Neurology® Neuroimmunology & Neuroinflammation最新文献

Background and objectives: Myopathy is one of the most common neurologic immune-related adverse events (irAEs) reported after treatment with immune checkpoint inhibitor (ICI) cancer immunotherapies. Current knowledge on disease course relates to short-term outcomes, and long-term outcome data are lacking. The aim of this study was to evaluate the long-term outcomes of patients with ICI-related myopathy.

Methods: We reviewed Mayo Clinic patients diagnosed with ICI-related myopathy between 2013 and 2024 with at least 6 months of follow-up; we compared them with patients who died because of myopathy within 2 months from disease onset.

Results: Twenty-three patients were identified; the median follow-up duration was 13 months (range 6-76). The median age at presentation was 73 years (range 34-87), and 57% were male. The most common presentations were ocular involvement (78%, including oculomotor and ptosis), followed by proximal limb (74%), axial (61%), and bulbar (48%) weakness. Myocarditis was present in 35%. At disease nadir, 43% had an irAE grade >2. All patients were treated with corticosteroids; 61% received additional immunosuppressive/immunomodulatory treatment in the acute setting. The median treatment duration was 5 months (range 1-17). At the last follow-up, 87% of patients had a favorable outcome (irAE grade ≤2), yet residual symptoms/signs were common (48%). Gradual improvement was observed in most patients, even after immunosuppressive/immunomodulatory treatment was discontinued. The only patient with a truly refractory course had biopsy findings of nemaline rods. Compared with patients with long-term follow-up, patients who died within 2 months (N = 9) were more commonly men (57% vs 100%, p = 0.03) and more likely to have bulbar or axial involvement (p = 0.01 and p = 0.04, respectively).

Discussion: Approximately half of the patients with ICI-related myopathy and long-term follow-up had some residual symptoms/signs, despite good functional outcomes. Symptoms continue to improve over 12 months regardless of immunosuppressive/immunomodulatory treatment duration. Male sex and axial and bulbar symptoms/signs were all associated with a terminal disease course. A prolonged refractory disease course might suggest an atypical pathology.

Objectives: To report a case of paraneoplastic motor neuron disease (MND) with a favorable outcome after cancer treatment.

Methods: Clinical, electrophysiologic, radiologic, and serum/CSF study of a patient with brachial amyotrophic diplegia/flail-arm syndrome (BAS/FAS).

Results: A 68-year-old man presented with a subacute-onset upper limb weakness and atrophy evocative of BAD/FAS. Electrodiagnostic study (EDX) confirmed MND; CSF examination found oligoclonal bands and elevated neurofilament light chains (NfL). A prostate adenocarcinoma was concomitantly diagnosed in a context of dysuria and elevated prostate-specific antigen level. One month after onset of cancer treatment (double hormonotherapy), the patient's impairment started to improve. Subsequently, the muscle denervation signs on EDX disappeared and CSF NfL levels decreased. At last follow-up visit, 2 years after onset, he was asymptomatic and unimpaired. Anti-ankyrin-3 (Ank3) autoantibodies were detected in the CSF by tissue-based immunofluorescence and confirmed by cell-based assay.

Discussion: We herein describe an original case of subacute-onset BAD/FAS with evidence of CSF inflammatory changes, autoantibodies of unknown significance, and simultaneous diagnosis of prostate cancer suggesting a possible paraneoplastic neurological syndrome (PNS). The outcome was remarkably favorable after hormonotherapy. Even in the absence of usual onconeural antibodies, MND may be encountered among PNS, and their prognosis is not always poor.

Background: Autologous chimeric antigen receptor (CAR) T-cell therapy has recently gained interest in the treatment of rheumatic and neuroimmunologic diseases.

Methods: We report a 62-year-old female patient with a 14-year history of treatment-refractory anti-GAD-positive stiff-person syndrome (SPS) and concomitant anti-AChR-positive myasthenia gravis. Despite a relatively stable disease course in the first 8 years, SPS dramatically progressed afterward. In 2023, she was able to walk less than 10-15 m and suffered from severe persistent stiffness in the left arm superimposed with painful muscle spasm attacks (MSAs). Numerous immunotherapies, including intravenous immunoglobulins, plasma exchange, steroids, azathioprine, and rituximab, were ineffective. Consequently, she was escalated to compassionate use of autologous anti-CD19 CAR T-cell therapy (KYV-101).

Results: From the third month post-CAR-T, we observed a substantial improvement in walking distance, pain, anxiety, and MSAs in the arm. By the sixth month, she was able to walk 500 m. The anti-GAD titers declined from 1:320 to 1:32. Side effects included grade 2 cytokine release syndrome and moderate leukopenia, without serious infections.

Discussion: CAR T-cell therapy was effective at mitigating SPS symptoms, despite the long history and severe refractory disease course in our patient. Controlled trials are needed to evaluate its potential in SPS.

Epstein-Barr virus (EBV) is a very common herpesvirus that infects more than 90% of the general population. Epidemiologic data indicate that EBV is a requisite risk factor for the development of multiple sclerosis (MS); however, the mechanisms by which EBV contributes to MS pathogenesis are unclear. In this review, we discuss how EBV alters the functions of B cells, its primary cellular reservoir, and the associated dysregulation of anti-EBV immunity in patients with MS. We comprehensively explore the evidence for different potential mechanisms by which EBV may lead to the development of MS, including the so-called driver and hit-and-run models. Finally, we discuss key outstanding scientific questions that must be addressed to advance not only our understanding of the role of EBV in MS pathology but also the development of novel disease therapies.

Background and objectives: Beta-synuclein (beta-syn), synaptosomal-associated protein 25 (SNAP-25), and neurogranin are CSF biomarkers of synaptic damage, which have been poorly investigated in non-neurodegenerative neurologic diseases. In this study, we examined the diagnostic and prognostic role of these markers compared with the neuroaxonal damage marker neurofilament light chain protein (NfL) in infectious and autoimmune inflammatory neurologic diseases (IINDs and AINDs).

Methods: This cohort study included CSF samples from patients with different etiologies of IIND (varicella-zoster virus, herpes simplex virus, tick-borne meningoencephalitis, bacterial meningitis/(meningo)encephalitis, neuroborreliosis, or other/unknown etiology) or AIND (autoimmune encephalitis or other etiology) as well as controls.

Results: A total of 123 patients with IINDs (mean age 55.23 ± 18.04 years, 43.2% female), 22 with AINDs (age 60.41 ± 16.03 years, 81.8% female), and 95 controls (age 52.39 ± 17.94 years, 56.9% female) were enrolled. Compared with the control group, participants with IINDs and AINDs showed higher concentrations of beta-syn (p < 0.001 and p = 0.038, respectively), neurogranin (p = 0.039 and p = 0.002, respectively), and NfL (p < 0.001 and p = 0.001, respectively), with no differences between the 2 latter groups. Overall, synaptic markers and NfL demonstrated poor-to-moderate diagnostic accuracy in discriminating between diagnostic groups (area under the curve 0.366-0.809). All synaptic biomarkers were elevated in participants with IINDs presenting with altered mental status (beta-syn, p < 0.001; SNAP-25, p = 0.002; and neurogranin, p = 0.008), seizures (beta-syn, p = 0.013; SNAP-25, p = 0.005; and neurogranin, p = 0.004), and inflammatory changes on neuroimaging (beta-syn, p = 0.016; SNAP-25, p = 0.029; and neurogranin, p = 0.007). Participants with AINDs requiring intensive care showed higher levels of beta-syn (p = 0.033) and NfL (p = 0.002). Participants with IINDs with a poor functional status (modified Rankin Scale [mRS] scores of 3-6) exhibited higher concentrations of beta-syn (p < 0.001), SNAP-25 (p = 0.022), neurogranin (p = 0.004), and NfL (p < 0.001) compared with those with mRS scores of 0-2. Accordingly, higher levels of synaptic markers were associated with poorer short-term outcomes in patients with IINDs, but not in those with AINDs.

Discussion: Elevated CSF levels of beta-syn, neurogranin, and NfL may suggest a common pattern of synaptic and neuroaxonal damage in both IINDs and AINDs. Although these biomarkers have limited value in distinguishing between different diseases, they are associated with clinical severity and with short-term outcome, particularly in patients with IINDs.

Background and objectives: Histiocytoses are diverse hematopoietic diseases with disabling neurologic involvement. Recently, targeted mitogen-activated protein kinase pathway inhibitors have been used with clinical and radiologic response; however, some patients are unable to tolerate these treatments or have isolated and/or refractory neurologic, ocular, or head and neck (NOHN) disease. Intra-arterial administration of chemotherapy has conferred favorable responses in various neoplasms; however, treatment and outcomes across histiocytosis subtypes have not been examined.

Methods: Patients with biopsy-proven histiocytosis involving NOHN structures underwent an outpatient interventional procedure with angiography, selective catheterization, and intra-arterial infusion of melphalan, with target arteries depending on the site of disease. Patients were followed with radiologic (i.e., PET/CT, CT, MRI, or ophthalmic ultrasound and optical coherence tomography) and quantified functional assessments (i.e., vision, speech, or balance) as appropriate. Complete or partial radiologic and functional response rates were captured as well as frequency of subsequent progression.

Results: Eighteen patients underwent 74 total treatment instances. For 14 patients with radiologically evaluable tumorous disease, 10 (71%) had partial or complete response and the remaining 4 had stable disease; 3 of 14 (21%) had subsequent radiologic progression. Of 13 functionally evaluable patients, including 6 with neurodegenerative histiocytosis, 12 (92%) experienced functional improvement; 7 of 13 (54%) had subsequent functional worsening consistent with disease progression. There were no intraprocedural complications; 3 patients required hospitalization following treatment, including 1 patient with allergic reaction to melphalan.

Discussion: For patients with tumorous and neurodegenerative histiocytosis, intra-arterial melphalan represents a safe and highly effective treatment with potential to improve neurologic function. Additional study may clarify patients most suitable for this intervention. This novel treatment modality may represent a practice-changing innovation for refractory histiocytosis involving neurologic and ocular structures, as well as neurodegenerative forms. The treatment delivery form is novel, and future work should be directed at studying the efficacy of this modality to other forms of neurologic, ocular, head, and neck cancers.

Classification of evidence: This study provides Class IV evidence that in patients with tumorous or neurodegenerative histiocytosis, selective angiographic catheterization and intra-arterial infusion of melphalan result in radiologic and functional improvement.

Background and objectives: Retinal optical coherence tomography (OCT) in rodent models has been used to longitudinally image retinal changes, to define end points for more costly or time-consuming experiments, and to better understand the pathophysiology underlying OCT findings in human diseases. No standardization of rodent OCT reporting currently exists. Here, we aim to establish consensus recommendation for reporting results from retinal OCT studies in rodents.

Methods: Initial recommendations were developed based on the APOSTEL criteria for quantitative OCT reporting in humans by a core team. Using a modified Delphi process, an expert panel of rodent OCT researchers (N = 31) and the wider scientific community discussed, refined, and voted on these initial recommendations. The list of recommendations was then revised and approved by the expert panel.

Results: The final 7-point checklist includes reporting recommendations regarding the study protocol, OCT device, acquisition settings and modifications, scanning protocol, funduscopic imaging, postacquisition data selection and image data analyses, and qualitative and quantitative results. With a median agreement score of 3 or 4 out of 4, the scientific community agreed with these recommendations. After revisions, the expert panel accepted the final recommendations.

Discussion: The Advised Protocol for OCT Study Terminology and Elements for reporting OCT studies in rodents (APOSTEL-R) originates from an expert consensus. They will provide guidance throughout the experimental process and will contribute to the standardization and quality improvement of preclinical OCT studies.

Background and objectives: Anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis is the most common antibody-mediated encephalitis in adults older than 50 years. In addition to antibody effects, cytokines and chemokines drive neuroinflammation in other autoimmune encephalitides. However, their role in anti-LGI1 encephalitis is underexplored. We evaluated cytokine profiles in serum and CSF, correlating them with acute severity and long-term outcome.

Methods: Cytokine/chemokine levels from 57 untreated patients with anti-LGI1 encephalitis were measured in serum and CSF (34 paired samples) with a bead-based multiplex assay and compared with those of patients with noninflammatory neurologic disorders (serum = 24; CSF = 21). Clinical information including degree of severity (modified Rankin Scale, mRS) and 12-month functional outcomes (resume previous activities and work) was assessed.

Results: Patients with anti-LGI1 encephalitis exhibited an increased proinflammatory profile in CSF and serum, with elevated levels of IL-1β, IL-1RA, IL-6, IL-8, IL-10, IL-18, IL-35, IP-10, granzyme B, CX3CL1, MIG, TNFα, and SDF1. A higher CSF/serum IL-6 ratio correlated with disease severity at onset (mRS score >2: 1.67 [0.50-7.20] vs 0.39 [0.07-1.22], p = 0.0069). Elevated acute-phase serum IL-35 predicted poorer 12-month outcomes (81.34 vs 9.19 pg/mL in partial vs complete recovery, p = 0.0003). Increased B cell-related markers (IL-21, BAFF, APRIL, CXCL13) in CSF (all p < 0.05) were also observed.

Discussion: In this study, we show that the acute-phase IL-6 CSF/serum ratio and serum IL-35 levels in immunotherapy-naive patients with anti-LGI1 encephalitis are associated with disease severity and poor outcomes, respectively, highlighting their potential as biomarkers for risk stratification and therapeutic targeting.

Background and objectives: The aim of this study was to describe the clinical features and long-term outcome of patients with glycine receptor (GlyR) antibody-mediated progressive encephalomyelitis with rigidity and myoclonus (PERM), a disease commonly included under the term of stiff-person spectrum disorders (SPSDs).

Methods: We conducted a retrospective analysis of patients with PERM and GlyR antibodies diagnosed in our laboratory and a systematic literature review (following Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA] 2020 reporting guideline) of previously reported patients with sufficient clinical information and ≥12 months of follow-up. Neurologic disability was measured with the modified Rankin Scale (mRS). Relapses were defined as any event occurring >6 months after the first episode that required immunotherapy.

Results: Forty-one patients were identified, 22 from our database and 19 from the literature. The median age was 58 years (IQR: 43-66 years), and 36 (88%) were male and 5 female. The median time from symptom onset to admission was 2 weeks (IQR: 1-4 weeks). Predominant presentations included brainstem symptoms, mainly dysphagia and trismus, in 23 patients (56%); muscle stiffness and myoclonus in 9 (22%); dysesthesias or pruritus in 7 (17%); and cacosmia with dysgeusia in 2 (5%). Five patients (12%) never developed muscle stiffness. The median (range) mRS score at nadir was 5 (3-5). All patients received immunotherapy. Eleven patients died, 8 from complications of PERM. There were 12 relapses in 10 (28%) of 36 patients who lived >6 months. All relapses responded to immunotherapy. The functional status at the last visit, median time 24 months (IQR: 18-72 months), was good (mRS score <3) in 23 (70%) of the 33 patients who did not die from PERM. Age (HR: 1.06; 95% CI 1.01-1.11; p = 0.019) and admission to the intensive care unit (HR: 5.26; 95% CI 1.41-19.57, p = 0.013) were independent predictors of bad outcome (mRS score ≥3).

Discussion: GlyR antibody-mediated PERM is a rapidly progressive and severe disease that predominantly affects men and frequently presents with brainstem involvement. Its distinct demographic and clinical features suggest that it should be considered separately from SPSDs, which typically follows a chronic course and is more commonly associated with glutamic acid decarboxylase antibodies.