Neurophysiologic Monitoring of Oculomotor Nerves During Transorbital Surgery: Proof of Concept and Anatomic Demonstration.

BACKGROUND AND OBJECTIVES: Transorbital neuroendoscopic surgery (TONES) is continuously evolving and gaining terrain in approaching different skull base pathologies. The objective of this study was to present our methodology for introducing recording electrodes, which includes a new transconjunctival pathway, to monitor the extraocular muscle function during TONES. METHODS: A translational observational study was performed from an anatomic demonstration focused on the transconjunctival electrode placement technique to a descriptive analysis in our series of 6 patients operated using TONES in association with intraoperative neurophysiologic monitoring of the oculomotor nerves from 2017 to 2023. The stepwise anatomic demonstration for the electrode placement and correct positioning in the target muscle was realized through cadaveric dissection. The descriptive analysis evaluated viability (obtention of the electromyography in each cranial nerve [CN] monitored), security (complications), and compatibility (interference with TONES). RESULTS: In our series of 6 patients, 16 CNs were correctly monitored: 6 (100%) CNs III, 5 (83.3%) CNs VI, and 5 (83.3%) CNs IV. Spontaneous electromyography was registered correctly, and compound muscle action potential using triggered electromyography was obtained for anatomic confirmation of structures (1 CN III and VI). No complications nor interference with the surgical procedure were detected. CONCLUSION: The methodology for introducing the recording electrodes was viable, secure, and compatible with TONES.

Mitochondrial DNA deletions in the cerebrospinal fluid of patients with idiopathic REM sleep behaviour disorder.

BACKGROUND: Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) represents the prodromal stage of Lewy body disorders (Parkinson's disease (PD) and dementia with Lewy bodies (DLB)) which are linked to variations in circulating cell-free mitochondrial DNA (cf-mtDNA). Here, we assessed whether altered cf-mtDNA release and integrity are already present in IRBD. METHODS: We used multiplex digital PCR (dPCR) to quantify cf-mtDNA copies and deletion ratio in cerebrospinal fluid (CSF) and serum in a cohort of 71 participants, including 1) 17 patients with IRBD who remained disease-free (non-converters), 2) 34 patients initially diagnosed with IRBD who later developed either PD or DLB (converters), and 3) 20 age-matched controls without IRBD or Parkinsonism. In addition, we investigated whether CD9-positive extracellular vesicles (CD9-EVs) from CSF and serum samples contained cf-mtDNA. FINDINGS: Patients with IRBD, both converters and non-converters, exhibited more cf-mtDNA with deletions in the CSF than controls. This finding was confirmed in CD9-EVs. The high levels of deleted cf-mtDNA in CSF corresponded to a significant decrease in cf-mtDNA copies in CD9-EVs in both IRBD non-converters and converters. Conversely, a significant increase in cf-mtDNA copies was found in serum and CD9-EVs from the serum of patients with IRBD who later converted to a Lewy body disorder. INTERPRETATION: Alterations in cf-mtDNA copy number and deletion ratio known to occur in Lewy body disorders are already present in IRBD and are not a consequence of Lewy body disease conversion. This suggests that mtDNA dysfunction is a primary molecular mechanism of the pathophysiological cascade that precedes the full clinical motor and cognitive manifestation of Lewy body disorders. FUNDING: Funded by Michael J. Fox Foundation research grant MJFF-001111. Funded by MICIU/AEI/10.13039/501100011033 "ERDF A way of making Europe", grants PID2020-115091RB-I00 (RT) and PID2022-143279OB-I00 (ACo). Funded by Instituto de Salud Carlos III and European Union NextGenerationEU/PRTR, grant PMP22/00100 (RT and ACo). Funded by AGAUR/Generalitat de Catalunya, grant SGR00490 (RT and ACo). MP has an FPI fellowship, PRE2018-083297, funded by MICIU/AEI/10.13039/501100011033 "ESF Investing in your future".

Presynaptic Dopaminergic Imaging Characterizes Patients with REM Sleep Behavior Disorder Due to Synucleinopathy.

OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024.

Neurological, psychiatric, and sleep investigations after treatment of anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis in Spain: a prospective cohort study.

BACKGROUND: Anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis is an autoimmune disorder that can be treated with immunotherapy, but the symptoms that remain after treatment have not been well described. We aimed to characterise the clinical features of patients with anti-LGI1 encephalitis for 1 year starting within the first year after initial immunotherapy. METHODS: For this prospective cohort study, we recruited patients with anti-LGI1 encephalitis as soon as possible after they had received conventional immunotherapy for initial symptoms; patients were recruited from 21 hospitals in Spain. Patients were excluded if they had an interval of more than 1 year since initial immunotherapy, had pre-existing neurodegenerative or psychiatric disorders, or were unable to travel to Hospital Clínic de Barcelona (Barcelona, Spain). Patients visited Hospital Clínic de Barcelona on three occasions-the first at study entry (visit 1), the second 6 months later (visit 2), and the third 12 months after the initial visit (visit 3). They underwent neuropsychiatric and videopolysomnography assessments at each visit. Healthy participants who were matched for age and sex and recruited from Hospital Clínic de Barcelona underwent the same investigations at study entry and at 12 months. Cross-sectional comparisons of clinical features between groups were done with conditional logistic regression, and binary logistic regression was used to assess associations between cognitive outcomes at 12 months and clinical features before initial immunotherapy and at study entry. FINDINGS: Between May 1, 2019, and Sept 30, 2022, 42 participants agreed to be included in this study. 24 (57%) participants had anti-LGI1 encephalitis (mean age 63 years [SD 12]; 13 [54%] were female and 11 [46%] were male) and 18 (43%) were healthy individuals (mean age 62 years [10]; 11 [61%] were female and seven [39%] were male). At visit 1 (median 88 days [IQR 67-155] from initiation of immunotherapy), all 24 patients had one or more symptoms; 20 (83%) patients had cognitive deficits, 20 (83%) had psychiatric symptoms, 14 (58%) had insomnia, 12 (50%) had rapid eye movement (REM)-sleep behaviour disorder, nine (38%) had faciobrachial dystonic seizures, and seven (29%) had focal onset seizures. Faciobrachial dystonic seizures were unnoticed in four (17%) of 24 patients and focal onset seizures were unnoticed in five (21%) patients. At visit 1, videopolysomnography showed that 19 (79%) patients, but no healthy participants, had disrupted sleep structure (p=0·013); 15 (63%) patients and four (22%) healthy participants had excessive fragmentary myoclonus (p=0·039), and nine (38%) patients, but no healthy participants, had myokymic discharges (p=0·0051). These clinical and videopolysomnographic features led to additional immunotherapy in 15 (63%) of 24 patients, which resulted in improvement of these features in all 15 individuals. However, at visit 3, 13 (65%) of 20 patients continued to have cognitive deficits. Persistent cognitive deficits at visit 3 were associated with no use of rituximab before visit 1 (odds ratio [OR] 4·0, 95% CI 1·5-10·7; p=0·0015), REM sleep without atonia at visit 1 (2·2, 1·2-4·2; p=0·043), and presence of LGI1 antibodies in serum at visit 1 (11·0, 1·1-106·4; p=0·038). INTERPRETATION: Unsuspected but ongoing clinical and videopolysomnography alterations are common in patients with anti-LGI1 encephalitis during the first year or more after initial immunotherapy. Recognising these alterations is important as they are treatable, can be used as outcome measures in clinical trials, and might influence cognitive outcome. FUNDING: Fundació La Caixa.

Is REM Sleep Behavior Disorder Changing? Secular Changes Versus Referral Patterns.

Background: Since 2014, there has been increasing public outreach effort regarding isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) in Montreal. Objective: To assess if, over time, milder iRBD cases are presenting earlier. Methods: Disease-free survival was compared in two iRBD recruitment epochs: 2004 to 2013 ("earlier") versus 2014to 2022 ("later") and by referral type ("self-referral" vs. "conventional-referral") in three large centers. Results: In Montreal, among 209 subjects followed prospectively, shorter time to phenoconversion was observed in the earlier epoch (5-year phenoconversion = 42% earlier vs. 23% later); diagnosis before 2014 had a 1.8-fold phenoconversion hazard. However, no difference was observed in 248 subjects from Barcelona and 166 from Innsbruck. Analysis of Montreal data found that increased survival in the later epoch was driven by an increasing number of self-referrals, who phenoconverted at 1/3 the rate of physician-referred subjects. Conclusions: Increased patient awareness of iRBD results in earlier presentation to clinical attention, with a longer time to phenoconversion.

Prior exposure to concussions in patients with isolated REM sleep behavior disorder.

OBJECTIVE: Traumatic brain injury is associated with the late development of neurodegenerative diseases such as the synucleinopathies. Isolated REM sleep behavior disorder (IRBD) constitutes an early manifestation of the synucleinopathies. We assessed whether lifetime history of concussive episodes is common in IRBD and examined its characteristics and clinical significance. METHODS: Prior exposure to concussions was evaluated by interviewing polysomnographically-confirmed IRBD patients and controls without IRBD, and by the BRAIN-Q questionnaire. RESULTS: We recruited 199 IRBD patients aged 73.2 ± 7.7 years and 168 age and sex matched controls. Previous history of concussion was more common in patients than in controls (21.1% versus 10.1%, p = 0.004). In patients, concussions occurred at the age of 24.7 ± 20.6 years. The interval between concussion and IRBD diagnosis was 43.0 ± 19.0 years. There were no differences between patients and controls in the causes of concussions (e.g., traffic accidents, sport practice), and number of events resulting in skull fractures, urgent medical assistance, and hospitalization. After a follow-up of 5.7 ± 4.7 years from IRBD diagnosis, 21.1% patients developed an overt synucleinopathy with an interval of 49.3 ± 24.2 years between concussion and synucleinopathy diagnosis. The risk to develop a synucleinopathy was similar between patients with and without concussions (p = 0.57). CONCLUSIONS: Previous history of concussion is common in IRBD. Our observations may suggest that in individuals with increased susceptibility, early-life concussions may trigger a slow neurodegenerative process leading four decades later to IRBD. This study highlights the need for head injury prevention, particularly in early life.

Scoring sleep in neurodegenerative diseases: A pilot study in the synucleinopathies.

BACKGROUND: Neurodegenerative diseases often alter sleep architecture, complicating the application of the standard sleep scoring rules. There are no recommendations to overcome this problem. Our aim was to develop a scoring method that incorporates the stages previously applied in dementia with Lewy Bodies (DLB), anti-IgLON5 disease, and fatal insomnia, and to test it in patients with alpha-synucleinopathies. METHODS: Video-polysomnographies (VPSG) of nine patients (DLB:3, Parkinson's disease (PD):3, and multiple system atrophy (MSA):3) selected for their difficulty in applying standard rules were scored independently by two authors, using additional Sleep/Wake stages. These included Abnormal Wake, Subwake, Undifferentiated NREM sleep (UNREM), Poorly structured N2 (P-S N2) and abnormal REM sleep including REM without atonia (RWA), REM without low-amplitude, mixed-frequency EEG activity (RWL) and REM without rapid eye movements (RWR). RESULTS: Patients (4 females) had a median age of 74 (range 63-85). Six patients (all with PD or DLB) had abnormal EEG awake and Subwake stage. UNREM sleep was present in all patients, typically at sleep onset, and was the most common sleep stage in five. P-S N2 was recorded only in the three patients with MSA. Periods of normal and abnormal NREM coexisted in three patients. RWA was the predominant REM subtype, RWR occurred mainly in patients with MSA and RWL in those with DLB. Six patients had brief REM episodes into NREM sleep which we termed "Encapsulated RBD". CONCLUSION: Our scoring system allows an accurate description of the complex sleep-wake changes in patients with alpha-synucleinopathies.

Peripheral α-synuclein isoforms are potential biomarkers for diagnosis and prognosis of isolated REM sleep behavior disorder.

INTRODUCTION: Isolated REM sleep behavior disorder (IRBD) represents an early manifestation of the synucleinopathies Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Aggregation of abnormal α-synuclein and its increased expression in the brain is crucial in the development of the synucleinopathies. Whereas α-synuclein gene (SNCA) transcripts are overexpressed in brain, a concomitant reduction occurs in blood of DLB patients. We assessed whether this decrease is also detectable in IRBD. METHODS: 108 IRBD patients and 149 controls were included of which 29 IRBD and 32 control cases were available for expression studies. Expression of SNCAtv1, SNCAtv2, SNCAtv3 and SNCA126 isoforms, and GBA were determined by real-time PCR. Genotype distribution of SNCA SNPs, rs356219 and rs2736990, and correlation with SNCA expression was analyzed. RESULTS: Expression of all SNCA transcripts was reduced in IRBD blood whereas GBA expression did not change. SNCAtv3 expression correlated inversely with IRBD duration, being lower in patients with longer follow-up. Rs356219-AA genotype frequency was increased in IRBD patients who later developed PD and DLB. Rs2736990-CC frequency was increased among IRBD cases who remained disease-free. No correlation was observed between rs356219 and rs2736990 genotypes and SNCA transcript levels. CONCLUSION: SNCA transcript expression is decreased in blood in IRBD, and levels decrease with IRBD duration. Our findings indicate that changes in SNCA expression occur in the earliest stages of the synucleinopathies before motor and cognitive symptoms become apparent.

Sleep in Gerstmann-Straüssler-Scheinker disease.

BACKGROUND: Gerstmann-Sträussler-Scheinker (GSS) is a rare prion disease with heterogeneous clinical presentation. Although sleep-related abnormalities are prominent and well-known in other prion diseases such as fatal familial insomnia and Creutzfeldt-Jakob disease, information on sleep is limited in GSS. METHODS: We evaluated sleep in three genetically confirmed GSS cases using clinical history, sleep scales and video-polysomnography. In addition, patients underwent neurological assessment, neurological scales, neuropsychological testing, lumbar puncture, brain MRI and brain 18F-FDG-PET. RESULTS: Two patients reported sleep maintenance insomnia attributed to leg stiffness and back pain while the remaining patient did not report sleep problems. Video-polysomnography showed normal sleep staging in all of them. Findings such as reduced sleep efficiency in two patients, a confusional arousal in one patient, obstructive apneas in one patient, and periodic legs movements in sleep in two patients were observed. CONCLUSIONS: In contrast to fatal familial insomnia, the normal sleep staging in GSS may suggest dissimilar involvement of the neuronal structures that regulate sleep. We found non-specific sleep alterations in GSS such as obstructive apneas and periodic leg movements in sleep which are of unknown origin and of uncertain clinical relevance. Studies including a larger number of patients, serial sleep evaluations and incorporating neuropathological assessment will further help to understand sleep in GSS.

Former participation in professional football as an occupation in patients with isolated REM sleep behavior disorder leading to a synucleinopathy: a case-control study.

BACKGROUND: Contact sports such as football are associated with late development of neurodegenerative diseases, in part due to the deleterious effect of repetitive head impacts during participation. Isolated REM sleep behavior disorder (IRBD) represents an early manifestation of neurodegenerative diseases including Parkinson disease (RBD) and dementia with Lewy bodies (DLB). We hypothesized that former professional football participation would be overrepresented in IRBD. OBJECTIVE: To assess former participation in professional football as an occupation in IRBD. METHODS: In a case-control retrospective study, having played football as a professional occupation in the Spanish Football Professional Leagues was examined interviewing polysomnographically confirmed IRBD patients and matched controls without IRBD. RESULTS: Among 228 Caucasian Spanish IRBD patients with 68.5 ± 7.2 years, six (2.63%) were retired professional footballers. Length professional football career ranged between 11 and 16 years. Interval between football retirement and IRBD diagnosis was 39.5 ± 6.4 years. At IRBD diagnosis, the six footballers had synucleinopathy biomarkers including pathologic synuclein in the CSF and tissues, nigrostriatal dopaminergic deficit and hyposmia. Follow-up showed that three footballers developed PD and two DLB. None of the controls was a professional footballer. The percentage of professional footballers was higher in IRBD patients than in controls (2.63% versus 0.00%; p = 0.030) and among the general Spanish population (2.63% versus 0.62%; p < 0.0001). CONCLUSION: We found an overrepresentation of former professional footballers in IRBD patients who later developed PD and DLB after four decades from professional retirement. In professional footballers the development of a neurodegenerative disease may be first manifested by IRBD. Screening for IRBD in former footballers might identify individuals with underlying synucleinopathies. Further studies with larger samples are needed to confirm our observations.

Misfolded α-Synuclein Assessment in the Skin and CSF by RT-QuIC in Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Real-time quaking-induced conversion (RT-QuIC) assay detects misfolded α-synuclein (AS) in the skin and CSF of patients with the synucleinopathies Parkinson disease and dementia with Lewy bodies. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of these synucleinopathies. We aimed to compare the ability of RT-QuIC to identify AS in the skin and CSF of patients with IRBD. METHODS: This was a cross-sectional study where consecutive patients with polysomnographic-confirmed IRBD and age-matched controls without RBD underwent skin biopsy and lumbar puncture the same day. Three-millimeter skin punch biopsies were obtained bilaterally in the cervical region from dorsal C7 and C8 dermatomes and in distal legs. RT-QuIC assessed AS in these 6 skin sites and the CSF. RESULTS: We recruited 91 patients with IRBD and 41 controls. In the skin, sensitivity to detect AS was 76.9% (95% CI 66.9-85.1), specificity 97.6% (95% CI 87.1-99.9) positive predictive value 98.6% (95% CI 91.0-99.8), negative predictive value 65.6% (95% CI 56.6-73.6), and accuracy 83.3% (95% CI 75.9-89.3). In the CSF, the sensitivity was 75.0% (95% CI 64.6-83.6), the specificity was 97.5% (95% CI 86.8-99.9), the positive predictive value was 98.5% (95% CI 90.5-99.8), the negative predictive value was 63.9% (95% CI 55.2-71.9), and the accuracy was 82.0% (95% CI 74.3-88.3). Results in the skin and CSF samples showed 99.2% agreement. Compared with negative patients, RT-QuIC AS-positive patients had a higher likelihood ratio of prodromal Parkinson disease (p < 0.001) and showed more frequently hyposmia (p < 0.001), dopamine transporter imaging single-photon emission CT deficit (p = 0.002), and orthostatic hypotension (p = 0.014). No severe or moderate adverse effects were reported. There was no difference between the percentage of participants reporting mild adverse events secondary to skin biopsy or lumbar puncture (9.1% vs 17.2%; p = 0.053). One hundred and ten (83%) and 104 (80%) participants, respectively, stated they would accept to undergo skin biopsy and lumbar puncture again for research purposes. DISCUSSION: Our study in IRBD shows that (1) RT-QuIC detects AS in the skin and CSF with similar high sensitivity, specificity, and agreement, (2) AS RT-QuIC positivity is associated with supportive features and biomarkers of synucleinopathy, and (3) skin punch biopsy and lumbar puncture have comparable mild adverse effects, tolerance, and acceptance. RT-QuIC in the skin or CSF might represent a patient selection strategy for future neuroprotective trials targeting AS in IRBD. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that RT-QuIC-detected AS in the skin and CSF distinguishes patients with IRBD from controls.

Sleep architecture and sleep-disordered breathing in fatal insomnia.

STUDY OBJECTIVES: Fatal insomnia (FI) is a rare prion disease severely affecting sleep architecture. Breathing during sleep has not been systematically assessed. Our aim was to characterize the sleep architecture, respiratory patterns, and neuropathologic findings in FI. METHODS: Eleven consecutive FI patients (ten familial, one sporadic) were examined with video-polysomnography (vPSG) between 2002 and 2017. Wake/sleep stages and respiration were evaluated using a modified scoring system. Postmortem neuropathology was assessed in seven patients. RESULTS: Median age at onset was 48 years and survival after vPSG was 1 year. All patients had different combinations of breathing disturbances including increased respiratory rate variability (RRV; n = 7), stridor (n = 9), central sleep apnea (CSA) (n = 5), hiccup (n = 6), catathrenia (n = 7), and other expiratory sounds (n = 10). RRV in NREM sleep correlated with ambiguous and solitary nuclei degeneration (r = 0.9, p = 0.008) and reduced survival (r = -0.7, p = 0.037). Two new stages, Subwake1 and Subwake2, present in all patients, were characterized. NREM sleep (conventional or undifferentiated) was identifiable in ten patients but reduced in duration in eight. REM sleep occurred in short segments in nine patients, and their reduced duration correlated with medullary raphe nuclei degeneration (r = -0.9, p = 0.005). Seven patients had REM without atonia. Three vPSG patterns were identified: agitated, with aperiodic, manipulative, and finalistic movements (n = 4); quiet-apneic, with CSA (n = 4); and quiet-non-apneic (n = 3). CONCLUSIONS: FI patients show frequent breathing alterations, associated with respiratory nuclei damage, and, in addition to NREM sleep distortion, have severe impairment of REM sleep, related with raphe nuclei degeneration. Brainstem impairment is crucial in FI.

Clinical characterisation of patients in the post-acute stage of anti-NMDA receptor encephalitis: a prospective cohort study and comparison with patients with schizophrenia spectrum disorders.

BACKGROUND: Anti-NMDA receptor (NMDAR) encephalitis is associated with a post-acute stage that is not well known. We aimed to describe the clinical features of this stage, similarities with schizophrenia spectrum disorders, and the factors that predict cognitive-psychiatric outcomes and could serve as prognostic biomarkers. METHODS: In this prospective cohort study, participants (aged 12-60 years) with anti-NMDAR encephalitis during the post-acute stage visited Hospital Clínic de Barcelona (Barcelona, Spain) on three occasions (at study entry [V1], at 6 months [V2], and at 12 months [V3]) and underwent comprehensive neuropsychiatric evaluations. Similar evaluations were done in a group of age-matched participants with schizophrenia spectrum disorders and a group of age-matched and sex-matched healthy participants also recruited from Hospital Clínic de Barcelona. We analysed differences between and within groups in the longitudinal follow-up using multilevel linear mixed-effect models, adjusting for group, age, sex, and socioeconomic status to control for possible confounding. FINDINGS: Between Jan 1, 2017, and Sept 30, 2020, 82 participants were recruited, 28 (34%) with anti-NMDAR encephalitis, 27 (33%) with schizophrenia spectrum disorders, and 27 (33%) healthy participants. Although, by V1 (median 4 months [IQR 3-7] from disease onset), many acute-stage symptoms in participants with anti-NMDAR encephalitis had resolved (acute stage median modified Rankin Scale [mRS] score 5 [IQR 4-5] vs V1 mRS score 2 [1-2]; p<0·0001), 25 (89%) participants showed deficits in at least one cognitive domain. In this group, 15 (68%) of 22 cognitive domain variables were impaired at V1, whereas only eight (36%) were altered at V3 (p=0·016). In participants with schizophrenia spectrum disorders, 11 (50%) of 22 variables (all shared with participants with anti-NMDAR encephalitis) were impaired at V1, without changes at V3. Two acute-stage features of anti-NMDAR encephalitis (ie, decreased consciousness and no improvement within the first 4 weeks of treatment) predicted cognitive domain outcomes, and a visuospatial task (ie, serial biases) at V1 showed potential in predicting learning and memory outcomes. At V1, all psychiatric symptom clusters were similarly altered in participants with anti-NMDAR encephalitis and in those with schizophrenia spectrum disorders, but only those in individuals with anti-NMDAR encephalitis subsequently improved (p=0·031). The greatest cognitive-psychiatric improvement in participants with anti-NMDAR encephalitis occurred between V1 and V2. During this interval, four (14%) participants with anti-NMDAR encephalitis would have met the diagnostic criteria of schizophrenia if CSF antibody findings had not been investigated. INTERPRETATION: The cognitive-psychiatric symptoms of anti-NMDAR encephalitis in the post-acute stage resembled those of stabilised schizophrenia, but only those in participants with anti-NMDAR encephalitis progressively improved, predominantly during V1-V2. These findings are important for clinical trials on anti-NMDAR encephalitis and suggest that prompt cognitive-psychosocial rehabilitation might be a valuable intervention. FUNDING: Instituto Salud Carlos III, NEURON Network of European Funding for Neuroscience Research, National Alliance for Research in Schizophrenia and Affective Disorders, and la Caixa Health-Research Foundation.

Neurofilament Light Chain Levels in Anti-NMDAR Encephalitis and Primary Psychiatric Psychosis.

BACKGROUND AND OBJECTIVES: An important challenge in diagnosing anti-NMDA receptor (NMDAR) encephalitis (NMDARe) is differentiating it from a first episode of psychosis (FEP) caused by a psychiatric disease (pFEP). CSF antibody testing distinguishes these diseases, but spinal taps are difficult to obtain in psychiatric facilities. A separate problem is the lack of biomarkers of NMDARe severity and outcome. Here we assessed the performance of neurofilament light chain (NfL) testing in these settings. METHODS: In this observational study, NfL levels were determined with single-molecule array in patients with NMDARe, pFEP, herpes simplex encephalitis (HSE), and healthy participants (HC), with the last 2 groups used as controls. Receiver operating characteristic (ROC) analyses were performed to assess the prediction accuracy of serum NfL (sNfL) levels for NMDARe and pFEP and to obtain clinically useful cutoffs. RESULTS: One hundred eighteen patients with NMDARe (33 with isolated psychosis at presentation), 45 with pFEP, 36 with HSE, and 36 HC were studied. Patients with NMDARe with seizures/status epilepticus, intensive care unit admission, and CSF pleocytosis (>20 white blood cells/µL) and without early immunotherapy were more likely to have higher NfL (mainly in CSF) than individuals with NMDARe without these features. NfL levels at diagnosis of NMDARe did not correlate with outcome at 1-year follow-up assessed with the modified Rankin Scale. Patients with NMDARe had significantly higher sNfL than individuals with pFEP and HC and lower sNfL than patients with HSE. ROC analysis of sNfL between NMDARe with isolated psychosis and pFEP provided an area under the curve of 0.93 (95% CI 0.87-0.99) and an sNfL cutoff ≥15 pg/mL to distinguish these disorders (sensitivity 85%, specificity 96%, positive likelihood ratio 19.3). Forty-three of 45 (96%) patients with pFEP had sNfL<15 pg/mL, whereas only 5 of 33 (15%) with NMDARe with isolated psychosis were below this cutoff (risk estimation NMDARe vs pFEP: odds ratio 120.4 [95% CI 21.8-664], p < 0.001). None of the patients with HSE and 35 of 36 (97%) HC had sNfL<15 pg/mL. DISCUSSION: NfL measured at diagnosis of NMDARe associated with features of disease severity but not with long-term outcome. Young patients with FEP and sNfL ≥15 pg/mL had a 120 times higher chance of having NMDARe than those with pFEP. This cutoff correctly classified 96% of patients with pFEP and 85% of patients with NMDARe with isolated psychosis. Patients with FEP of unclear etiology and sNfL ≥15 pg/mL should undergo CSF NMDAR antibody testing.

Thymoma and Autoimmune Encephalitis: Clinical Manifestations and Antibodies.

OBJECTIVE: To report the clinical, neuroimaging, and antibody associations in patients with autoimmune encephalitis (AE) and thymoma. METHODS: A retrospective cohort study of 43 patients was conducted. Antibody determination and immunoprecipitation to characterize novel antigens were performed using reported techniques. RESULTS: Patients' median age was 52 years (range: 23-88 years). Forty (93%) had neuronal surface antibodies: gamma-aminobutyric acid receptor A (GABAAR) (15), amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) (13), contactin-associated protein-like 2 (CASPR2) (4), leucine-rich, glioma inactivated 1 (LGI1) (3), glycine receptor (GlyR) (3), and unknown antigens (2). Concurrent antibodies against intracellular antigens occurred in 13 (30%; 9 anti-collapsin response mediator protein 5 [CRMP5]) and were more frequent in anti-AMPAR encephalitis (54% vs 20%; p = 0.037). The most common clinical presentation was encephalitis with multiple T2/fluid-attenuated inversion recovery hyperintense lesions in 23 (53%) patients (15 GABAAR, 5 AMPAR, and 1 unknown neuropil antibody), followed by encephalitis with peripheral nerve hyperexcitability in 7 (16%; 4 CASPR2, 2 LGI1, and 1 unknown antibody), limbic encephalitis in 6 (14%; 4 AMPAR, 1 LGI1, and 1 antibody negative), progressive encephalomyelitis with rigidity and myoclonus in 4 (9%; 3 GlyR and 1 AMPAR antibodies), and encephalitis with normal MRI in 3 (7%; AMPAR antibodies). Anti-GABAAR encephalitis was more prevalent in Japanese patients compared with Caucasians and other ethnicities (61% vs 16%; p = 0.003). In anti-AMPAR encephalitis, 3/4 patients with poor and 0/6 with good outcome had concurrent CRMP5 antibodies (p = 0.033). Immunoprecipitation studies identified metabotropic glutamate receptor 3 antibodies that were additionally found in 5 patients (3 with and 2 without encephalitis). CONCLUSIONS: AE in patients with thymoma include several clinical-radiologic syndromes that vary according to the associated antibodies. Anti-GABAAR encephalitis was the most frequent AE and occurred more frequently in Japanese patients.

Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score.

OBJECTIVE: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing. METHODS: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic. RESULTS: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2-18). Twenty patients (3.4%) had AES, of whom 3 had anti-leucine-rich glioma inactivated 1, 3 had anti-contactin-associated protein-like 2, 1 had anti-N-methyl-D-aspartate receptor, and 13 had anti-glutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% confidence interval [CI] = 19.6-3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1-56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2-49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1-56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4-382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0-46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥ 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%. INTERPRETATION: Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021;89:698-710.

Stridor during sleep: description of 81 consecutive cases diagnosed in a tertiary sleep disorders center.

STUDY OBJECTIVES: To describe the characteristics of stridor during sleep (SDS) in a series of adults identified by video-polysomnography (V-PSG). METHODS: Retrospective clinical, V-PSG, laryngoscopic, and therapeutic data of patients diagnosed with SDS in a tertiary referral sleep disorders center between 1997 and 2017. RESULTS: A total of 81 patients were identified (56.8% males, age 61.8 ± 11.2 years). Related etiologies were multiple system atrophy (MSA), amyotrophic lateral sclerosis, spinocerebellar ataxia type 1, anti-IgLON5 disease, fatal familial insomnia, brainstem structural lesions, vagus nerve stimulation, recurrent laryngeal nerve injury, the effect of radiotherapy on the vocal cords, cervical osteophytes, and others. Stridor during wakefulness coexisted in 13 (16%) patients and in MSA was only seen in the parkinsonian form. Laryngoscopy during wakefulness in 72 (88.9%) subjects documented vocal cord abductor impairment in 65 (90.3%) and extrinsic lesions narrowing the glottis in 2 (2.4%). The mean apnea-hypopnea index (AHI) was 21.4 ± 18.6 and CT90 was 11.5 ± 19.1. Obstructive AHI > 10 occurred in 52 (64.2%) patients and central apnea index >10 in 2 (2.4%). CPAP abolished SDS, obstructive apneic events and oxyhemoglobin desaturations in 58 of 60 (96.7%) titrated patients with optimal pressure of 9.0 ± 2.3 cm H20. Tracheostomy in 19 (23.4%) and cordotomy in 3 (3.7%) subjects also eliminated SDS. CONCLUSIONS: SDS in adults is linked to conditions that damage the brainstem, recurrent laryngeal nerve, and vocal cords. V-PSG frequently detects obstructive sleep apnea and laryngoscopy usually shows vocal cord abductor dysfunction. CPAP, tracheostomy, and laryngeal surgery abolish SDS.

Magnetic resonance imaging abnormalities as a marker of multiple system atrophy in isolated rapid eye movement sleep behavior disorder.

STUDY OBJECTIVES: Patients with isolated rapid eye movement (REM) sleep behavior disorder (IRBD) develop Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). Magnetic resonance imaging (MRI) is abnormal in MSA showing abnormalities in the putamen, cerebellum, and brainstem. Our objective was to evaluate the usefulness of MRI to detect MRI abnormalities in IRBD and predict development of MSA and not PD and DLB. METHODS: In IRBD patients that eventually developed PD, DLB, and MSA, we looked for the specific structural MRI abnormalities described in manifest MSA (e.g. hot cross-bun sign, putaminal rim, and cerebellar atrophy). We compared the frequency of these MRI changes among groups of converters (PD, DLB, and MSA) and analyzed their ability to predict development of MSA. The clinical and radiological features of the IRBD patients that eventually converted to MSA are described in detail. RESULTS: A total of 61 IRBD patients who underwent MRI phenoconverted to PD (n = 30), DLB (n = 26), and MSA (n = 5) after a median follow-up of 2.4 years from neuroimaging. MRI changes typical of MSA were found in four of the five (80%) patients who converted to MSA and in three of the 56 (5.4%) patients who developed PD or DLB. MRI changes of MSA had sensitivity of 80.0%, specificity of 94.6%, positive likelihood ratio of 14.9 (95% CI 4.6-48.8), and negative likelihood ratio of 0.2 (95% CI 0.04-1.2) to predict MSA. CONCLUSIONS: In IRBD, conventional brain MRI is helpful to predict conversion to MSA. The specific MRI abnormalities of manifest MSA may be detected in its premotor stage.

Sleep disorders in autoimmune encephalitis.

Sleep disorders in people with autoimmune encephalitis have received little attention, probably overshadowed by the presence of other neurological and psychiatric symptoms in this group of conditions. However, sleep disorders are frequent, often severe, and usually persist beyond the acute disease stage, interfering with patients' recovery and quality of life. Because autoimmune encephalitis can affect any brain network involved in sleep initiation and regulation, all types of sleep disorders can occur, with varying distinct associations, frequency, and intensity. Anti-IgLON5 and anti-NMDA receptor encephalitis exemplify two diseases in which sleep disorders are prominent. In anti-IgLON5 disease, sleep disorders were the core symptoms that led to the description of this disease, whereas in anti-NMDA receptor encephalitis, sleep disorders vary according to the disease stage along with other neuropsychiatric symptoms. Comprehensive, systematic, multicentre studies are needed to characterise sleep disorders and their mechanisms in autoimmune encephalitis.