A systematic review and meta-analysis on the outcomes of carotid endarterectomy after intravenous thrombolysis for acute ischemic stroke.

BACKGROUNDS: Intravenous thrombolysis (IVT) is the mainstay of treatment for patients presenting with acute ischemic stroke, while carotid endarterectomy (CEA) is indicated in patients with symptomatic carotid stenosis. However, the impact of prior IVT on the outcomes of CEA (IVT-CEA) is not clear. The aim of this study was to determine whether IVT may create additional stroke and death risk for CEA, compared to CEA performed in the absence of a history of recent IVT, and to determine the optimal timing for CEA after IVT METHODS: We conducted a systematic review and metanalysis on studies comparing the outcomes of IVT-CEA versus CEA, using Medline, Embase and Cochrane databases. RESULTS: We included 11 retrospective comparative studies, in which 135644 patients underwent CEA and 2070 underwent IVT-CEA. The pooled rate of perioperative stroke was 4.2% in the IVT-CEA group and 1.3% in the CEA group (OR 0.44, 95% CI 0.12-1.58, p =.21), with a high heterogenicity (I2 = 93%). The rate of stroke/death was 5.9% in patients undergoing IVT-CEA 1.9% in those receiving CEA only (OR 0.42, 95% CI 0.15-1.14, I2 = 92%, p=.09); after exclusion of studies including TIA as presenting symptom, stroke/death risk was 3.6% in IVT-CEA and 3.0% in CEA (OR 1.42, 95%CI 0.80-2.53, I2=50%, p=.11). The risk of stoke decreased with a delay in the performance of CEA (p=.268). Using results of the meta-regression, the calculated delay of CEA that allows for a <6% risk was 4.6 days. Compared to CEA, patients undergoing IVT-CEA had a significantly higher risk of ICH (2.5% vs 0.1% OR 0.11, 95% CI 0.06-0.21, I2 = 28%, p < .001) and neck haematoma requiring reintervention (3.6% vs 2.3%, OR 0.61, 95% CI 0.43-0.85, I2 = 0%, p = .003). CONCLUSION: In patients presenting with an acute ischemic stroke, CEA can be safely performed after a prior endovenous thrombolysis, maintaining a stroke/death risk <6%. After IVT, CEA should be deferred for at least 5 days to minimize the risk for ICH and neck bleeding.

Combining Intravenous Thrombolysis and Dual Antiplatelet Treatment in Patients With Minor Ischemic Stroke: A Propensity Matched Analysis of the READAPT Study Cohort.

BACKGROUND: The optimal treatment for acute minor ischemic stroke is still undefined. and options include dual antiplatelet treatment (DAPT), intravenous thrombolysis (IVT), or their combination. We aimed to investigate benefits and risks of combining IVT and DAPT versus DAPT alone in patients with MIS. METHODS AND RESULTS: This is a prespecified propensity score-matched analysis from a prospective multicentric real-world study (READAPT [Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or Transient Ischemic Attack]). We included patients with MIS (National Institutes of Health Stroke Scale score at admission ≤5), without prestroke disability (modified Rankin scale [mRS] score ≤2). The primary outcomes were 90-day mRS score of 0 to 2 and ordinal mRS distribution. The secondary outcomes included 90-day risk of stroke and other vascular events and 24-hour early neurological improvement or deterioration (≥2-point National Institutes of Health Stroke Scale score decrease or increase from the baseline, respectively). From 1373 patients with MIS, 240 patients treated with IVT plus DAPT were matched with 427 patients treated with DAPT alone. At 90 days, IVT plus DAPT versus DAPT alone showed similar frequency of mRS 0 to 2 (risk difference, 2.3% [95% CI -2.0% to 6.7%]; P=0.295; risk ratio, 1.03 [95% CI 0.98-1.08]; P=0.312) but more favorable ordinal mRS scores distribution (odds ratio, 0.57 [95% CI 0.41-0.79]; P<0.001). Compared with patients treated with DAPT alone, those combining IVT and DAPT had higher 24-hour early neurological improvement (risk difference, 20.9% [95% CI 13.1%-28.6%]; risk ratio, 1.59 [95% CI 1.34-1.89]; both P<0.001) and lower 90-day risk of stroke and other vascular events (hazard ratio, 0.27 [95% CI 0.08-0.90]; P=0.034). There were no differences in safety outcomes. CONCLUSIONS: According to findings from this observational study, patients with MIS may benefit in terms of better functional outcome and lower risk of recurrent events from combining IVT and DAPT versus DAPT alone without safety concerns. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05476081.

Mechanical thrombectomy in patients with heart failure: the Italian registry of Endovascular Treatment in Acute Stroke.

BACKGROUND: Heart failure (HF) is the second most important cardiac risk factor for stroke after atrial fibrillation (AF). Few data are available on mechanical thrombectomy (MT) in acute ischemic stroke (AIS) patients with HF. METHODS: The source of data is the multicentre Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS). All AIS patients ≥ 18 years receiving MT were categorised in two groups: HF and no-HF. Baseline clinical and neuroradiological findings on admission were analysed. RESULTS: Of 8924 patients, 642 (7.2%) had HF. Compared to the no-HF group, HF patients had higher prevalence of cardiovascular risk factors. Rate of complete recanalisation (TICI 2b-3) was 76.9% in HF vs 78.1% in no-HF group (p = 0.481). Rate of symptomatic intracerebral haemorrhage at 24-h non-contrast computed tomography (NCCT) was 7.6% in HF vs 8.3% in no-HF patients (p = 0.520). At 3 months, 36.4% of HF patients and 48.2% of no-HF patients (p < 0.001) had mRS 0-2, and mortality was, respectively, 30.7% and 18.5% (p < 0.001). In multivariate logistic regression, HF was independently associated with mortality at 3 months (OR 1.53, 1.24-1.88 95% CI, p < 0.001). In multivariate ordinal regression, HF patients had a probability of transitioning to a higher mRS level of 1.23 (1.05-1.44 95% CI, p = 0.012). The propensity score analysis of two groups matched for age, sex, and NIHSS at admission yielded the same results. CONCLUSION: MT is safe and effective in HF patients with AIS. Patients with HF and AIS suffered from higher 3-month mortality and unfavourable outcome regardless of acute treatments.

Early atrial fibrillation detection is associated with higher arrhythmic burden in patients with loop recorder after an embolic stroke of undetermined source.

Background: After an embolic stroke of undetermined source (ESUS), long-term monitoring is recommended to start an anticoagulation therapy in patients with documented atrial fibrillation (AF). Literature is sparse about the AF burden following an ESUS, although this might have significant implications in terms of clinical management and therapeutic strategy. Our primary aim was to evaluate a possible association between early detection of AF (within 90 days from the ILR implantation) and higher AF burden. Methods: This is a retrospective single-center study of 129 consecutive patients who received implantable loop recorders (ILRs) after an ESUS for detection of subclinical AF and their AF burden. Results: Mean age was 70.3 ± 10.4 years old (males: 51.9%). Atrial fibrillation was found in 40.3% of patients. Patients with AF were older, presented a higher CHAD2S2-Vasc Score and greater left atrial volume compared with patients without AF. The median AF burden was 1.2%; 59% of patients had the first AF episode within 90 days from the ILR implant while 41% experienced the first episode later than 90 days. The AF burden was significantly higher in the former group. Of note, the univariate analysis showed that only early AF detection was significantly associated with AF burden >1% (OR 20.0; 95% CI 1.68-238.6, p = 0.01). Conclusions: The early AF detection was found to be significantly associated with a higher burden of AF.

SARS-CoV-2 antibodies in inflammatory neurological conditions: a multicentre retrospective comparative study.

It is well established that neurological and non-neurological autoimmune disorders can be triggered by viral infections. It remains unclear whether SARS-CoV-2 infection induces similar conditions and whether they show a distinctive phenotype. We retrospectively identified patients with acute inflammatory CNS conditions referred to our laboratory for antibody testing during the pandemic (March 1 to August 31, 2020). We screened SARS-COV-2 IgA/IgG in all sera by ELISA and confirmed the positivity with additional assays. Clinical and paraclinical data of SARS-COV-2-IgG seropositive patients were compared to those of seronegative cases matched for clinical phenotype, geographical zone, and timeframe. SARS-CoV-2-IgG positivity was detected in 16/339 (4%) sera, with paired CSF positivity in 3/16. 5 of these patients had atypical demyelinating disorders and 11 autoimmune encephalitis syndromes. 9/16 patients had a previous history of SARS-CoV-2 infection and 6 of them were symptomatic. In comparison with 32 consecutive seronegative controls, SARS-CoV-2-IgG-positive patients were older, frequently presented with encephalopathy, had lower rates of CSF pleocytosis and other neurological autoantibodies, and were less likely to receive immunotherapy. When SARS-CoV-2 seropositive versus seronegative cases with demyelinating disorders were compared no differences were seen. Whereas seropositive encephalitis patients less commonly showed increased CSF cells and protein, our data suggest that an antecedent symptomatic or asymptomatic SARS-CoV-2 infection can be detected in patients with autoimmune neurological conditions. These cases are rare, usually do not have specific neuroglial antibodies.

Application of the "1-2-3-4-day" rule to stroke severity at baseline versus at 24 h to start direct oral anticoagulant for atrial fibrillation within 7 days from symptom onset.

INTRODUCTION: The aim of this study is to compare the "1-2-3-4-day" rule applied to stroke severity at baseline versus at 24 h to start DOAC for AF within 7 days from symptom onset. PATIENTS AND METHODS: We conducted a prospective cohort observational study based on 433 consecutive AF-related stroke patients starting DOAC within 7 days from symptom onset. Four groups were identified according to the timing of DOAC introduction: 2-day, 3-day, 4-day, and 5-7-day. RESULTS: Three models of multivariate ordinal regression including unbalanced variables among four groups (enrolment year, dyslipidemia, known AF, thrombolysis, thrombectomy, hemorrhagic transformation, DOAC type) were used to estimate the association of neurological severity categories (reference: NIHSS > 15) at baseline (Brant test: 0.818), at 24 h (Brant test: 0.997), and radiological severity categories (reference: major infarct) at 24 h (Brant test: 0.902) in the direction of earlier DOAC introduction on days (from 5-7-day to 2-day). Number of deaths was higher in early DOAC group than in late DOAC group according to the "1-2-3-4-day" rule (5.4% versus 1.3%, 6.8% versus 1.1%, and 4.2% versus 1.7% when it was applied to baseline neurological severity, 24-h neurological and radiological severity, respectively), but no significant difference was found and deaths were not caused by early DOAC introduction. Rates of ischemic stroke and intracranial hemorrhage were not different between early and late DOAC groups. CONCLUSIONS: The application of "1-2-3-4-day" rule to start DOAC for AF within 7 days from symptom onset differed when applied to baseline neurological stroke severity versus 24-h neurological and radiological severity, but safety and effecacy are similar.

AMPAR autoimmunity: Neurological and oncological accompaniments and co-existing neural autoantibodies.

α -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) encephalitis is rare but treatable. We reviewed the clinical and autoantibody profiles of 52 AMPAR-IgG-positive patients (median age 48 years [range 12-81]; 38 female) identified at the Mayo Clinic neuroimmunology laboratory. Main presentation was encephalitis; symptoms other than encephalitis associated with co-existing antibodies (p = 0.004). A tumor was found in 33/44; mostly thymoma. Most patients had partial (14/29) or complete (11/29) immunotherapy response. Thirty-one patients had at least one co-existing antibody that predicted thymoma in paraneoplastic patients (p = 0.008). In conclusion, in AMPAR encephalitis co-existing antibodies predict clinical presentation other than encephalitis and thymoma.

Benefit from successful recanalization in an Italian cohort of stroke patients receiving endovascular treatments according to the DIRECT-MT trial criteria.

INTRODUCTION: To identify predictors of 3-month mRS score and to estimate the benefit from successful recanalization across baseline subgroups of Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS) cohort of stroke patients receiving endovascular treatments according to the DIRECT-MT criteria. METHODS: Using a model of propensity score matching, we retrospectively identified an IRETAS cohort of 137 patients receiving bridging who were matched with 137 patients receiving MT alone according to the DIRECT-MT criteria. RESULTS: Differences were found between DIRECT-MT and IRETAS cohorts for 3-month mRS score 0 to 1 (23.5% vs. 33.1%) and 0 to 2 (36.7% vs. 47.1%), successful (82% vs. 76.7%) and complete recanalization (32.3% vs. 58.8%). Among unfavorable predictors for 3-month mRS shift, diabetes mellitus (18.9% vs. 13.9%) and asymptomatic intracerebral hemorhage (ICH) (34.8% vs. 25.5%) were more frequent in the DIRECT-MT, whereas age ≥80 years (23.7% vs. 15.3%) and pre-stroke mRS score >0 (16.1% vs. 7.8%) were more frequent in the IRETAS.The direction of effect on the 3-month mRS shift (6 to 0) favored successful recanalization across all strata. Greatest benefit from successful recanalization was observed in patients with most severe strokes (NIHSS ≥20, OR:4.002; 16-19, OR:3.292; 2-5, OR:2.470) and most proximal occlusion site (intra-cranial ICA, OR:4.092; M1-MCA, OR:3.705; M2-MCA, OR:2.001), in younger patients (18-59 years, OR:3.677; 60-79, OR:3.267; ≥80, OR:1.993), and in patients who started the treatment earlier (onset-to-groin time ≤205 min, OR:4.361; onset-to-groin time >205, OR:2.326). CONCLUSIONS: The benefit from successful recanalization for 3-month mRS shift in the direction of favorable outcome was different across baseline subgroups.

Septin-5 and -7-IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics.

BACKGROUND AND OBJECTIVES: We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects. METHODS: Septin-IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform. RESULTS: Septin-IgGs were identified in 23 patients. All 8 patients with septin-5-IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co-existing septin-7-IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin-7 autoimmunity, without septin-5-IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre- and post-synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation. INTERPRETATION: Septin-IgGs are predictive of distinct treatment-responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin-specific pathophysiology. ANN NEUROL 2022;92:1090-1101.

Favourable collaterals according to the Careggi Collateral Score grading system in patients treated with thrombectomy for stroke with middle cerebral artery occlusion.

The ability of the current grading systems to predict optimal outcomes in stroke patients with favourable collaterals remains unexplored. We evaluated differences in the performance of grading systems between Careggi Collateral Score and ASITN/SIR collateral score to predict clinical and radiological outcomes in stroke patients with favourable collaterals who underwent thrombectomy. We included stroke patients receiving thrombectomy within 360 min after symptom onset with MCA occlusion and favourable collaterals (i.e., without poor collaterals) defined by ASITN/SIR collateral score between 2 and 4. Using ordinal regression, we estimated the association of each CCS and ASITN/SIR grade with mRS shift (0-6) at 3 months, NIHSS score (0-42) and ASPECT score (10-0) at baseline, TICI score (3-0), infarct growth, cerebral bleeding, and cerebral edema grading at 24 h by calculating the odds ratios (ORs) with two-sided 95% confidence intervals after adjustment for predefined variables. Using the best collateral grade (CCS = 4) as reference, ORs of the CCS grades were associated in the direction of unfavourable outcome on 3-month mRS shift (2.325 for CCS = 3; 5.092 for CCS = 2), in the direction of more severe baseline NIHSS score (5.434 for CCS = 3; 16.041 for CCS = 2), 24-h infarct growth (2.659 for CCS = 3; 8.288 for CCS = 4) and 24-h cerebral edema (1.057 for CCS = 3; 5.374 for CCS = 2) shift. ORs of the ASITN/SIR grades were associated in the direction of more severe baseline NIHSS score (4.332 for ASITN/SIR = 3; 16.960 for ASITN/SIR = 2) and 24-h infarct growth (2.138 for ASITN/SIR = 3; 7.490 for ASITN/SIR = 2) shift. The AUC ROC of CCS and ASITN/SIR for predicting 3-month mRS score 0-1 were 0.681 (95% CI: 0.562-0.799; p = 0.009) and 0.599 (95% CI: 0.466-0.73; p = 0.156), respectively. CCS = 4 and ASITN/SIR ≥ 3 were the optimal cut-offs to predict 3-month mRS score 0-1, respectively. CCS grading system performed better than the ASITN/SIR collateral score predicting 3-month mRS score and 24-h CED grading in stroke patients with favourable collaterals who received thrombectomy for MCA occlusion.

Association of the careggi collateral score with radiological outcomes after thrombectomy for stroke with an occlusion of the middle cerebral artery.

We aimed to examine the association between Careggi Collateral Score (CCS) and radiological outcomes in a large multicenter cohort of patients receiving thrombectomy for stroke with occlusion of middle cerebral artery (MCA). We conducted a study on prospectively collected data from 1785 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke. According to the extension of the retrograde reperfusion in the cortical anterior cerebral artery-MCA territories, CCS ranges from 0 (absence of retrograde filling) to 4 (visualization of collaterals until the alar segment of the MCA). Radiological outcomes at 24 h were the presence and severity of infarct growth defined by the absolute change in ASPECTS from baseline to 24 h; presence and severity of cerebral bleeding defined as no ICH, HI-1, HI-2, PH-1, or PH-2; presence and severity of cerebral edema (CED) defined as no CED, CED-1, CED-2, or CED-3. Using CCS = 0 as reference, ORs of CCS grades were significantly associated in the direction of better radiological outcome on infarct growth (0.517 for CCS = 1, 0.413 for CCS = 2, 0.358 for CCS = 3, 0.236 for CCS = 4), cerebral bleeding grading (0.485 for CCS = 1, 0.445 for CCS = 2, 0.400 for CCS = 3, 0.379 for CCS = 4), and CED grading (0.734 for CCS = 1, 0.301 for CCS = 2, 0.295 for CCS = 3, 0.255 for CSS = 4) shift in ordinal regression analysis after adjustment for pre-defined variables (age, NIHSS score, ASPECTS, occlusion site, onset-to-groin puncture time, procedure time, and TICI score). Using CCS = 4 as reference, ORs of CCS grades were significantly associated in the direction of worse radiological outcome on infarct growth (1.521 for CCS = 3, 1.754 for CCS = 2, 2.193 for CCS = 1, 4.244 for CCS = 0), cerebral bleeding grading (2.498 for CCS = 0), and CED grading (1.365 for CCS = 2, 2.876 for CCS = 1, 3.916 for CCS = 0) shift. The CCS could improve the prognostic estimate of radiological outcomes in patients receiving thrombectomy for stroke with MCA occlusion.

Association of the Careggi Collateral Score with 3-month modified Rankin Scale score after thrombectomy for stroke with occlusion of the middle cerebral artery.

BACKGROUND: The Careggi Collateral Score (CCS) (qualitative-quantitative evaluation) was developed from a single-centre cohort as an angiographic score to describe both the extension and effectiveness of the pial collateral circulation in stroke patients with occlusion of the anterior circulation. We aimed to examine the association between CCS (quantitative evaluation) and 3-month modified Rankin Scale (mRS) score in a large multi-center cohort of patients receiving thrombectomy for stroke with occlusion of middle cerebral artery (MCA). METHODS: We conducted a study on prospectively collected data from 1284 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke. According to the extension of the retrograde reperfusion in the cortical anterior cerebral artery (ACA)-MCA territories, CCS ranges from 0 (absence of retrograde filling) to 4 (visualization of collaterals until the alar segment of the MCA). RESULTS: Using CCS of 4 as reference, CCS grades were associated in the direction of unfavourable outcome on 3-month mRS shift (0 to 6); significant difference was found between CCS of 0 and CCS of 1 and between CCS of 3 and CCS of 4. CCS ≥ 3 was the optimal cut-off for predicting 3-month excellent outcome, while CCS ≥ 1 was the optimal cut-off for predicting 3-month survival. CCS of 0 and CCS < 3 were associated in the direction of unfavourable recanalization on TICI shift (0 to 3) compared with CCS ≥ 1 and CCS ≥ 3, respectively. Compared with CCS ≥ 3 as reference, CCS of 0 and CCS 1 to 2 were associated in the direction of unfavourable recanalization on TICI shift. There was no evidence of heterogeneity of effects of successful recanalization and procedure time ≤ 60 min on 3-month mRS shift across CCS categories. CONCLUSION: The CCS could provide a future advantage for improving the prognosis in patients receiving thrombectomy for stroke with M1 or M1-M2 segment of the MCA occlusion.

Thrombectomy for ischemic stroke with large vessel occlusion and concomitant subarachnoid hemorrhage.

To report our experience in treating one patient with nontraumatic subarachnoid hemorrhage (SAH) and concurrent acute ischemic stroke (AIS) due to large vessels occlusion (LVO). A man in his 50 s presented with acute right hemiparesis and aphasia. Brain CT showed a SAH in the left central sulcus; CT-angiography revealed a tandem occlusion of the left internal carotid artery and homolateral middle cerebral artery. He underwent an angiographic procedure with successful recanalization. Follow-up CT demonstrated a striatal-lenticular stroke without SAH progression. While the absolute contraindication to IVT during intracranial bleeding remains unquestionable, the potential injury/benefit from MT is still debatable. Such cases constitute a blind spot in the guidelines where physicians face the dilemma of choosing between an acute endovascular treatment with the risks of hemorrhage progression and a conservative treatment with the associated poor clinical outcome. We decided to treat our patient invasively, considering the young age, also given the absence of prognostic factors that generally predict post-procedural reperfusion injury. We believe that, in similar cases, MT should be considered-despite not free of risks and drawbacks-to avoid the detrimental consequences of untreated AIS from LVO.

Neurological complications of immune checkpoint inhibitor cancer immunotherapy.

Neurological autoimmunity is increasingly recognized as a complication of immune checkpoint inhibitor (ICI) cancer immunotherapy. ICIs act by enhancing endogenous anti-tumor immune responses and can also lead to autoimmunity affecting all organs. ICI-related neurological autoimmunity is rare, most often manifests with neuromuscular involvement and more rarely affects the central nervous system. Neurological complications often often present in the first three months of ICI treatment but can also appear after ICI discontinuation. These can occur in patients with tumors not traditionally associated with paraneoplastic neurological autoimmunity, such as melanoma and renal-cell carcinoma and should be suspected when a new neurological symptoms present while on ICI and cannot be explained by disease progression or as a consequence of metabolic dysfunction. Treatment consists of ICI discontinuation or withdrawal depending on the severity with or without immunosuppression. Generally, improvement is observed depending on the patient's baseline characteristics and neurological presentation.

Neuronal intermediate filament IgGs in CSF: Autoimmune Axonopathy Biomarkers.

OBJECTIVES: To describe CSF-defined neuronal intermediate filament (NIF) autoimmunity. METHODS: NIF-IgG CSF-positive patients (41, 0.03% of 118599 tested, 1996-2019) were included (serum was neither sensitive nor specific). Criteria-based patient NIF-IgG staining of brain and myenteric NIFs was detected by indirect immunofluorescence assay (IFA); NIF-specificity was confirmed by cell-based assays (CBAs, alpha internexin, neurofilament light [NF-L]), heavy-[NF-H] chain). RESULTS: Sixty-one percent of 41 patients were men, median age, 61 years (range, 21-88). Syndromes were encephalopathy predominant (23), cerebellar ataxia predominant (11), or myeloradiculoneuropathies (7). MRI abnormalities (T2 hyperintensities of brain, spinal cord white matter tracts. and peripheral nerve axons) and neurophysiologic testing (EEG, EMG, evoked potentials) co-localized with clinical neurological phenotypes (multifocal in 29%). Thirty patients (73%) had ≥ 1 immunological perturbation: cancer (paraneoplastic), 22; systemic infection (parainfectious [including ehrlichosis, 3] or HIV), 7; checkpoint-inhibitor cancer immunotherapy, 4; other, 5. Cancers were as follows: neuroendocrine-lineage carcinomas, 12 (small cell, 6; Merkel cell, 5; pancreatic, 1 [11/12 had NF-L-IgG detected, versus 8/29 others, P = 0.0005]) and other, 11. Onset was predominantly subacute (92%) and accompanied by inflammatory CSF (75%), and immunotherapy response (77%). In contrast, CSF controls (15684 total) demonstrated NIF-IgG negativity (100% of test validation controls), and low frequencies of autoimmune diagnoses (20% of consecutively referred clinical specimens) and neuroendocrine-lineage carcinoma diagnosis (3.1% vs. 30% of NIF cases), P < 0.0001. Median NF-L protein concentration was higher in 8 NF-L-IgG-positive patients (median, 6718 ng/L) than 16 controls. INTERPRETATION: Neurological autoimmunity, defined by CSF-detected NIF-IgGs, represents a continuum of treatable axonopathies, sometimes paraneoplastic or parainfectious.