter was 14.9 mm (range: 7.2 to 27.3 mm). All but two of the superficial BS CMs could be completely removed. New permanent neurologic deficits were observed in two patients (5.9%) after surgery. The median follow-up time in this group was 3.6 years. Conclusions: The treatment of BS CMs remains complex. However, the results of this study demonstrate that with less invasive posterior fossa approaches, brainstem mapping, and neuronavigation combined with the use of a blunt "spinal cord" dissection technique, deep-seated BS CMs can be completely removed in selected cases, with good functional outcomes comparable to those of superficial BS CM.

CD19-Targeting CAR T Cells for Myositis and Interstitial Lung Disease Associated With Antisynthetase Syndrome.

Importance: Autoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting-chimeric antigen receptor (CAR) T cells were efficacious as an immune suppressive agent in 6 patients with refractory systemic lupus erythematosus and in 1 patient with antisynthetase syndrome. Objective: To test the safety and efficacy of CD19-targeting CAR T cells in a patient with severe antisynthetase syndrome, a complex autoimmune disorder with evidence for B- and T-cell involvement. Design, Setting, and Participants: This case report describes a patient with antisynthetase syndrome with progressive myositis and interstitial lung disease refractory to available therapies (including rituximab and azathioprine), who was treated with CD19-targeting CAR T cells in June 2022 at University Hospital Tübingen in Tübingen, Germany, with the last follow-up in February 2023. Mycophenolate mofetil was added to the treatment to cotarget CD8+ T cells, hypothesized to contribute to disease activity. Exposure: Prior to treatment with CD19-targeting CAR T cells, the patient received conditioning therapy with fludarabine (25 mg/m2 [5 days before until 3 days before]) and cyclophosphamide (1000 mg/m2 [3 days before]) followed by infusion of CAR T cells (1.23×106/kg [manufactured by transduction of autologous T cells with a CD19 lentiviral vector and amplification in the CliniMACS Prodigy system]) and mycophenolate mofetil (2 g/d) 35 days after CD19-targeting CAR T-cell infusion. Main Outcomes and Measures: The patient's response to therapy was followed by magnetic resonance imaging of the thigh muscle, Physician Global Assessment, functional muscle and pulmonary tests, and peripheral blood quantification of anti-Jo-1 antibody levels, lymphocyte subsets, immunoglobulins, and serological muscle enzymes. Results: Rapid clinical improvement was observed after CD19-targeting CAR T-cell infusion. Eight months after treatment, the patient's scores on the Physician Global Assessment and muscle and pulmonary function tests improved, and there were no detectable signs of myositis on magnetic resonance imaging. Serological muscle enzymes (alanine aminotransferase, aspartate aminotransferase, creatinine kinase, and lactate dehydrogenase), CD8+ T-cell subsets, and inflammatory cytokine secretion in the peripheral blood mononuclear cells (interferon gamma, interleukin 1 [IL-1], IL-6, and IL-13) were all normalized. Further, there was a reduction in anti-Jo-1 antibody levels and a partial recovery of IgA (to 67% of normal value), IgG (to 87%), and IgM (to 58%). Conclusions and Relevance: CD19-targeting CAR T cells directed against B cells and plasmablasts deeply reset B-cell immunity. Together with mycophenolate mofetil, CD19-targeting CAR T cells may break pathologic B-cell, as well as T-cell responses, inducing remission in refractory antisynthetase syndrome.

First case of adult onset neuronal intranuclear inclusion disease with both typical radiological signs and NOTCH2NLC repeat expansions in a Caucasian individual.

BACKGROUND AND PURPOSE: Adult onset neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder with a heterogeneous clinical presentation that can mimic stroke and various forms of dementia. To date, it has been described almost exclusively in Asian individuals. METHODS: This case presentation includes magnetic resonance imaging (MRI) of the neurocranium, histology by skin biopsy, and long-read genome sequencing. RESULTS: A 75-year-old Caucasian female presented with paroxysmal encephalopathy twice within a 14-month period. Brain MRI revealed high-intensity signals at the cerebral corticomedullary junction (diffusion-weighted imaging) and the paravermal area (fluid-attenuated inversion recovery), a typical distribution observed in adult onset NIID. The diagnosis was corroborated by skin biopsy, which demonstrated eosinophilic intranuclear inclusion bodies, and confirmed by long-read genome sequencing, showing an expansion of the GGC repeat in exon 1 of NOTCH2NLC. CONCLUSIONS: Our case proves adult onset NOTCH2NLC-GGC-positive NIID with typical findings on MRI and histology in a Caucasian patient and underscores the need to consider this diagnosis in non-Asian individuals.

Surgical Treatment of Craniopharyngiomas in Adults: Comparison between Primary Surgery and Surgery for Recurrence.

OBJECTIVE: Few studies have investigated the differences in outcomes between primary and repeat surgery for a craniopharyngioma in adults. As a result, a treatment concept for adult patients with a craniopharyngioma has not yet been established. The present study aimed to retrospectively analyze adult patients with craniopharyngioma to compare surgical outcomes between primary surgery and surgery for recurrence. METHODS: The demographic and clinical data of 68 adult patients with craniopharyngioma who had primary surgery (n=50) or surgery for recurrence (n=18) were retrospectively analyzed. In addition, the patients were followed up for an average of 38.6 months (range: 1-133 months). RESULTS: The cohorts of patients undergoing primary surgery or repeat surgery did not differ preoperatively in terms of demographic data, or radiological tumor features. However, patients with recurrent craniopharyngioma had significantly more pituitary hormone deficits and hypothalamo-pituitary disorders before surgery compared with patients with newly diagnosed craniopharyngioma. The success rate of complete resection in primary surgery was 53.2%. Even after repeat surgery, a satisfactory rate of complete resection of 35.7% was achieved. Operative morbidity was increased neither in patients with repeat surgery compared with those with primary surgery (postoperative bleeding P=0.560; meningitis P=1.000; CSF leak P=0.666; visual disturbance P=0.717) nor in patients with complete resection compared with those with partial resection. We found no difference in recurrence-free survival between initial surgery and repeat surgery (P=0.733). The recurrence rate was significantly lower after complete resection (6.9%) than after partial resection (47.8%; P<0.001). CONCLUSION: Attempting complete resection is justified for not only those with newly diagnosed craniopharyngioma but also for those with recurrent craniopharyngioma. However, the surgeon must settle for less than total resection if postoperative morbidity is anticipated.

A Novel, Apparently Silent Variant in MFSD8 Causes Neuronal Ceroid Lipofuscinosis with Marked Intrafamilial Variability.

Variants in MFSD8 can cause neuronal ceroid lipofuscinoses (NCLs) as well as nonsyndromic retinopathy. The mutation spectrum includes mainly missense and stop variants, but splice sites and frameshift variants have also been reported. To date, apparently synonymous substitutions have not been shown to cause MFSD8-associated diseases. We report two closely related subjects from a consanguineous Turkish family who presented classical features of NCLs but demonstrated marked intrafamilial variability in age at the onset and severity of symptoms. In fact, the difference in the onset of first neurologic symptoms was 15 years and that of ophthalmologic symptoms was 12 years. One subject presented an intellectual disability and a considerable cerebellar ataxia syndrome, while the other subject showed no intellectual disability and only a mild atactic syndrome. The diagnostic genetic testing of both subjects based on genome sequencing prioritized a novel, apparently synonymous variant in MFSD8, which was found in homozygosity in both subjects. The variant was not located within an integral part of the splice site consensus sequences. However, the bioinformatic analyses suggested that the mutant allele is more likely to cause exon skipping due to an altered ratio of exonic splice enhancer and silencer motifs. Exon skipping was confirmed in vitro by minigene assays and in vivo by RNA analysis from patient lymphocytes. The mutant transcript is predicted to result in a frameshift and, if translated, in a truncated protein. Synonymous variants are often given a low priority in genetic diagnostics because of their expected lack of functional impact. This study highlights the importance of investigating the impact of synonymous variants on splicing.

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition.

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Transplantation of a latissimus dorsi flap after nearly 6 hr of extracorporal perfusion: A case report.

Prolonged ischemia of tissues inevitably leads to their necrosis. This is especially relevant in the case of transplantation or replantation. In such situations, reperfusion in a timely manner might not be possible due to transportation times or other unforeseen complications. Therefore, a readily available and simple method to oxygenate the tissue and thus widen the time frame to reperfusion seems desirable. Here, we present the case of extracorporal perfusion of a latissimus dorsi (LD) flap that was successfully transplanted after nearly 6 hr of ischemia. A 41-year-old patient suffered multiple injuries including complete severance of the popliteal artery requiring emergency bypass. After stabilization of the patient and subsequent debridement, a LD flap was performed for soft tissue coverage. However, there was an acute occlusion of the bypass during flap inset. To salvage the free flap, a one-way extracorporal perfusion of the flap with heparinized isotonic saline solution was performed for a total of 5 hr and 47 min. The flap survived with minimal tip necrosis. This case report describes the application of a simple extracorporal perfusion technique for salvage of a free flap over a prolonged ischemia time and discusses the relevant literature. Due to its ease and quickness of application as well as ubiquitous availability, it might serve as a valuable tool in cases of acute problems with the recipient vessels or other incidents where several hours of ischemia time are to be anticipated.

Surgical management of primary and secondary pilocytic astrocytoma of the cerebellopontine angle (in adults and children) and review of the literature.

Glial tumors in the cerebellopontine angle (CPA) are uncommon and comprise less than 1% of CPA tumors. We present four cases of pilocytic astrocytoma of the CPA (PA-CPA) that were treated in our department. Patients who received surgical treatment for PA-CPA from January 2004 to December 2019 were identified by a computer search of their files from the Department of Neurosurgery, Tübingen. Patients were evaluated for initial symptoms, pre- and postoperative facial nerve function and cochlear function, complications, and recurrence rate by reviewing surgical reports, patient documents, neuroradiological data, and follow-up data. We identified four patients with PA-CPA out of about 1500 CPA lesions (~ 0.2%), which were surgically treated in our department in the last 16 years. Of the four patients, three were male, and one was a female patient. Two were adults, and two were children (mean age 35 years). A gross total resection was achieved in three cases, and a subtotal resection was attained in one case. Two patients experienced a moderate facial palsy immediately after surgery (House-Brackmann grade III). In all cases, the facial function was intact or good (House-Brackmann grades I-II) at the long-term follow-up (mean follow-up 4.5 years). No mortality occurred during follow-up. Three of the patients had no recurrence at the latest follow-up (mean latest follow-up 4.5 years), while one patient had a slight recurrence. PA-CPA can be safely removed, and most complications immediately after surgery resolve in the long-term follow-up.

CNS Invasion in Meningioma-How the Intraoperative Assessment Can Improve the Prognostic Evaluation of Tumor Recurrence.

The detection of the infiltrative growth of meningiomas into CNS tissue has been integrated into the WHO classification as a stand-alone marker for atypical meningioma. However, its prognostic impact has been questioned. Infiltrative growth can also be detected intraoperatively. The prognostic impact of the intraoperative detection of the central nervous system tissue invasion of meningiomas was analyzed and compared to the histopathological assessment. The clinical data of 1517 cases with follow-up data regarding radiographic recurrence was collected. Histopathology and operative reports were reviewed and invasive growth was seen during resection in 23.7% (n = 345) while histopathology detected it in 4.8% (n = 73). The histopathological and intraoperative assessments were compatible in 63%. The prognostic impact of histopathological and intraoperative assessment was significant in the univariate but not in the multivariate analysis. Both methods of assessment combined reached statistical significance in the multivariate analysis (p = 0.0409). A score including all independent prognostic factors divided the cohort into three prognostic subgroups with a risk of recurrence of 33.8, 64.7 and 88.5%, respectively. The intraoperative detection of the infiltrative growth of primary meningiomas into the central nervous system tissue can complement the histopathological assessment of CNS invasion. The combined assessment is an independent prognostic factor regarding tumor recurrence and allows a risk-adapted tumor stratification.

COX2 expression is associated with proliferation and tumor extension in vestibular schwannoma but is not influenced by acetylsalicylic acid intake.

Acetylsalicylic acid has been linked to a lower risk for different cancer types, presumably through its inhibitory effect on cyclooxygenase 2. This has also been investigated in vestibular schwannomas with promising results suggesting an antiproliferative effect and recently the intake has been recommended for vestibular schwannomas as a conservative treatment option. We constructed tissue microarrays from paraffin-embedded tissue samples of 1048 vestibular schwannomas and analyzed the expression of cyclooxygenase 2 and the proliferation marker MIB1 (Molecular Immunology Borstel) via immunohistochemistry together with clinical data (age, gender, tumor extension, prior radiotherapy, neurofibromatosis type 2, tumor recurrence, cyclooxygenase 2 responsive medication). Univariate analysis showed that cyclooxygenase 2 expression was increased with age, female gender, prior radiotherapy and larger tumor extension. MIB1 expression was also associated with higher cyclooxygenase 2 expression. Schwannomas of neurofibromatosis type 2 patients had lower cyclooxygenase 2 levels. Use of acetylsalicylic acid, non-steroidal anti-inflammatory drugs, glucocorticoids or other immunosuppressants did not show differences in cyclooxygenase 2 or MIB1 expression. Instead, cyclooxygenase 2 expression increases with tumor extension while MIB1 expression is not associated with tumor size. Overall, cyclooxygenase 2 expression is associated with proliferation but not influenced by regular intake of acetylsalicylic acid or other cyclooxygenase 2-responsive medications. Acetylsalicylic acid intake does not alter cyclooxygenase 2 expression and has no antiproliferative effect in vestibular.

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.

Surgical Management of Primary Cerebellopontine Angle Melanocytoma: Outcome, Recurrence and Additional Therapeutic Options.

OBJECTIVE: Meningeal melanocytomas of the central nervous system are extremely rare, with an incidence of 1 per 10 million individuals. Cases of primary cerebellopontine angle melanocytoma (PCPAM) have only been described in single case reports. The goal of the present study was to analyze the surgical management of PCPAM, with a particular focus on early and late treatment outcomes and recurrence rates. METHODS: The patients who had undergone surgery for PCPAM from January 2004 to May 2018 were identified by a local database query. The patients were evaluated for initial symptoms, pre- and postoperative facial and cochlear nerve function, complications, and recurrence rate by reviewing the patients' medical records. RESULTS: We identified 4 patients with PCPAM of >1500 cerebellopontine angle lesions (∼0.2%) that had been surgically treated at our department in the past 14 years. Of the 4 patients, 2 were men and 2 were women, with a mean age of 47 years. Anatomical facial and cochlear nerve preservation was achieved in all 4 patients. One patient experienced a new moderate facial palsy immediately after surgery (House-Brackmann grade III). Of the 4 patients, 3 had undergone radiotherapy and 1 had undergone ion beam therapy for tumor recurrence (6 years after surgery). Of the 4 patients, 3 had presented with tumor recurrence at 2, 3, and 6 years of follow-up respectively. The long-term follow-up examination had not yet been conducted for 1 patient. CONCLUSIONS: At long-term follow-up, 3 patients had developed recurrence. Because of the high recurrence rate of PCPAM, we believe that radiotherapy in addition to surgery should be considered in the future to avoid early recurrence.

Nerve Ultrasound Predicts Treatment Response in Chronic Inflammatory Demyelinating Polyradiculoneuropathy-a Prospective Follow-Up.

As reliable biomarkers of disease activity are lacking, monitoring of therapeutic response in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) remains a challenge. We sought to determine whether nerve ultrasound and electrophysiology scoring could close this gap. In CIDP patients (fulfilling EFNS/PNS criteria), we performed high-resolution nerve ultrasound to determine ultrasound pattern sum scores (UPSS) and predominant echotexture nerve conduction study scores (NCSS) as well as Medical Research Council sum scores (MRCSS) and inflammatory neuropathy cause and treatment disability scores (INCAT) at baseline and after 12 months of standard treatment. We retrospectively correlated ultrasound morphology with nerve histology when available. 72/80 CIDP patients featured multifocal nerve enlargement, and 35/80 were therapy-naïve. At baseline, clinical scores correlated with NCSS (r2 = 0.397 and r2 = 0.443, p < 0.01), but not or hardly with UPSS (Medical Research Council sum scores MRCSS r2 = 0.013, p = 0.332; inflammatory neuropathy cause and treatment disability scores INCAT r2 = 0.053, p = 0.048). Longitudinal changes in clinical scores, however, correlated significantly with changes in both UPSS and NCSS (r2 = 0.272-0.414, p < 0.0001). Combining nerve/fascicle size with echointensity and histology at baseline, we noted 3 distinct classes: 1) hypoechoic enlargement, reflecting active inflammation and onion bulbs; 2) nerve enlargement with additional hyperechogenic fascicles/perifascicular tissue in > 50% of measured segments, possibly reflecting axonal degeneration; and 3) almost no enlargement, reflecting "burned-out" or "cured" disease without active inflammation. Clinical improvement after 12 months was best in patients with pattern 1 (up to 75% vs up to 43% in pattern 2/3, Fisher's exact test p < 0.05). Nerve ultrasound has additional value not only for diagnosis, but also for classification of disease state and may predict treatment response.

Sporadic late-onset nemaline myopathy: clinico-pathological characteristics and review of 76 cases.

BACKGROUND: Sporadic late-onset nemaline myopathy (SLONM) is a rare, late-onset muscle disorder, characterized by the presence of nemaline rods in muscle fibers. Phenotypic characterization in a large cohort and a comprehensive overview of SLONM are lacking. METHODS: We studied the clinico-pathological features, treatment and outcome in a large cohort of 76 patients with SLONM, comprising 10 new patients and 66 cases derived from a literature meta-analysis (PubMed, 1966-2016), and compared these with 15 reported HIV-associated nemaline myopathy (HIV-NM) cases. In 6 SLONM patients, we performed a targeted next-generation sequencing (NGS) panel comprising 283 myopathy genes. RESULTS: SLONM patients had a mean age at onset of 52 years. The predominant phenotype consisted of weakness and atrophy of proximal upper limbs in 84%, of proximal lower limbs in 80% and both in 67%. Other common symptoms included axial weakness in 68%, as well as dyspnea in 55% and dysphagia in 47% of the patients. In 53% a monoclonal gammopathy of unknown significance (MGUS) was detected in serum. The mean percentage of muscle fibers containing rods was 28% (range 1-63%). In 2 cases ultrastructural analysis was necessary to detect the rods. The most successful treatment in SLONM patients (all with MGUS) was autologous peripheral blood stem cell therapy. A targeted NGS gene panel in 6 SLONM patients (without MGUS) did not reveal causative pathogenic variants. In a comparison of SLONM patients with and without MGUS, the former comprised significantly more males, had more rapid disease progression, and more vacuolar changes in muscle fibers. Interestingly, the muscle biopsy of 2 SLONM patients with MGUS revealed intranuclear rods, whereas this feature was not seen in any of the biopsies from patients without paraproteinemia. Compared to the overall SLONM cohort, significantly more HIV-NM patients were male, with a lower age at onset (mean 34 years). In addition, immunosuppression was more frequently applied with more favorable outcome, and muscle biopsies revealed a significantly higher degree of inflammation and necrosis in this cohort. Similar to SLONM, MGUS was present in half of the HIV-NM patients. CONCLUSIONS: SLONM presents a challenging, but important differential diagnosis to other neuromuscular diseases of adult onset. Investigations for MGUS and HIV should be performed, as they require distinct but often effective therapeutic approaches. Even though SLONM and HIV-NM show some differences, there exists a large clinico-pathological overlap between the 2 entities.

Late onset Krabbe disease due to the new GALC p.Ala543Pro mutation, with intriguingly high residual GALC activity in vitro.

BACKGROUND: Krabbe disease (KD) is an inherited leukodystrophy due to a defect in the GALC gene which encodes the lysosomal galactosylceramide ß-galactosidase (GALC). About two thirds of patients show the early onset form of KD dominated by cerebral demyelination leading to death in early infancy. Late onset forms include a spectrum of late infantile, juvenile and adult clinical courses. The deficiency of GALC leads to a galactosylceramide lipidosis in which lysosomal storage phenomena are seen almost only at the ultrastructural level. RESULTS: In a 4-year-old boy, the clinical suspicion of KD was high according to neurologic and neuroimaging findings. However, laboratory results were inconclusive; white blood cell GALC activity being at 23 to 25% of the normal level, and GALC genotyping revealing the new homozygous p.Ala543Pro variant which, ex silico, was of unclear significance. Studying a skin biopsy, cultured fibroblasts showed the GALC activity at 21 to 30% of the normal level; ultrastructurally, clearly KD-specific inclusions were seen in the eccrine sweat gland cells, confirming a KD diagnosis. CONCLUSION: The high clinical suspicion combined with the morphologic evidence for KD predict that the p.Ala543Pro variant is pathogenic for (late onset) KD. A hypothesis linked to the proline in the mutant GALC may explain the in vitro effect with high residual GALC activity. This patient would not have been correctly diagnosed, despite the strong clinical criteria of KD, if the electron microscopic results had not been available. The detailed knowledge of neurologic and neuroimaging signs is important in diagnostically problematic KD patients in which also an electron microscopic approach can be crucial.

Graft versus self (GvS) against T-cell autoantigens is a mechanism of graft-host interaction.

Graft-versus-host disease (GVHD) represents the major nonrelapse complication of allogeneic hematopoietic cell transplantation. Although rare, the CNS and the eye can be affected. In this study, manifestation in the retina as part of the CNS and T-cell epitopes recognized by the allogeneic T cells were evaluated. In 2 of 6 patients with posttransplantation retina diseases and 6 of 22 patients without ocular symptoms, antigen-specific T-cell responses against retina-specific epitopes were observed. No genetic differences between donor and recipient could be identified indicating T-cell activation against self-antigens (graft versus self). Transplantation of a preexisting immunity and cross-reactivity with ubiquitous epitopes was excluded in family donors and healthy individuals. In summary, an immunological reaction against retina cells represents a mechanism of graft-versus-host interaction following hematopoietic cell transplantation.

Multimodal Assessment Reveals Late-Onset Hemispheric Shift of Language in a Child with Meningocerebral Dysplasia.

We report on a girl with progressive left frontal tissue destruction starting at the age of almost 8 years. She manifested acutely with epileptic seizures accompanied by Broca aphasia as well as transient right hemiparesis. Due to refractory epilepsy developing over the next years, which originated from the left frontal lobe, the decision was made to proceed to epilepsy surgery. By then, her language functions had recovered despite progressive left frontal tissue-destruction, raising the possibility of a hemispheric shift of language. Clinical functional magnetic resonance imaging (fMRI) was conducted to localize brain regions involved in language production. A complex pattern of clear right-hemispheric dominance, but with some left-sided contribution was found. However, a Wada test suggested the left hemisphere to be critical, seemingly contradicting fMRI. Invasive electroencephalogram recordings could reconcile these results by identifying the fMRI-detected, residual left-sided activation as being relevant for speech production. Only by combining the localizing information from fMRI with the information obtained by two invasive procedures could the unusual pattern of late-onset language reorganization be uncovered. This allowed for extensive left frontal resection, with histology confirming meningocerebral angiodysplasia. Postoperatively, language functions were preserved and seizure outcome was excellent. The implications of our findings for presurgical assessments in children are discussed.