COVID-19 outcomes in patients with multiple sclerosis: Understanding changes from 2020 to 2022.

BACKGROUND: Epidemiologic studies on coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (pwMS) have focused on the first waves of the pandemic until early 2021. OBJECTIVES: We aimed to extend these data from the onset of the pandemic to the global coverage by vaccination in summer 2022. METHODS: This retrospective, multicenter observational study analyzed COVISEP registry data on reported COVID-19 cases in pwMS between January 2020 and July 2022. Severe COVID-19 was defined as hospitalization or higher severity. RESULTS: Among 2584 pwMS with confirmed/highly suspected COVID-19, severe infection rates declined from 14.6% preomicron wave to 5.7% during omicron wave (p < 0.001). Multivariate analysis identified age (odds ratio (OR) = 1.43, 95% confidence interval (CI) = [1.25-1.64] per 10 years), male sex (OR = 2.01, 95% CI = [1.51-2.67]), obesity (OR = 2.36, 95% CI = [1.52-3.68]), cardiac comorbidities (OR = 2.36, 95% CI = [1.46-3.83]), higher Expanded Disability Status Scale (EDSS) scores (OR = 2.09, 95% CI = [1.43-3.06] for EDSS 3-5.5 and OR = 4.53, 95% CI = [3.04-6.75] for EDSS ⩾6), and anti-CD20 therapies (OR = 2.67, 95% CI = [1.85-3.87]) as risk factors for COVID-19 severity. Vaccinated individuals experienced less severe COVID-19, whether on (risk ratio (RR) = 0.64, 95% CI = [0.60-0.69]) or off (RR = 0.32, 95% CI = [0.30-0.33]) anti-CD20. DISCUSSION: In pwMS, consistent risk factors were anti-CD20 therapies and neurological disability, emerging as vital drivers of COVID-19 severity regardless of wave, period, or vaccination status.

Early use of high efficacy therapies in pediatric forms of relapsing-remitting multiple sclerosis: A real-life observational study.

BACKGROUND: Pediatric forms of multiple sclerosis are more active than those in adults. Yet, the effectiveness of different therapeutic approaches is not well studied in this population. Our objective was to compare the effectiveness of the early use of high efficacy therapies (HETs) with the effectiveness of moderate efficacy therapies (METs) in children with MS. METHODS: This observational study included patients diagnosed with pediatric MS, at 4 hospital centers in France, during a 10-year period. METs included: interferon ß-1a, glatiramer acetate, dimethyl fumarate, teriflunomide; HETs included: fingolimod, natalizumab, ocrelizumab, alemtuzumab. The primary endpoint was the occurrence of a new relapse, the secondary endpoint was EDSS worsening. RESULTS: Sixty-four patients were included in the analysis (80% women; mean age 15.5 years, 81% treated with MET) with a median follow-up of 22.5 months. At baseline, 52 patients were on MET (interferon ß-1a, glatiramer acetate, dimethyl fumarate, teriflunomide) and 12 patients were on HET (natalizumab, ocrelizumab). The cumulative probability of being relapse-free at 6.5 years was 23.3% on MET, vs 90.9% on HET (p = 0.013). The cumulative probability of no EDSS worsening did not differ between the 2 groups. CONCLUSION: Patients starting with METs had much higher clinical disease activity than those starting early with HETs. Rapid initiation of more aggressive treatment may allow better disease control; however, the data on EDSS worsening are not conclusive.

Association Between Anti-CD20 Therapies and COVID-19 Severity Among Patients With Relapsing-Remitting and Progressive Multiple Sclerosis.

Importance: In patients with multiple sclerosis (MS), factors associated with severe COVID-19 include anti-CD20 therapies and neurologic disability, but it is still unclear whether these 2 variables are independently associated with severe COVID-19 or whether the association depends on MS clinical course. Objective: To assess the association between anti-CD20 therapies and COVID-19 severity in patients with relapsing-remitting MS (RRMS) and progressive MS (PMS). Design, Setting, and Participants: This multicenter, retrospective cohort study used data from the COVISEP study, which included patients with MS and COVID-19 from February 1, 2020, to June 30, 2022, at 46 French MS expert centers, general hospitals, and private neurology practices. Eligible patients with RRMS were those treated with high-efficacy MS therapy (ie, anti-CD20, fingolimod, or natalizumab), and eligible patients with PMS were those younger than 70 years with an Expanded Disability Status Scale (EDSS) score of 8 or lower. Patients were monitored from COVID-19 symptom onset until recovery or death. Exposures: Current anti-CD20 therapy (ocrelizumab or rituximab). Main Outcomes and Measures: The main outcome was severe COVID-19 (ie, hospitalization with any mode of oxygenation or death). All analyses were conducted separately in patients with RRMS and PMS using propensity score-weighted logistic regression. Subgroup analyses were performed according to COVID-19 vaccine status, sex, EDSS score, and age. Results: A total of 1400 patients, 971 with RRMS (median age, 39.14 years [IQR, 31.38-46.80 years]; 737 [76.1%] female) and 429 with PMS (median age, 54.21 years [IQR, 48.42-60.14 years]; 250 [58.3%] female) were included in the study. A total of 418 patients with RRMS (43.0%) and 226 with PMS (52.7%) were treated with anti-CD20 therapies. In weighted analysis, 13.4% and 2.9% of patients with RRMS treated and not treated with anti-CD20 had severe COVID-19, respectively, and anti-CD20 treatment was associated with increased risk of severe COVID-19 (odds ratio [OR], 5.20; 95% CI, 2.78-9.71); this association persisted among vaccinated patients (7.0% vs 0.9%; OR, 8.85; 95% CI, 1.26-62.12). Among patients with PMS, 19.0% and 15.5% of patients treated and not treated with anti-CD20 had severe COVID-19, respectively, and there was no association between anti-CD20 treatment and severe COVID-19 (OR, 1.28; 95% CI, 0.76-2.16). In PMS subgroup analysis, anti-CD20 exposure interacted negatively with EDSS score (P = .009 for interaction) and age (P = .03 for interaction); anti-CD20 therapies were associated with risk of severe COVID-19 only in patients with less neurologic disability and younger patients with PMS. Conclusions and Relevance: In this cohort study, risk of severe COVID-19 was higher in patients with PMS than in those with RRMS. Use of anti-CD20 therapies was associated with an increased risk of severe COVID-19 among patients with RRMS. In patients with PMS, there was no association between anti-CD20 therapies and risk of severe COVID-19.

Epileptic Prodromal Alzheimer's Disease Treated with Antiseizure Medications: Medium-Term Outcome of Seizures and Cognition.

BACKGROUND: The medium term outcome (over more than one year) of epileptic prodromal AD (epAD) patients treated with antiseizure medications (ASMs) is unknown in terms of seizure response, treatment tolerability, and cognitive and functional progression. OBJECTIVE: To describe such medium term outcome over a mean of 5.1±2.1 years. METHODS: We retrospectively compared 19 epAD patients with 16 non-epileptic prodromal AD (nepAD) patients: 1) at baseline for demographics, medical history, cognitive fluctuations (CFs), psychotropic medications, MMSE scores, visually rated hippocampal atrophy, CSF neurodegenerative biomarkers, and standard EEG recordings; 2) during follow-up (FU) for psychotropic medications, MMSE progression, and conversion to dementia. In the epAD group, we analyzed baseline and FU types of seizures as well as each line of ASM with the corresponding efficacy and tolerability. RESULTS: At baseline, the epAD group had more CFs than the nepAD group (58% versus 20%, p = 0.03); focal impaired awareness seizures were the most common type (n = 12, 63.1%), occurring at a monthly to quarterly frequency (89.5%), and were well controlled with monotherapy in 89.5% of cases (including 63.1% seizure-free individuals). During FU, treated epAD patients did not differ significantly from nepAD patients in MMSE progression or in conversion to dementia. CONCLUSION: Epilepsy is commonly controlled with ASMs over the medium term in epAD patients, with similar functional and cognitive outcomes to nepAD patients. Pathophysiologically, epilepsy is likely to be an ASM-modifiable cognitive aggravating factor at this stage of AD.

Letter and Category Fluency: Normative Data for Lebanese Older Adults.

BACKGROUND: Verbal fluency tasks are frequently used for neuropsychological assessment in clinical practice and research. It consists of two tasks namely category and letter fluency tests. OBJECTIVE: To determine normative values in category (animals, vegetables, fruits) and letter fluency [Mim () "M", Alif () "A", Baa () "B"] tasks in Arabic language in 60 s. METHODS: This study was a cross-sectional national survey and included 859 community-dwelling, cognitively intact Lebanese residents aged ≥55 years. Norms were presented according to age (55-64 years, 65-74 years, ≥75 years), sex and level of education (illiterate, no diploma, primary certificate, baccalaureate or higher). RESULTS: Level of education had the most significant positive effect on verbal fluency tasks performance amongst Lebanese older adults. The negative effect of older age was more prominent in the category fluency task compared to the letter fluency task. Women outperformed men in vegetables and fruits categories. CONCLUSION: This study provides clinicians with normative scores of category and letter fluency tests, which can be used for neuropsychological assessment of older Lebanese patients being evaluated for cognitive disorders.

An adapted Arabic version of the Test of Nine Images for the illiterate Lebanese population: Validation and preliminary normative data.

OBJECTIVES: In the absence of a simple validated instrument to screen for cognitive impairment among illiterate Lebanese older adults, the aims of this study were to validate an Arabic version of the Test of Nine Images (A-TNI93) adapted by the Working Group on Dementia at Saint Joseph University: Groupe de Travail sur les Démences de l'Univesité Saint Joseph (GTD-USJ) for illiterate older Lebanese and to establish normative data. METHOD: A national population-based sample of 332 community-dwelling illiterate Lebanese aged 55 years and older was administered the A-TNI93 (GTD-USJ) scoring free and overall recall. The sample is part of a larger national sample (1342 participants) used to validate an Arabic version of the Mini-Mental State Examination already reported. Reproducibility, sensitivity, specificity, and area under the curve of the A-TNI93 (GTD-USJ) scoring to detect cognitive impairment according to Clinical Dementia Rating (CDR) as the gold standard were measured. Normative data were established among 188 cognitively normal participants. RESULTS: A threshold score of six on free recall (FR) provided a sensitivity of 66.7% and a specificity of 90.5%. The area under the curve was 0.93. By taking either scores, that is, a FR ≤ 6 or a total recall ≤ 8, the A-TNI93 (GTD-USJ) slightly improved dementia case detection with a sensitivity of 70.8% and a specificity of 88%. Normative data illustrate the distribution of cognitive performance among illiterate older adults. CONCLUSIONS: Compared to the CDR requiring physician's competence, the A-TNI93 (GTD-USJ) is a valid Arabic adaptation to screen for cognitive impairment among illiterate Lebanese older adults.

[Memory diseases]. / Maladies de la mémoire.

MEMORY DISEASES. There are many diseases that permanently affect longterm memory and all of them have in common that they permanently and usually bilaterally disrupt specific neural circuits that underlie it. In the forefront is the Papez circuit, or hippocampo-mamillo-thalamo-cingular circuit, which is also connected to the fronto-basal regions. Its impairment leads to disorders of episodic memory, with relative preservation of semantic memory and implicit learning. The anterior temporal pole is a hub allowing access to general knowledge distributed in the cortex. Its damage results in an amnesic picture in which the loss of semantic memory dominates. The richness of memory disorders is largely deduced, in its nuances, from the lesion topographies. The most frequent aetiology of memory diseases is represented by neurodegenerative diseases, dominated by Alzheimer's disease, but the semiology of these is by far not limited to a memory disorder, because of the diffusion of lesions. Dysimmune, infectious or toxic encephalitis affecting the hippocampi, Korsakoff's syndrome affecting the thalamus and mamillary bodies, « semantic dementia ¼ affecting the temporal pole, give pictures where memory disorders are in the foreground with remarkable semiological nuances. Post-traumatic amnesia, due to the heterogeneity of the lesions, offers a more complex picture, where memory disorders are complemented by executive disorders, sometimes major.

MALADIES DE LA MÉMOIRE. Les maladies qui affectent durablement la mémoire à long terme sont nombreuses et ont en commun de perturber de façon permanente et, en règle, bilatérale des circuits neuronaux spécifiques qui en sont le substratum. Au premier rang figure le circuit de Papez, ou circuit hippocampo-mamillo-thalamo-cingulaire, par ailleurs connecté aux régions frontobasales. Son atteinte engendre des troubles de la mémoire épisodique, avec une relative préservation de la mémoire sémantique et des apprentissages implicites. Le pôle temporal antérieur est quant à lui un noeud fonctionnel permettant d'accéder aux connaissances générales distribuées dans le cortex. Son atteinte donne un tableau amnésique où domine la perte de la mémoire sémantique. La richesse sémiologique des troubles de la mémoire se déduit largement, dans ses nuances, des topographies lésionnelles. La cause la plus fréquente des maladies de la mémoire est représentée par des maladies neurodégénératives, dominées par la maladie d'Alzheimer, mais la sémiologie de celles-ci ne se limite, de loin, pas à un trouble de la mémoire, du fait de la diffusion des lésions. Les encéphalites dysimmunitaires, infectieuses ou toxiques touchant les hippocampes, le syndrome de Korsakoff touchant les thalamus et corps mamillaires, la « démence sémantique ¼ donnent des tableaux où les troubles mnésiques sont au premier plan, avec des nuances sémiologiques remarquables. L'amnésie post-traumatique, en raison de l'hétérogénéité des lésions, offre un tableau plus complexe, où les troubles de la mémoire se complètent de troubles exécutifs parfois majeurs.

The challenge of diagnosing Guillain-Barre syndrome in patients with COVID-19 in the intensive care unit.

Various neurological complications have been described in COVID-19 patients, especially Guillain-Barre syndrome (GBS). The underlying mechanisms on the association between SARS-CoV-2 infection and GBS remain unclear, but several hypotheses have been proposed. It seems that post-SARS-CoV-2 GBS shares many characteristics with classic post-infectious GBS; however, it may occur in sedated and intubated patients hospitalized in the intensive care unit for SARS-CoV-2 acute respiratory distress syndrome, which presents challenges in the diagnosis and treatment of GBS. In this study, we describe three cases of post-SARS-CoV-2 GBS that were hospitalized in the intensive care unit.

Glial Fibrillary Acidic Protein Autoimmunity: A French Cohort Study.

BACKGROUND AND OBJECTIVES: To report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies. METHODS: We retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers. RESULTS: We identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies. DISCUSSION: GFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.

Multifocal and Microvascular Involvement in Ischemic Stroke During COVID-19: A Cohort Study With Comparison With Non-COVID-19 Stroke.

Introduction: Thromboembolic events, including ischemic stroke, are major complications of coronavirus disease 2019 (COVID-19). The clinical characteristics of COVID-19-related stroke are not clearly defined, and few controlled studies assessed the underlying mechanisms of cerebrovascular complications of COVID-19. This single-center retrospective observational study compared stroke characteristics between patients with and without COVID-19. Methods: This study included all patients hospitalized between March 1, 2020, and April 30, 2020, in Colmar Hospital for ischemic stroke as confirmed by imaging. The characteristics of patients with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection by real-time reverse transcriptase polymerase chain reaction or serology were compared with those without SARS-CoV-2 infection. Result: Among 772 patients, nine COVID-19 patients were compared with 50 patients without COVID-19. The following inflammatory and procoagulant marker levels were significantly higher in the COVID-19 group than those in the control group: C-reactive protein, 57.3 ± 43.4 vs. 15.0 ± 30.6 mg/L, p < 0.001; fibrinogen, 5.89 ± 1.75 vs. 4.03 ± 1.26 g/L, p < 0.001; and D-dimer, 4,833.9 ± 6,549.4 vs. 1,028.6 ± 942.6 ng/ml, p < 0.001. The rates of multifocal cerebral territory involvement (4 vs. 7, p = 0.05), microvascular involvement (4 vs. 6, p = 0.04), and thrombophilia (4 vs. 4, p = 0.014) were significantly higher in the COVID-19 group than in the control group, whereas no significant intergroup differences were found in the stroke mechanisms, i.e., cardio-embolic, atherosclerotic, small vessel disease, and cryptogenic. Conclusion: COVID-19-related stroke is characterized by hypercoagulability and hyperinflammation that may favor strokes via microvascular circulation abnormalities, microthrombus formation, and multifocal lesions.

SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration.

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

CSF in Epileptic Prodromal Alzheimer's Disease: No Diagnostic Contribution but a Pathophysiological One.

Objective: To study whether cerebrospinal fluid (CSF) analysis may serve as a diagnostic test for the screening of epilepsy in sporadic prodromal Alzheimer's disease (AD). Methods: A total of 29 patients with epileptic prodromal sporadic AD patients (epADs) were included and were retrospectively compared with 38 non-epileptic prodromal AD patients (nepADs) for demographics, clinical features, Mini-Mental Status Examination (MMSE) results, CSF biomarkers, and electro-radiological features. Results: Our study did not show any significant differences in CSF biomarkers regarding neurodegeneration, albumin levels, and inflammation between epADs and nepADs. The epADs were significantly older at diagnosis (p = 0.001), more hypertensive (p = 0.01), and displayed larger white matter hyperintensities on brain magnetic resonance imaging (MRI; p = 0.05). There was a significant correlation between the CSF Aß-42 and Aß-40 levels with interictal epileptiform discharges and delta slowing on EEGs recordings, respectively (p = 0.03). Conclusions: Our study suggests that CSF may not serve as a surrogate marker of epilepsy in prodromal AD and cannot circumvent the operator-dependent and time-consuming interpretation of EEG recordings. In humans, AD-related epileptogenesis appears to involve the Aß peptides but likely also additional non-amyloid factors such as small-vessel disease (i.e., white matter hyperintensities).

Transient epileptic amnesia is significantly associated with discrete CA1-located hippocampal calcifications but not with atrophic changes on brain imaging.

BACKGROUND: The exact etiology of transient epileptic amnesia (TEA) is currently unknown. In older individuals, common neurodegenerative dementias and small-vessel diseases (SVDs) could be major contributors. We examined these hypotheses on the basis of imaging analysis. METHODS: In total, 36 TEA patients were compared with 25 healthy controls for (1) cortical atrophic changes (in the mesial temporal, frontal, anterior temporal, and parietal regions) using four established MRI-based visual rating scales, and for (2) SVD evidence using two MRI-based visual rating scales (Fazekas and MARS scores). In 24 TEAs cases, there were also brain CT scans available that were compared with 57 controls for the presence of hippocampal calcifications (HCs). RESULTS: We did not find significant differences in cortical atrophy between TEAs and controls, nor did we observe a different SVD brain load on MRI. However, TEAs were significantly associated (p < 0.01) with uni- or bilateral CA1-located HCs in half of the patients compared with the controls (less than 20 %). CONCLUSIONS: This study argues in favor of a hippocampal-restricted SVD (as indicated by HCs) as one of the major etiologies of TEA, while neurodegenerative dementias are probably minor causes. It furthermore highlights the pivotal role of the CA1 hippocampal subfield in the pathophysiology of this syndrome.

Clinical and neuropathological diversity of tauopathy in MAPT duplication carriers.

Microduplications of the 17q21.31 chromosomal region encompassing the MAPT gene, which encodes the Tau protein, were identified in patients with a progressive disorder initially characterized by severe memory impairment with or without behavioral changes that can clinically mimic Alzheimer disease. The unique neuropathological report showed a primary tauopathy, which could not be unanimously classified in a given known subtype, showing both 4R- and 3R-tau inclusions, mainly within temporal cortical subregions and basal ganglia, without amyloid deposits. Recently, two subjects harboring the same duplication were reported with an atypical extrapyramidal syndrome and gait disorder. To decipher the phenotypic spectrum associated with MAPT duplications, we studied ten carriers from nine families, including two novel unrelated probands, gathering clinical (n = 10), cerebrospinal fluid (n = 6), MRI (n = 8), dopamine transporter scan (n = 4), functional (n = 5), amyloid (n = 3) and Tau-tracer (n = 2) PET imaging data as well as neuropathological examination (n = 4). Ages at onset ranged from 37 to 57 years, with prominent episodic memory impairment in 8/10 patients, associated with behavioral changes in four, while two patients showed atypical extrapyramidal syndrome with gait disorder at presentation, including one with associated cognitive deficits. Amyloid imaging was negative but Tau imaging showed significant deposits mainly in both mesiotemporal cortex. Dopaminergic denervation was found in 4/4 patients, including three without extrapyramidal symptoms. Neuropathological examination exclusively showed Tau-immunoreactive lesions. Distribution, aspect and 4R/3R tau aggregates composition suggested a spectrum from predominantly 3R, mainly cortical deposits well correlating with cognitive and behavioral changes, to predominantly 4R deposits, mainly in the basal ganglia and midbrain, in patients with prominent extrapyramidal syndrome. Finally, we performed in vitro seeding experiments in HEK-biosensor cells. Morphological features of aggregates induced by homogenates of three MAPT duplication carriers showed dense/granular ratios graduating between those induced by homogenates of a Pick disease and a progressive supranuclear palsy cases. These results suggest that MAPT duplication causes a primary tauopathy associated with diverse clinical and neuropathological features.

Effect of a strutted intradiscal spacer (DIVA®) on disc reherniation following lumbar discectomy: A 2-year retrospective matched cohort study.

INTRODUCTION: Discectomy for lumbar disc herniation has a high rate of reoperation and recurrent herniation. METHODS: Retrospectively matched cohort of patients undergoing lumbar discectomy alone or with a strutted intradiscal spacer. RESULTS: 133 discectomy and 112 patients with discectomy plus spacer were included. Pain and disability scores were significantly lower for both groups at 2 years. Patients receiving a strutted intradiscal spacer following discectomy had a reduced rate of all-cause reoperations and operations for recurrent herniations compared to discectomy alone. CONCLUSION: Use of a strutted intradiscal spacer following discectomy improves surgical outcomes following surgery for lumbar herniation versus discectomy alone.

Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant.

OBJECTIVE: To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic correlates. METHODS: Patients with PPA carrying GRN mutations (PPA-GRN) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA. RESULTS: Among the 235 patients with PPA, 45 (19%) carried GRN mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%). CONCLUSIONS: This study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene-specific therapies.

SOFIA catheter for direct aspiration of large vessel occlusion stroke: A single-center cohort and meta-analysis.

BACKGROUND AND PURPOSE: Direct aspiration (DA) using large-bore distal aspiration catheters is an established strategy for the endovascular thrombectomy (EVT) of large-vessel occlusion stroke (LVOS). However, the performance of individual catheters like SOFIA has yet to be examined. METHODS: We present a cohort of 144 consecutive patients treated with first-line DA and SOFIA 6 F Plus catheter for LVOS. We also conducted a systematic review of the literature searching multiple databases for reports on thrombectomy with DA and SOFIA catheters and performed a meta-analysis of recanalization, safety, and clinical outcomes. RESULTS: In the study cohort a successful recanalization (mTICI 2b-3) rate of 75.7% was achieved with DA alone, the global rate for functional independence (90-day mRS 0-2) was 40.3%. For the metanalysis we selected nine articles that included a total of 758 patients treated with first-line thrombectomy with the SOFIA catheters. The mTICI 2b-3 rate was 71.6% (95%CI, 66.3-76.5%) while a rescue stent-retriever was used in 24.1% (95%CI, 17.7-31.9%) of cases. The overall mTICI2b-3 rate after DA and rescue therapy was 88.9% (95%CI, 82.6-93.1%). We found a pooled estimate of 45.6% (95%CI, 38.6-52.8%) for functional independence, a mortality within 90 days of 19% (95%CI, 14.1-25.0%) and a rate of 5.8% (95%CI, 4.2-8.0%) of symptomatic intracranial hemorrhage. CONCLUSION: The DA approach for LVOS with the SOFIA catheters is highly effective with an efficacy and safety profile comparable to those found in contemporary thrombectomy trials and observational studies that use other devices or approaches.

CSF interleukin 6 is a useful marker to distinguish pseudotumoral CNS inflammatory diseases from primary CNS lymphoma.

BACKGROUND: Interleukin 6 (IL-6) is a pleomorphic cytokine that can be found in the cerebrospinal fluid (CSF) in a wide spectrum of inflammatory pathologies of the central nervous system (CNS). OBJECTIVE: Our aim was to characterize the diagnostic significance of CSF IL-6 among various CNS inflammatory diseases with pseudotumoral lesions (CNSID) and primary CNS lymphoma (PCNSL). METHODS: We retrospectively analyzed the CSF IL-6 concentrations in 43 consecutive patients with suspected PCNSL. A total of 28 patients were positively diagnosed with PCNSL and 15 with CNSID. We verified the results with CSF IL-10, an established biomarker for PCNSL. RESULTS: In the PCNSL group, the median CSF IL-6 concentration was 8 pg/ml, interquartile range (IQR) 5-18.5. For the patients with CNSID, the median concentration was 70 pg/ml, IQR 5-1368. A group comparison showed significantly higher CSF IL-6 levels in patients with CNSID than in those with PCNSL (p = 0.032). Moreover, IL-6 was correlated with CSF cell count in the CNSID group (r = 0.56, p = 0.028), but not in the PCNSL group (r = 0.3, p = 0.13). We found significantly higher CSF IL-10 levels in patients with PCNSL than in patients with CNS inflammatory lesions (p < 0.001). DISCUSSION AND CONCLUSIONS: Our study suggests that CSF IL-6 levels could represent, in addition to CSF IL-10, a useful biomarker in the differential diagnosis of CNSID and suspected PCNSL.

Long-term effect of natalizumab in patients with RRMS: TYSTEN cohort.

BACKGROUND: Data are needed on long-term effect of natalizumab (NTZ) in relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: To evaluate the time of onset of secondary progressive phase in patients with an RRMS treated with NTZ and to investigate predictive factors. METHODS: TYSTEN is an observational study. Patients starting NTZ between 2007 and 2012 were included and followed up until October 2018. Relapses, Expanded Disability Status Scale (EDSS) scores, and results of brain magnetic resonance imaging (MRI) were collected each year. Data were used to estimate the cumulative probability of several poor outcomes such as secondary progressive multiple sclerosis (SPMS) conversion, EDSS worsening, EDSS 4.0, and EDSS 6.0. RESULTS: 770 patients were included. The mean follow-up duration was 97 months and the mean time exposure to NTZ was 66 months. At 10 years, the cumulative probability of SPMS was 27.7%. Predictive factors for poor outcomes were a ⩾1-point increase in EDSS score from baseline, new T2 lesion or T1 gadolinium-enhancing lesion, the occurrence of relapse at 1 or 2 years and No Evidence of Disease Activity (NEDA-3; no relapse, no new T2 or T1 gadolinium-enhancing lesions, no progression) was a protective factor. CONCLUSION: In our cohort of patients treated with NTZ, poor outcomes were infrequent and are driven by disease activity.

The Babinski sign in Renaissance paintings-a reappraisal of the toe phenomenon in representations of the Christ Child: observational analysis.

OBJECTIVE: To investigate systematically the presence of the Babinski sign in paintings of the Christ Child by the greatest painters of the Renaissance. DESIGN: Observational analysis. SETTING: Large collection of paintings depicting the Christ Child from Flemish, Rhenish, and Italian schools between 1400 and 1550 CE, searched using published catalogues and Google. STUDY SAMPLE: 302 Renaissance paintings (by 19 painters) depicting the Christ Child. MAIN OUTCOME MEASURE: Babinski sign, defined as a hallux extension with an amplitude greater than 30°. The presence of foot sole stimulation was also noted. RESULTS: An unquestionable upgoing toe was apparent in 90 (30%) of the 302 paintings. The Babinski sign was present in more than 60% of Christ Child paintings by Rogier van der Weyden, Hans Memling, Martin Schongauer, and Matthias Grünewald. A bilateral Babinski sign was observed in three paintings. Stimulation of the sole was noted in 48/90 (53%) paintings and was always present in paintings by Andrea del Verrocchio, Leonardo da Vinci, and Giorgione. No association existed between the presence of the Babinski sign and the period during which the painter was active. CONCLUSIONS: Four main factors were noted in relation to the representation of the Babinski sign in paintings of the Christ Child: the physiological toe phenomenon in infants, the representation of the nudity of the Christ by painters during the 15th century to demonstrate the incarnation, Renaissance painters' need for precise observation of anatomy, and the desire of some Rhenish and Flemish painters to depict very realistic details. Italian Renaissance painters, whether Mannerist or not, tended to idealise the beauty of human body, and they often did not reproduce the Babinski sign.