Guido Cammà

Background and ObjectivesAnti–leucine-rich glioma–inactivated 1 encephalitis (LGI1E) is traditionally considered as limbic encephalitis, but emerging evidence characterizes LGI1E as a whole-brain d...

NMDAR and LGI1 encephalitis are the two most common forms of autoimmune encephalitis and are associated with persistent cognitive sequelae, particularly episodic memory impairment. Patients also report lasting difficulties with spatial orientation and navigation, yet these symptoms remain poorly characterized. Both disorders affect neural systems supporting spatial navigation, including prominent hippocampal pathology alongside cingulate, temporo-parietal, thalamic and cerebellar alterations identified in advanced neuroimaging studies. Here, we therefore investigated the frequency and clinical relevance of spatial navigation impairment in post-acute NMDAR and LGI1 encephalitis, its relationship with episodic memory dysfunction, and its structural correlates. We included 80 post-acute patients from the autoimmune encephalitis outpatient clinic at Charité – Universitätsmedizin Berlin: 50 with NMDAR encephalitis (mean age 35.0 years, range 19-71; 90% female; median 6.9 years from onset) and 30 with LGI1 encephalitis (mean age 63.6 years, range 33-84; 67% male; median 2.7 years from onset). Spatial navigation was assessed using a passive map-assisted task (VIENNA Young) and an active wayfinding task (Sea Hero Quest), and its relationship with verbal episodic memory was examined using the Rey Auditory Verbal Learning Test. Structural MRI analyses assessed cortical thickness, subcortical volumes and diffusion measures in preselected navigation- and memory-related regions. Patients with NMDAR and LGI1 encephalitis performed worse than matched controls on map-assisted navigation, and navigation performance showed strong convergence across the two navigation paradigms. Norm-referenced navigation impairment affected 57% of patients with NMDAR encephalitis and 70% with LGI1 encephalitis. In NMDAR encephalitis, selective navigation impairment was more common than selective memory impairment (41% versus 14%; χ ² = 6.26, p = .012), supporting partial dissociation. In LGI1 encephalitis, navigation and memory impairments were similarly frequent and strongly overlapping, with 53% of patients impaired in both domains. Older age was a shared risk factor for navigation impairment. Structurally, NMDAR encephalitis showed partly distinct navigation- and memory-related alteration patterns, with navigation-specific parietal-paracentral and cerebellar abnormalities and memory-specific temporal-hippocampal-thalamic involvement. LGI1 encephalitis showed more widespread, predominantly memory-related alterations without a robust navigation-specific structural signature. Our findings identify spatial navigation as a frequently affected but under-assessed cognitive domain in post-acute NMDAR and LGI1 encephalitis. They provide clinical evidence that navigation and episodic memory are partially dissociable yet overlapping functions whose degree of separability varies with the extent and distribution of network pathology. Incorporating norm-referenced navigation assessment into longitudinal follow-up could improve the characterization of cognitive profiles and related support needs, while reducing the risk that impairments relevant to everyday functioning and long-term quality of life remain undetected.

Anti–seizure-related 6 homolog like 2 (SEZ6L2) antibodies are a rare cause of immune-mediated cerebellar syndromes. The clinical phenotype, diagnostic features, and outcomes have not been systematically synthesized, and the evidence is limited to case reports and case series. We, therefore, aimed to (1) characterize the clinical course and longitudinal brain volumetric changes in a patient with anti-SEZ6L2 syndrome and (2) systematically review the published evidence regarding clinical features, diagnostics, treatment, and outcomes. We performed a single-patient observational study with serial clinical assessments and cross-sectional and longitudinal MRI volumetry and compared the findings with those from age-matched and sex-matched healthy controls. In addition, we conducted a PRISMA-compliant systematic review of MEDLINE and EMBASE from 1964 to December 1, 2025, including published reports of patients with anti-SEZ6L2 antibodies. Data were synthesized descriptively, and because of disease rarity, this case was included in aggregated analyses. A 45-year-old man developed a severe subacute cerebellar syndrome with cognitive, psychiatric, pyramidal, and parkinsonian features. The peak SARA score was 30, and the peak modified Rankin Scale (mRS) score was 5. Despite sequential immunotherapy, only mild improvement occurred and substantial disability persisted. Longitudinal MRI volumetry demonstrated progressive cerebellar atrophy relative to healthy controls, while whole-brain and subcortical volumes remained within normal range. The systematic review identified 21 previously reported patients, yielding 22 including the current case. Cerebellar syndrome was present in all patients; cognitive symptoms were reported in 14 of 22 (64%), parkinsonism in 8 of 22 (36%), and psychiatric symptoms in 6 of 22 (27%). Cerebellar atrophy was reported in 19 of 22 (86%). Two patients had temporally associated tumors. CSF pleocytosis was present in 7 of 21 (33%). The median peak SARA score was 27 (interquartile range [IQR] 23–30; n = 7) and improved to 20 (IQR 18–22), whereas the median mRS score remained 4 at both peak disease and follow-up (n = 11). Among 21 patients with outcome data, 2 (9.5%) died of tumor-related complications, 2 (9.5%) deteriorated neurologically, 8 (38.1%) stabilized, and 9 (42.9%) improved. Anti-SEZ6L2 syndrome is characterized by severe cerebellar dysfunction frequently accompanied by parkinsonism, cognitive, and psychiatric features. This case demonstrated progressive cerebellar atrophy on longitudinal volumetry despite immunotherapy. Our systematic synthesis highlights that noncerebellar manifestations are common, and that substantial long-term disability often persists despite partial improvement in ataxia severity.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by profound fatigue, cognitive impairment, autonomic dysfunction, and exertional intolerance with strongly impaired physical functioning. Hyperbaric oxygen therapy (HBOT) has been proposed as a potential treatment, but its effects on ME/CFS patients remain largely unexplored. This study aimed to evaluate the effectiveness and feasibility of HBOT in ME/CFS patients and to investigate its effects on functional brain changes. Methods: 30 ME/CFS patients (mean age: 42·3 ± 11·7 years; seven males, 23 females) received 40 HBOT sessions each. Outcomes were assessed at baseline, during treatment, and four weeks post-treatment. The primary outcome was change in the Physical Functioning subscale of the Short Form-36 Health Survey (SF-36 PF). Secondary outcomes included severity of core symptoms assessed via questionnaires, exercise capacity, handgrip strength, cognitive per-formance, orthostatic intolerance, and brain MRI (volumetry and functional connectivity, (FC)). Thirty age- and sex-matched healthy controls (HCs) (mean age: 42·3 ± 11·3 years; seven males, 23 females) were included for MRI comparison. Findings: In the linear mixed model, SF-36 PF significantly improved during HBOT compared with baseline (g = 0.71, p = 0.006). SF36 pain (p = 0·002, g = 0·79) and CFQ fatigue showed clinically meaningful reductions (p < 0·001, g = - 0·87) during HBOT. Exercise capacity (g = 0·66), muscle strength (g = 0·40), and information processing speed (g = 0·52), all improved significantly after HBOT compared to baseline (all p < 0·05). Treatment adherence was high, and tolerability was favorable, with no major side effects reported. Functional MRI analyses revealed increased thalamic FC in ME/CFS patients compared to HCs in bilateral sensorimotor (p < 0·001, t = 5·65, FDR-corrected) and visuo-occipital regions (p < 0·001, t = 5·4, FDR-corrected) at baseline. After HBOT, thalamic hyperconnectivity normalized. Responders (defined as a ≥ 10 point increase in SF-36 PF) showed greater reductions in thalamic hyperconnectivity than non-responders (p < 0·001, t = - 4·34 to -5·18, FDR-corrected). Interpretation: HBOT was well-tolerated and was associated with significant improvements in physical functioning, fatigue, pain, and cognitive performance and provides the rationale for a controlled trial in ME/CFS to confirm thera-peutic efficacy. The normalization of thalamic hyperconnectivity following HBOT and its association with clinical re-sponse highlights the role of thalamic FC in ME/CFS pathophysiology and underscores the need for larger, controlled trials in ME/CFS to confirm therapeutic efficacy.

BACKGROUND: White matter hyperintensities (WMH) are associated with cognitive dysfunction after ischemic stroke. Yet, uncertainty remains about affected domains, the role of other preexisting brain injury, and infarct types in the relation between WMH burden and poststroke cognition. We aimed to disentangle these factors in a large sample of patients with ischemic stroke from different cohorts. METHODS: We pooled and harmonized individual patient data (n=1568) from 9 cohorts, through the Meta VCI Map consortium ( www.metavcimap.org ). Included cohorts comprised patients with available magnetic resonance imaging and multidomain cognitive assessment Z scores; attention and executive functioning, processing speed, language and verbal memory) for the total sample and stratified by infarct type. Preexisting brain injury was accounted for in the multivariable models and all analyses were corrected for the study site as a random effect. RESULTS: In the total sample (67 years [SD, 11.5], 40% female), we found a dose-dependent inverse relationship between WMH volume and poststroke cognitive functioning across all 4 cognitive domains (coefficients ranging from −0.09 [SE, 0.04, P =0.01] for verbal memory to −0.19 [SE, 0.03, P <0.001] for attention and executive functioning). This relation was independent of acute infarct volume and the presence of lacunes and old infarcts. In stratified analyses, the relation between WMH volume and domain-specific functioning was also largely independent of infarct type. CONCLUSIONS: In patients with ischemic stroke, increasing WMH volume is independently associated with worse cognitive functioning across all major domains, regardless of old ischemic lesions and infarct type.