Corticospinal tract hyperintensity in patients with LGI1-antibody encephalitis and other central nervous system disorders with neuroglial antibodies.

The frequency of corticospinal tract (CST) T2/FLAIR hyperintensity in disorders with neuroglial antibodies is unclear. Herein, we retrospectively reviewed brain MRIs of 101 LGI1-antibody encephalitis patients, and observed CST hyperintensity in 30/101 (30%). It was mostly bilateral (93%), not associated with upper motor neuron signs/symptoms (7%), and frequently decreased over time (39%). In a systematic review including patients with other neuroglial antibodies, CST hyperintensity was reported in 110 with neuromyelitis optica (94%), myelin oligodendrocyte glycoprotein-associated disease (2%), Ma2-antibody (3%) and GAD65-antibody paraneoplastic neurological syndrome (1%). CST hyperintensity is not an infrequent finding in LGI1-Ab encephalitis and other disorders with neuroglial antibodies.

Paraneoplastic autoimmune neurologic disorders associated with thymoma.

Thymoma is often associated with paraneoplastic neurologic diseases. Neural autoantibody testing is an important tool aiding diagnosis of thymoma and its autoimmune neurologic complications. Autoantibodies specific for muscle striational antigens and ion channels of the ligand-gated nicotinic acetylcholine receptor superfamily are the most prevalent biomarkers. The autoimmune neurologic disorders associating most commonly with thymoma are myasthenia gravis (MG), peripheral nerve hyperexcitability (neuromyotonia and Morvan syndrome), dysautonomia, and encephalitis. Patients presenting with these neurologic disorders should be screened for thymoma at diagnosis. Although they can cause profound disability, they usually respond to immunotherapy and treatment of the thymoma. Worsening of the neurologic disorder following surgical removal of a thymoma may herald tumor recurrence. Prompt recognition of paraneoplastic neurologic disorders is critical for patient management. A multidisciplinary approach is required for optimal management of neurologic autoimmunity associated with thymoma.

Crigler-Najjar syndrome: looking to the future does not make us forget the present.

Recently, the safety and efficacy of gene therapy were evaluated in patients with Crigler-Najjar syndrome (CNS). Although it is a promising curative option for CNS, many doubts still persist about its long-term efficacy and safety. Furthermore, there is a risk of overlooking several unresolved problems still present in current clinical practice. This letter is a call for action on crucial open issues that remain nowadays an unmet need in the management of CNS patients.

Epidemiology of seropositive myasthenia gravis in Sardinia: A population-based study in the district of Sassari.

INTRODUCTION/AIMS: The global incidence and prevalence of myasthenia gravis (MG) range between 6-31/million and 10-37/100,000, respectively. Sardinia is a high-risk region for different immune-mediated disorders, but the epidemiology of MG remains unclear. We determined the epidemiology of MG with acetylcholine receptor (AChR)-immunoglobulin G (IgG) and muscle-specific tyrosine kinase (MuSK)-IgG in the district of Sassari (North-Western Sardinia; population, 325,288). METHODS: From the laboratory of the University Hospital of Sassari (reference for AChR/MuSK-IgG testing in Sardinia since 1998) and the main neurology units in Sardinia, we retrospectively identified MG patients with (1) AChR-IgG and/or MuSK-IgG positivity by radioimmunoprecipitation assay; and (2) residency in the district of Sassari. Incidence (January 2010-December 2019) and prevalence (December 31, 2019) were calculated. RESULTS: A total of 202 patients were included (incident, 107; prevalent, 180). Antibody specificities were AChR (n = 187 [93%]) and MuSK (n = 15 [7%]). The crude MG incidence (95% confidence interval) was 32.6 (26.8-39.2)/million, while prevalence was 55.3 (47.7-63.9)/100,000. After age-standardization to the world population, incidence decreased to 18.4 (14.3-22.5)/million, while prevalence decreased to 31.6 (26.1-37.0)/100,000. Among incident cases, age strata (years) at MG onset were: <18 (2%), 18-49 (14%), 50-64 (21%), and ≥65 (63%). DISCUSSION: Sardinia is a high-risk region for MG, with a prevalence that exceeds the European threshold for rare disease. Identification of the environmental and genetic determinants of this risk may improve our understanding of disease pathophysiology.

Myasthenia gravis: the changing treatment landscape in the era of molecular therapies.

Myasthenia gravis (MG) is an autoimmune disorder that affects the neuromuscular junction, leading to muscle weakness and fatigue. MG is caused by antibodies against the acetylcholine receptor (AChR), the muscle-specific kinase (MuSK) or other AChR-related proteins that are expressed in the postsynaptic muscle membrane. The standard therapeutic approach for MG has relied on acetylcholinesterase inhibitors, corticosteroids and immunosuppressants, which have shown good efficacy in improving MG-related symptoms in most people with the disease; however, these therapies can carry a considerable burden of long-term adverse effects. Moreover, up to 15% of individuals with MG exhibit limited or no response to these standard therapies. The emergence of molecular therapies, including monoclonal antibodies, B cell-depleting agents and chimeric antigen receptor T cell-based therapies, has the potential to revolutionize the MG treatment landscape. This Review provides a comprehensive overview of the progress achieved in molecular therapies for MG associated with AChR antibodies and MuSK antibodies, elucidating both the challenges and the opportunities these therapies present to the field. The latest developments in MG treatment are described, exploring the potential for personalized medicine approaches.

Wilson's Disease with Acute Hepatic Onset: How to Diagnose and Treat It.

Wilson's disease (WD) with acute onset poses a diagnostic challenge because it is clinically indistinguishable from other acute liver diseases. In addition, serum ceruloplasmin and urinary copper excretion, the first-line diagnostic tools for WD, can show false positive results in the case of acute liver failure, and the diagnostic role of genetic analysis is limited by the time required to perform it. In the case of fulminant onset, there is a clear indication of liver transplantation. "New Wilson Index" is frequently used to discriminate between patients who need liver transplantation versus those who can be successfully managed by medical treatment, but its reliability remains controversial. Timely referral of patients with acute liver failure due to WD may be a key factor in improving patient survival. Although liver transplant very often represents the only chance for such patients, maximum effort should be made to promote survival with a native liver. The management of these aspects of WD is still a matter of debate and will be the subject of this review.

Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AND AIMS: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. APPROACH AND RESULTS: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation. CONCLUSIONS: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.

A Modified Technique for Two-Stage Revision in Knee PJI Treatment.

Knee PJIs represent one of the most important complications after joint replacement surgery. If the prerequisites for implant retention do not subsist, the surgical treatment of these conditions is performed using one-stage and two-stage revision techniques. In this study, an implemented two-stage revision technique was performed, adopting antibiotic calcium sulfate beads and tumor-like debridement guided by methylene blue, such as described for the DAPRI technique. The aim of the present study is to compare the implemented two-stage revision technique with the standard technique in order to assess its effectiveness. METHODS: Twenty patients affected by knee PJIs were prospectively enrolled in the study and underwent an implemented two-stage revision technique (Group A). Data collected and clinical results were compared with a matched control group treated with a standard two-stage technique (Group B). For each patient, the time of the reimplantation and length of antibiotic systemic therapy were recorded. Each patient underwent routine laboratory tests, including inflammatory markers. RESULTS: In Group A and in Group B, inflammatory markers normalized at 6.5 ± 1.1. weeks and 11.1 ± 2.3 weeks, respectively (p < 0.05). Also, the difference in length of antibiotic therapy and time to reimplantation were significantly shorter in Group A (p < 0.05). No recurrence of infection was found in Group A at the last follow-up. DISCUSSION: The implemented two-stage revision technique demonstrated a faster normalization of inflammatory markers, as well as a decrease in reimplantation time and duration of antibiotic therapy, compared to the traditional technique. The use of calcium sulfate antibiotic beads and tumor-like debridement seems to improve the results and reduce the time of healing. CONCLUSION: The implemented two-stage revision technique seems to improve the results and reduce the time of healing. This leads to a more rapid and less stressful course for the patient, as well as a reduction in health care costs.

"Single-use peripheral" vs "conventional" reaming in total hip arthroplasty: how to respect native centre of rotation and acetabular offset? A CT study.

PURPOSE: The respect of native hip offset represents a mainstay for satisfying results in total hip arthroplasty (THA). Historically, a great interest has been focused on restoration of femoral offset, while only in recent years, acetabular offset (AO) has been considered. The purpose of the current study was to compare the "single-use peripheral" reaming technique with the "conventional" one for the maintenance of the native COR of the hip and AO in patients undergoing to primary THA. METHODS: Eighty patients affected from primary hip osteoarthritis were prospectively enrolled in the study and were divided in two groups (Group A "single-use peripheral" and Group B "conventional" reaming technique). Pre- and post-operatively, AO, acetabular floor distance (AFd) and acetabular version (AV) were assessed through a CT scan. A comparison between groups for the radiological parameters, surgical time and complications was performed. RESULTS: The demographic data were similar in both groups. The complications rate and the AV did not differ statistically between groups. Group A presented a statistically significant shorter surgical time and lower variation between pre- and post-operative AO and AFd. Statistical significance was defined as p < 0.05. CONCLUSIONS: The "single-use peripheral" reaming technique demonstrated to be more reliable in reproducing the native COR and AO of patients undergoing to primary THA than the "conventional" one. The operative time was significantly reduced, and it may lead to a reduction in the infection risk even though it was not observed in the current study. Further research could be useful to validate such findings and to assess clinical impact and long-term survival of the implant.

Cancer detection after a 9-year course of Lambert-Eaton myasthenic syndrome complicated by anti-Hu associated limbic encephalitis.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune neuromuscular junction disorder, paraneoplastic in 55% of cases and commonly associated with small-cell lung cancer (SCLC). We report the case of a 61-year-old man presented who with a 3-month history of lower limb proximal weakness, progressing to upper limbs, associated with dysphagia, xerostomia and erectile dysfunction. Electrodiagnostic studies and anti voltage-gated calcium channel (VGCC) antibodies (Abs) detection confirmed LEMS diagnosis. Contrast-enhanced thorax computed tomography (CT) scan and subsequently [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) showed no malignancy. Two years after the onset of LEMS, he was diagnosed with anti-Hu limbic encephalitis (LE). FDG-PET/CT scan remained negative for the following seven years. Nine years after LEMS onset, a hypermetabolic lesion of the left lung hilus was detected. This is a case of a paraneoplastic LEMS where the interval between the onset of neurological disease and tumour detection was as long as nine years.

Clinical, neurophysiological and serological clues for the diagnosis of neuromyotonia and distinction from cramp-fasciculation syndrome.

Neuromyotonia and cramp-fasciculation syndrome diagnosis currently relies on neurophysiological examination. In this study we investigated the clinical features and neural antibody profile of patients with neuromyotonia and cramp-fasciculation syndrome to assess the diagnostic value of serological testing. Available sera from adult patients with electromyography-defined neuromyotonia and cramp-fasciculation syndrome were tested for neural antibodies by indirect immunofluorescence on mouse brain sections and live cell-based assays. Forty patients were included, 14 with neuromyotonia and 26 with cramp-fasciculation syndrome. Neural antibodies were detected in 10/10 neuromyotonia sera, most commonly against contactin-associated protein 2 (7/10, 70%), and in 1/20 (5%) cramp-fasciculation syndrome sera. Clinical myokymia, hyperhidrosis, and paresthesia or neuropathic pain were more common in neuromyotonia and mostly associated with contactin-associated protein 2 antibodies. Central nervous system involvement was present in 4/14 (29%) neuromyotonia patients. A tumor was detected in 13/14 (93%) neuromyotonia patients (thymoma, 13), and in 4/26 (15%) with cramp-fasciculation syndrome (thymoma, 1; other neoplasms, 3). Twenty-one/27 (78%) patients achieved a significant improvement or complete remission. Our findings highlight clinical, neurophysiological and serological clues that can be useful in the diagnosis of neuromyotonia and cramp-fasciculation syndrome. Antibody testing is valuable for neuromyotonia diagnosis, while its usefulness in cramp-fasciculation syndrome confirmation is limited.

Clinically relevant increases in serum neurofilament light chain and glial fibrillary acidic protein in patients with Susac syndrome.

BACKGROUND AND PURPOSE: Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising neuro-axonal damage and astrocytic activation biomarkers. Susac syndrome (SS) is an increasingly recognized neurological condition and biomarkers that can help assess and monitor disease evolution are highly needed for the adequate management of these patients. sNfL and sGFAP levels were evaluated in patients with SS and their clinical relevance in the relapse and remission phase of the disease was assessed. METHODS: As part of a multicentre study that enrolled patients diagnosed with SS from six international centres, sNfL and sGFAP levels were assessed in 22 SS patients (nine during a relapse and 13 in remission) and 59 age- and sex-matched healthy controls using SimoaTM assay Neurology 2-Plex B Kit. RESULTS: Serum NfL levels were higher than those of healthy controls (p < 0.001) in SS patients and in both subgroups of patients in relapse and in remission (p < 0.001 for both), with significantly higher levels in relapse than in remission (p = 0.008). sNfL levels showed a negative correlation with time from the last relapse (r = -0.663; p = 0.001). sGFAP levels were slightly higher in the whole group of patients than in healthy controls (p = 0.046) and were more pronounced in relapse than in remission (p = 0.013). CONCLUSION: In SS patients, both sNFL and sGFAP levels increased compared with healthy controls. Both biomarkers had higher levels during clinical relapse and much lower levels in remission. sNFL was shown to be time sensitive to clinical changes and can be useful to monitor neuro-axonal damage in SS.

Paediatric porto-sinusoidal vascular disease: Two different clinical phenotypes with subtle histological differences.

BACKGROUND AND AIMS: In paediatrics, porto-sinusoidal vascular disease (PSVD) is relatively unknown and probably underdiagnosed. We aimed to describe clinical phenotypes, histology and outcome of children diagnosed with PSVD. METHODS: Retrospective multicentre study of children diagnosed with PSVD. Diagnosis of PSVD was based on histopathology reports; liver specimens were re-evaluated by two expert liver pathologists. RESULTS: Sixty two children diagnosed with PSVD (M/F = 36/26, median age 6.6 years, range 3.3-10.6), from 7 centres, were included. Thirty-six presented with non-cirrhotic portal hypertension, PH, (PH-PSVD Group = 58%) while 26 had a liver biopsy because of chronic elevation of transaminases without PH (noPH-PSVD Group = 42%). On histology review, the two groups differed for the prevalence of obliterative portal venopathy (more prevalent in PH-PSVD, p = 0.005), and hypervascularised portal tracts (more common in noPH-PSVD, p = 0.039), the other histological changes were equally distributed. At multivariate analysis, platelet count ≤185 000/mm3 was the only independent determinant of PH (p < 0.001). After a median follow-up of 7 years (range 3.0-11.2), in PH-PSVD group 3/36 (8%) required TIPS placement, 5/36 (14%) developed pulmonary vascular complications of PH, and 7/36 (19%) required liver transplantation. In noPH-PSVD none progressed to PH nor had complications. CONCLUSIONS: Paediatric patients with PSVD present with two different clinical phenotypes, one characterised by PH and one by chronic elevation of transaminases without PH. PSVD should be included among the conditions causing isolated hypertransaminasaemia. On histology, the differences between the two groups are subtle. Medium-term outcome is favourable in patients without PH; progression of the disease is observed in those with PH.

A score that predicts aquaporin-4 IgG positivity in patients with longitudinally extensive transverse myelitis.

BACKGROUND AND PURPOSE: Longitudinally extensive transverse myelitis (LETM) associated with aquaporin-4 autoantibodies (AQP4-IgG) can cause severe disability. Early diagnosis and prompt treatment are critical to prevent relapses. A novel score is described based on clinical and neuroimaging characteristics that predicts AQP4-IgG positivity in patients with LETM. METHODS: Patients were enrolled both retrospectively and prospectively from multiple Italian centers. Clinical and neuroimaging characteristics of AQP4-IgG positive and negative patients were compared through univariate and multivariate analysis. RESULTS: Sixty-six patients were included. Twenty-seven (41%) were AQP4-IgG positive and median age at onset was 45.5 years (range 19-81, interquartile range 24). Female sex (odds ratio [OR] 17.9, 95% confidence interval [CI] 2.6-381.9; p = 0.014), tonic spasms (OR 45.6, 95% CI 3.1-2197; p = 0.017) and lesion hypointensity on T1-weighted images (OR 52.9, 95% CI 6.8-1375; p = 0.002) were independently associated with AQP4-IgG positivity. The AQP4-IgG positivity in myelitis (AIM) score predicted AQP4-IgG positivity with 85% sensitivity and 95% specificity. Positive and negative likelihood ratios were 16.6 and 0.2 respectively. The inter-rater and intra-rater agreement in the score application were both excellent. CONCLUSIONS: The AIM score predicts AQP4-IgG positivity with good sensitivity and specificity in patients with a first episode of LETM. The score may assist clinicians in early diagnosis and treatment of AQP4-IgG positive LETM.

MRI Liver Imaging Integrated with Texture Analysis in Native Liver Survivor Patients with Biliary Atresia after Kasai Portoenterostomy: Correlation with Medical Outcome after Surgical Treatment.

Kasai portoenterostomy (KP) plays a crucial role in the treatment of biliary atresia (BA). The aim is to correlate MRI quantitative findings of native liver survivor BA patients after KP with a medical outcome. Thirty patients were classified as having ideal medical outcomes (Group 1; n = 11) if laboratory parameter values were in the normal range and there was no evidence of chronic liver disease complications; otherwise, they were classified as having nonideal medical outcomes (Group 2; n = 19). Liver and spleen volumes, portal vein diameter, liver mean, and maximum and minimum ADC values were measured; similarly, ADC and T2-weighted textural parameters were obtained using ROI analysis. The liver volume was significantly (p = 0.007) lower in Group 2 than in Group 1 (954.88 ± 218.31 cm3 vs. 1140.94 ± 134.62 cm3); conversely, the spleen volume was significantly (p < 0.001) higher (555.49 ± 263.92 cm3 vs. 231.83 ± 70.97 cm3). No differences were found in the portal vein diameter, liver ADC values, or ADC and T2-weighted textural parameters. In conclusion, significant quantitative morpho-volumetric liver and spleen abnormalities occurred in BA patients with nonideal medical outcomes after KP, but no significant microstructural liver abnormalities detectable by ADC values and ADC and T2-weighted textural parameters were found between the groups.