Identifying large vessel occlusion at first glance in telemedicine.

BACKGROUND: Telemedicine has rapidly emerged as an important tool in emergency neurology. In particular, reliable biomarkers of large vessel occlusions (LVOs) are critically necessary in order to identify the need for in-hospital mechanical thrombectomy (MT). Based on pathophysiological factors, we propose that the presence of head and/or gaze deviation alone signifies cortical hypoperfusion and is therefore a highly sensitive marker for the presence of LVO. METHODS: We retrospectively analyzed a cohort of 160 patients, examined via telemedicine and suspected to have had an acute stroke; this included patients with ischemic or hemorrhagic stroke, transient ischemic attack, and stroke mimics. An assessment of head and gaze deviation and NIHSS score evaluation was performed. In a second analysis, patients who only had ischemia in the anterior circulation (n = 110) were evaluated. RESULTS: Head and/or gaze deviation alone was found to be a reliable marker of LVO (sensitivity: 0.66/specificity: 0.92), as well as a sound indicator for MT (0.82/0.91), in patients with suspected ischemic stroke. The performance of this indicator further improved when patients with ischemia in the anterior circulation only were assessed (LVO: 0.70/0.93; MT: 0.86/0.90). In both analyses, head and/or gaze deviation served as a better indicator for LVO or MT compared to the prevalence of motor deficits or aphasia. Of note, in patients who had ischemia in the anterior circulation, head and/or gaze deviation performed better than the NIHSS score as an indicator for MT. CONCLUSION: These findings confirm that the presence of head and/or gaze deviation serves as a reliable biomarker in stroke-based telemedicine for the diagnosis of LVO, as well as a strong indicator for MT. Furthermore, this marker is just as reliable as the NIHSS score but easier to assess. We therefore suggest that any stroke patient who displays head and/or gaze deviation should immediately be scheduled for vessel imaging and subsequently transported to a MT-competent center.

The Rydel Seiffer tuning fork - Age and gender matter.

BACKGROUND: The Rydel Seiffer tuning fork (RSTF) can be easily applied to evaluate deficits of vibration perception. Standard normative data as stated in textbooks (6/8-thresholds among the "elderly") is not suitable for an informed decision-making process. OBJECTIVE: To reevaluate the range of vibration detection thresholds (VDT) based on assessments in healthy Caucasians stratified for age and gender using the RSTF and on a short-review of literature on normative data on PubMed. METHODS: Monocentric, prospective assessment of VDT at the dorsal 1st metatarsophalangeal joint of both sides in 77 healthy volunteers. Participants were grouped according to age: 20-39 years (group I, n = 24), 40-59 years (group II, n = 29), 60-79 years (group III, n = 24). Data was stratified for gender. Means were compared via Mann-Whitney U-test; correlations were rated via Pearson correlation coefficient. A short-review of literature was performed on PubMed. RESULTS: Aging related to declined vibration perception (r = -0.446, p < 0.001). Women aged 60 years and older showed better vibration perception compared to men (men: 6.5 ± 1.3, women: 7.5 ± 0.9, p = 0.003). All VDT-limits were higher compared to results gathered in literature (I: 7.9 ± 0.3, II: 7.7 ± 0.5, III: 7.1 ± 1.1). Formerly reported VDT-limits at the lower limbs were scattered (e.g., >4.5/8 to ≥6.6/8 at age 18-29). Current data, especially VDT of participants aged 50 years and older, were largely in line with data reported by Hilz et al. 1998: 18-29 years: ≥ 6.6/8, 30-39 years: ≥ 5.5/8, 40-49 years: ≥ 5.7/8, 50-59 years: ≥ 5.4/8, 60-69 years ≥ 5.2/8, > 70 years ≥ 5.3/8, alternative: 30-39 years ≥ 6.2/8 Magerl et al. 2010. Data on diagnostic sensitivity by Xirou et al. 2020 supported a VDT-limit of 5.9/8 across all ages to aim for high sensitivity. A better vibration perception among elder women compared to men has been described by many studies. DISCUSSION: The current data and literature underline, that higher VDT-limits stratified for age and gender should be considered in a clinical setting. Until further validation within larger samples, we propose to consider the limits as reported by Hilz et al. 1998. Furthermore, women at age 60 + years presenting with borderline thresholds should be considered for further diagnostic workup.

Anatomical correlates of recovery in apraxia: A longitudinal lesion-mapping study in stroke patients.

OBJECTIVE: This study investigates the clinical course of recovery of apraxia after left-hemisphere stroke and the underlying neuroanatomical correlates for persisting or recovering deficits in relation to the major processing streams in the network for motor cognition. METHODS: 90 patients were examined during the acute (4.74 ± 2.73 days) and chronic (14.3 ± 15.39 months) stage after left-hemisphere stroke for deficits in meaningless imitation, as well as production and conceptual errors in tool use pantomime. Lesion correlates for persisting or recovering deficits were analyzed with an extension of the non-parametric Brunner-Munzel rank-order test for multi-factorial designs (two-way repeated-measures ANOVA) using acute images. RESULTS: Meaningless imitation and tool use production deficits persisted into the chronic stage. Conceptual errors in tool use pantomime showed an almost complete recovery. Imitation errors persisted after occipitotemporal and superior temporal lesions in the dorso-dorsal stream. Chronic pantomime production errors were related to the supramarginal gyrus, the key structure of the ventro-dorsal stream. More anterior lesions in the ventro-dorsal stream (ventral premotor cortex) were additionally associated with poor recovery of production errors in pantomime. Conceptual errors in pantomime after temporal and supramarginal gyrus lesions persisted into the chronic stage. However, they resolved completely when related to angular gyrus or insular lesions. CONCLUSION: The diverging courses of recovery in different apraxia tasks can be related to different mechanisms. Critical lesions to key structures of the network or entrance areas of the processing streams lead to persisting deficits in the corresponding tasks. Contrary, lesions located outside the core network but inducing a temporary network dysfunction allow good recovery e.g., of conceptual errors in pantomime. The identification of lesion correlates for different long-term recovery patterns in apraxia might also allow early clinical prediction of the course of recovery.

The correlation between apraxia and neglect in the right hemisphere: A voxel-based lesion-symptom mapping study in 138 acute stroke patients.

Apraxia is frequently described after left hemisphere stroke and results from lesions to a complex network for motor cognition with dorso-dorsal, ventro-dorsal and ventral processing streams. Apraxia also occurs after right hemisphere stroke, but lesion correlates and underlying mechanisms remain to be elucidated. To clarify the role of the right hemisphere in apraxic deficits and the influence of neglect, we prospectively examined apraxia (imitation of meaningless postures and pantomime of tool use) and neglect in 138 acute right hemisphere stroke patients with first-ever ischemic stroke in the middle cerebral artery territory and identified corresponding lesion correlates using voxel-based lesion-symptom mapping. Imitation of meaningless postures was impaired as frequently as after left hemisphere stroke (38.4%) and was significantly associated with neglect. Imitation of meaningless postures was related to temporal (middle temporal gyrus, temporoparietal junction, superior temporal gyrus and sulcus), parietal (angular gyrus, parieto-occpitpial sulcus), secondary sensorimotor cortex and (peri-)insular lesions. Presence of neglect dichotomized the results: a lesion correlate for isolated imitation without neglect was found in the right parieto-occipital cortex, while imitation deficits, when co-occurring with neglect, were related to lateral occipito-temporal, superior temporal sulcus and (peri-)insular lesions. Pantomime of tool use deficits, typical for apraxia after left hemisphere lesions, were found in only 5 cases (3.6%) and only in the context of neglect, and were associated with occipital lobe, ventral and anterior temporal lobe, and inferior frontal (areas 45/47) lesions. The syndrome of apraxia after right hemisphere stroke differs from apraxia after left hemisphere stroke. Imitation deficits are found in both hemispheres after dorso-dorsal stream lesions. Neglect also leads to and explains deficits in imitation and pantomime in patients with right ventral stream lesions. Therefore, in right hemisphere lesions, apraxia can either be explained as impaired visuomotor transformation or as a result of visuospatial deficits.

Dissociation of visual extinction and neglect in the left hemisphere.

Visual neglect and extinction are two distinct visuospatial attention deficits that frequently occur after right hemisphere cerebral stroke. However, their different lesion profiles remain a matter of debate. In the left hemisphere, a domain-general dual-loop model with distinct computational abilities onto which several cognitive functions may project, has been proposed: a dorsal stream for sensori-motor mapping in time and space and a ventral stream for comprehension and representation of concepts. We wondered whether such a distinction may apply to visual extinction and neglect in left hemisphere lesions. Of 165 prospectively studied patients with acute left hemispheric ischemic stroke with a single lesion on MRI, 122 had no visuospatial attention deficit, 10 had extinction, 31 neglect and 2 had both, visual extinction and neglect. Voxel-based-lesion-symptom mapping (VLSM, FDR<.05) showed a clear anatomical dissociation. Extinction occurred after damage to the parietal cortex (anterior bank of the intraparietal sulcus, inferior parietal lobe, and supramarginal gyrus), while visual neglect occurred after damage mainly to the temporal lobe (superior and middle temporal lobe, anterior temporal pole), inferior ventral premotor cortex, frontal operculum, angular gyrus, and insula. Direct comparison of both conditions linked extinction to intraparietal sulcus and supramarginal gyrus (FDR<.05). Thus, in the left hemisphere extinction seems to be related to dorsal stream lesions, whereas neglect maps more on the ventral stream. These data cannot be generalized to the right hemisphere. However, a domain-general point-of-view may stimulate discussion on visuospatial attention processing also in the right hemisphere.

Long-term outcome changes after mechanical thrombectomy for anterior circulation acute ischemic stroke.

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) improves early clinical outcome in patients with acute ischemic stroke but insights on determinants of long-term outcome after MT treatment are scarce. METHODS: Data from stroke patients with anterior circulation large vessel occlusion of a prospective MT registry (01/2014-06/2017) of a large comprehensive stroke center were analyzed regarding clinical outcome between short- (3 months) and long-term (12 months) assessment reflected by a change of modified Rankin scores (∆mRS). Secondary endpoints included favorable long-term outcome (mRS 0-2). Multi-variable regression analysis was performed to identify determinants of outcome changes and favorable outcome at long term. RESULTS: Of 264 patients included, 42.0% showed a favorable long-term outcome. Longitudinal analysis found that some individuals still improved, but no overall mRS difference between short and long-term follow-up was detected [∆mRS - 0.004 (95% CI - 0.020; 0.013); p = 0.672]. Right hemispheric stroke [∆mRS 0.286 (0.011; 0.561); p = 0.043] and high NIHSS at discharge [∆mRS, 0.039 (0.004; 0.074); p = 0.029] were associated with a longitudinal mRS decline. Favorable long-term outcome was associated with successful recanalization (p < 0.0001). CONCLUSIONS: A significant number of patients with MT experience a favorable long-term outcome. Outcomes remained stable between short- and long-term follow-up, but some individuals may still show improvement beyond short-term rehabilitation. Right hemispheric stroke and clinical stroke severity at hospital discharge may be frail predictors for delayed decline of functional status, whereas successful recanalization remains a positive outcome predictor. Death rarely occurs beyond 3 months after MT treatment.

Neural correlates of acute apraxia: Evidence from lesion data and functional MRI in stroke patients.

Behavioral deficits after stroke like apraxia can be related to structural lesions and to a functional state of the underlying network - three factors, reciprocally influencing each other. Combining lesion data, behavioral performance and passive functional activation of the network-of-interest, this study aims to disentangle those mutual influences and to identify 1) activation patterns associated with the presence or absence of acute apraxia in tool-associated actions and 2) the specific impact of lesion location on those activation patterns. Brain activity of 48 patients (63.31 ± 13.68 years, 35 male) was assessed in a fMRI paradigm with observation of tool-related actions during the acute phase after first-ever left-hemispheric stroke (4.83 ± 2.04 days). Behavioral assessment of apraxia in tool-related tasks was obtained independently. Brain activation was compared between patients versus healthy controls and between patient with versus without apraxia. Interaction effects of lesion location (frontal vs parietal) and behavioral performance (apraxia vs no apraxia) were assessed in a 2 × 2 factorial design. Action observation activated the ventro-dorsal parts of the network for cognitive motor function; activation was globally downregulated after stroke. Apraxic compared to non-apraxic patients showed relatively increased activity in bilateral posterior middle temporal gyrus and middle frontal gyrus/superior frontal sulcus. Altered activation occurred in regions for tool-related cognition, corroborating known functions of the ventro-dorsal and ventral streams for praxis, and comprised domain-general areas, functionally related to cognitive control. The interaction analyses revealed different levels of activation in the left anterior middle temporal gyrus in the ventral stream in apraxic patients with frontal compared to parietal lesions, suggesting a modulation of network activation in relation to behavioral performance and lesion location as separate factors. By detecting apraxia-specific activation patterns modulated by lesion location, this study underlines the necessity to combine structural lesion information, behavioral parameters and functional activation to comprehensively examine cognitive functions in acute stroke patients.

Primary intraspinal non-Hodgkin's lymphoma: Case report and review of literature.

We present the unique case of an 67-year-old female patient with primary intraspinal B-cell non-Hodgkin's lymphoma without cerebral manifestation mimicking myelitis in clinical presentation and neuroradiological diagnostic. It illustrates the broad spectrum of differential diagnoses for paraplegia and the importance of rapid interdisciplinary diagnostic work-up since the neurologic status after treatment mainly depends on the delay of treatment. Review of existing literature suggests combined radio- and chemotherapy as well as high-dose intravenous methotrexate or rituximab. The rising incidence of spinal lymphomas especially in patients with acquired immunodeficiency underlines the importance of fast diagnosis and initiation of treatment of this rare entity.

Large Vessel Occlusion in Acute Stroke.

Background and Purpose- To date, no clinical score has become widely accepted as an eligible prehospital marker for large vessel occlusion (LVO) and the need of mechanical thrombectomy (MT) in ischemic stroke. On the basis of pathophysiological considerations, we propose that cortical symptoms such as aphasia and neglect are more sensitive indicators for LVO and MT than motor deficits. Methods- We, thus, retrospectively evaluated a consecutive cohort of 543 acute stroke patients including patients with ischemia in the posterior circulation, hemorrhagic stroke, transient ischemic attack, and stroke mimics to best represent the prehospital setting. Results- Cortical symptoms alone showed to be a reliable indicator for LVO (sensitivity: 0.91; specificity: 0.70) and MT (sensitivity: 0.90; specificity: 0.60) in acute stroke patients, whereas motor deficits showed a sensitivity of 0.85 for LVO (specificity: 0.53) and 0.87 for MT (specificity: 0.48). Conclusions- We propose that in the prehospital setting, the presence of cortical symptoms is a reliable indicator for LVO and its presence justifies transportation to an MT-capable center.

Activation of disease during therapy with alemtuzumab in 3 patients with multiple sclerosis.

OBJECTIVE: To report 3 patients with multiple sclerosis showing severe activation of disease during immunotherapy with alemtuzumab. METHODS: Retrospective case series. RESULTS: Patient 1, a 21-year-old woman, developed severe cognitive impairment, sight deterioration, severe gait ataxia, urinary retention, and extensive progression of cerebral lesion load, including new lesions that exhibited gadolinium ring enhancement and dominance of CD19/20-positive B lymphocytes, 6 months after induction of alemtuzumab. Patient 2, a 28-year-old man, developed left-sided hemihypesthesia and ∼60 new cerebral and spinal lesions including lesions with gadolinium ring enhancement 6 months after induction of alemtuzumab. Patient 3, a 37-year-old woman, developed ataxia and numbness of the left thigh, 16 new gadolinium-positive supratentorial lesions, and partly ring-enhancing and dominance of CD19/20-positive B lymphocytes 6 months after induction of alemtuzumab. CONCLUSION: This is a case series reporting severe activation of disease during immunotherapy with alemtuzumab. All patients showed onset of symptoms 6 months after induction of alemtuzumab, strikingly similar MRI lesion morphology, and unexpected high total B cell count, which may suggest a B-cell-mediated activation of disease. Whether this is due to different rates of B- and T cell repopulation has to be the subject of further research. Moreover, further effects on the interactions between the adaptive and innate immunity as well as between B and T cell lineages might explain the observed disease activation.

Distinct Contributions of Dorsal and Ventral Streams to Imitation of Tool-Use and Communicative Gestures.

Imitation of tool-use gestures (transitive; e.g., hammering) and communicative emblems (intransitive; e.g., waving goodbye) is frequently impaired after left-hemispheric lesions. We aimed 1) to identify lesions related to deficient transitive or intransitive gestures, 2) to delineate regions associated with distinct error types (e.g., hand configuration, kinematics), and 3) to compare imitation to previous data on pantomimed and actual tool use. Of note, 156 patients (64.3 ± 14.6 years; 56 female) with first-ever left-hemispheric ischemic stroke were prospectively examined 4.8 ± 2.0 days after symptom onset. Lesions were delineated on magnetic resonance imaging scans for voxel-based lesion-symptom mapping. First, while inferior-parietal lesions affected both gesture types, specific associations emerged between intransitive gesture deficits and anterior temporal damage and between transitive gesture deficits and premotor and occipito-parietal lesions. Second, impaired hand configurations were related to anterior intraparietal damage, hand/wrist-orientation errors to premotor lesions, and kinematic errors to inferior-parietal/occipito-temporal lesions. Third, premotor lesions impacted more on transitive imitation compared with actual tool use, pantomimed and actual tool use were more susceptible to lesioned insular cortex and subjacent white matter. In summary, transitive and intransitive gestures differentially rely on ventro-dorsal and ventral streams due to higher demands on temporo-spatial processing (transitive) or stronger reliance on semantic information (intransitive), respectively.

Are semantic and phonological fluency based on the same or distinct sets of cognitive processes? Insights from factor analyses in healthy adults and stroke patients.

Verbal fluency for semantic categories and phonological letters is frequently applied to studies of language and executive functions. Despite its popularity, it is still debated whether measures of semantic and phonological fluency reflect the same or distinct sets of cognitive processes. Word generation in the two task variants is believed to involve different types of search processes. Findings from the lesion and neuroimaging literature further suggest a stronger reliance of phonological and semantic fluency on frontal and temporal brain areas, respectively. This evidence for differential cognitive and neural contributions is, however, strongly challenged by findings from factor analyses, which have consistently yielded only one explanatory factor. As all previous factor-analytical approaches were based on very small item sets, this apparent discrepancy may be due to methodological limitations. In this study, we therefore applied a German version of the verbal fluency task with 8 semantic (i.e. categories) and 8 phonological items (i.e. letters). An exploratory factor analysis with oblique rotation in N=69 healthy young adults indeed revealed a two-factor solution with markedly different loadings for semantic and phonological items. This pattern was corroborated by a confirmatory factor analysis in a sample of N=174 stroke patients. As results from both samples also revealed a substantial portion of common variance between the semantic and phonological factor, the present data further demonstrate that semantic and phonological verbal fluency are based on clearly distinct but also on shared sets of cognitive processes.

Distinct white matter alterations following severe stroke: Longitudinal DTI study in neglect.

OBJECTIVE: To distinguish white matter remodeling directly induced by stroke lesion from that evoked by remote network dysfunction, using spatial neglect as a model. METHODS: We examined 24 visual neglect/extinction patients and 17 control patients combining comprehensive analyses of diffusion tensor metrics and global fiber tracking with neuropsychological testing in the acute (6.3 ± 0.5 days poststroke) and chronic (134 ± 7 days poststroke) stroke phases. RESULTS: Compared to stroke controls, patients with spatial neglect/extinction displayed longitudinal white matter alterations with 2 defining signatures: (1) perilesional degenerative changes characterized by congruently reduced fractional anisotropy and increased radial diffusivity (RD), axial diffusivity, and mean diffusivity, all suggestive of direct axonal damage by lesion and therefore nonspecific for impaired attention network and (2) transneuronal changes characterized by an increased RD in contralesional frontoparietal and bilateral occipital connections, suggestive of primary periaxonal involvement; these changes were distinctly related to the degree of unrecovered neglect symptoms in chronic stroke, hence emerging as network-specific alterations. CONCLUSIONS: The present data show how stroke entails global alterations of lesion-spared network architecture over time. Sufficiently large lesions of widely interconnected association cortex induce distinct, large-scale structural reorganization in domain-specific network connections. Besides their relevance to unrecovered domain-specific symptoms, these effects might also explain mechanisms of domain-general deficits in stroke patients, pointing to potential targets for therapeutic intervention.

Automated Infarct Core Volumetry Within the Hypoperfused Tissue: Technical Implementation and Evaluation.

OBJECTIVE: The aim of this study was to develop a rapid and fully automatic infarct core and tissue at risk volumetry approach in acute ischemic stroke. METHODS: We evaluated an algorithm in which segmentation was restricted to 1 hemisphere and the potential lesion characterized on the basis of the perfusion parameter Tmax with a region-wise comparison of local histograms to its mirrored counterpart. RESULTS: We applied the "Tmax inside" method to 30 cases of a public data set with ground-truth segmentations for diffusion-weighted and perfusion magnetic resonance imaging. Lesions were robustly identified with significantly higher dice coefficients (apparent diffusion coefficient, 0.83 ± 0.22; Tmax, 0.80 ± 0.05, compared with 0.53 ± 0.27 and 0.56 ± 0.18) than for a global thresholding approach. CONCLUSIONS: The proposed "Tmax inside" method is superior to the commonly used global thresholding approach. Furthermore, the method allows evaluating changes in cerebral blood volume and blood flow by taking the counterpart in the healthy hemisphere as a patient-individual reference.

Visual neglect after left-hemispheric lesions: a voxel-based lesion-symptom mapping study in 121 acute stroke patients.

Visual neglect after left-hemispheric lesion is thought to be less frequent, less severe, and shorter lived than visuospatial attention deficits resulting from right-hemispheric lesions. However, reports exist opposing this assumption, and it is unclear how these findings fit into the current theories of visuospatial processing. Furthermore, only little is known about the exact structure-function relationship between visuospatial attention deficits and left-hemispheric stroke. We investigated neglect in 121 patients with acute left-hemispheric ischemic stroke by following clinical development from within the first 24 h of stroke onset until hospital discharge. Visuospatial attention deficits occurred in 17.4 % (n = 21). Voxel-based lesion-symptom mapping associated visual neglect to the right with lesion in the left superior and middle temporal gyrus, temporal pole, frontal operculum, and insula. Neglect severity, captured by the Center of Cancellation Score of the Bells test, was associated with lesion in the left anterior temporal lobe and the left frontal operculum. The left-hemispheric lesion pattern of neglect thus involves areas of the ventral attention system and partly mirrors the critical regions of the right hemisphere known to be associated with neglect. Based on our prospective analysis on a large cohort of patients with left-hemispheric stroke, this study shows that in a remarkable number of patients, the left hemisphere essentially contributes to an intact representation of space and clarifies the impact of the distinct left-hemispheric structures involved in visuospatial processing.

Componential Network for the Recognition of Tool-Associated Actions: Evidence from Voxel-based Lesion-Symptom Mapping in Acute Stroke Patients.

The study aimed to elucidate areas involved in recognizing tool-associated actions, and to characterize the relationship between recognition and active performance of tool use.We performed voxel-based lesion-symptom mapping in a prospective cohort of 98 acute left-hemisphere ischemic stroke patients (68 male, age mean ± standard deviation, 65 ± 13 years; examination 4.4 ± 2 days post-stroke). In a video-based test, patients distinguished correct tool-related actions from actions with spatio-temporal (incorrect grip, kinematics, or tool orientation) or conceptual errors (incorrect tool-recipient matching, e.g., spreading jam on toast with a paintbrush). Moreover, spatio-temporal and conceptual errors were determined during actual tool use.Deficient spatio-temporal error discrimination followed lesions within a dorsal network in which the inferior parietal lobule (IPL) and the lateral temporal cortex (sLTC) were specifically relevant for assessing functional hand postures and kinematics, respectively. Conversely, impaired recognition of conceptual errors resulted from damage to ventral stream regions including anterior temporal lobe. Furthermore, LTC and IPL lesions impacted differently on action recognition and active tool use, respectively.In summary, recognition of tool-associated actions relies on a componential network. Our study particularly highlights the dissociable roles of LTC and IPL for the recognition of action kinematics and functional hand postures, respectively.

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are present in a subset of aquaporin-4 (AQP4)-IgG-negative patients with optic neuritis (ON) and/or myelitis. Little is known so far about brainstem involvement in MOG-IgG-positive patients. OBJECTIVE: To investigate the frequency, clinical and paraclinical features, course, outcome, and prognostic implications of brainstem involvement in MOG-IgG-positive ON and/or myelitis. METHODS: Retrospective case study. RESULTS: Among 50 patients with MOG-IgG-positive ON and/or myelitis, 15 (30 %) with a history of brainstem encephalitis were identified. All were negative for AQP4-IgG. Symptoms included respiratory insufficiency, intractable nausea and vomiting (INV), dysarthria, dysphagia, impaired cough reflex, oculomotor nerve palsy and diplopia, nystagmus, internuclear ophthalmoplegia (INO), facial nerve paresis, trigeminal hypesthesia/dysesthesia, vertigo, hearing loss, balance difficulties, and gait and limb ataxia; brainstem involvement was asymptomatic in three cases. Brainstem inflammation was already present at or very shortly after disease onset in 7/15 (47 %) patients. 16/21 (76.2 %) brainstem attacks were accompanied by acute myelitis and/or ON. Lesions were located in the pons (11/13), medulla oblongata (8/14), mesencephalon (cerebral peduncles; 2/14), and cerebellar peduncles (5/14), were adjacent to the fourth ventricle in 2/12, and periaqueductal in 1/12; some had concomitant diencephalic (2/13) or cerebellar lesions (1/14). MRI or laboratory signs of blood-brain barrier damage were present in 5/12. Cerebrospinal fluid pleocytosis was found in 11/14 cases, with neutrophils in 7/11 (3-34 % of all CSF white blood cells), and oligoclonal bands in 4/14. Attacks were preceded by acute infection or vaccination in 5/15 (33.3 %). A history of teratoma was noted in one case. The disease followed a relapsing course in 13/15 (87 %); the brainstem was involved more than once in 6. Immunosuppression was not always effective in preventing relapses. Interferon-beta was followed by new attacks in two patients. While one patient died from central hypoventilation, partial or complete recovery was achieved in the remainder following treatment with high-dose steroids and/or plasma exchange. Brainstem involvement was associated with a more aggressive general disease course (higher relapse rate, more myelitis attacks, more frequently supratentorial brain lesions, worse EDSS at last follow-up). CONCLUSIONS: Brainstem involvement is present in around one third of MOG-IgG-positive patients with ON and/or myelitis. Clinical manifestations are diverse and may include symptoms typically seen in AQP4-IgG-positive neuromyelitis optica, such as INV and respiratory insufficiency, or in multiple sclerosis, such as INO. As MOG-IgG-positive brainstem encephalitis may take a serious or even fatal course, particular attention should be paid to signs or symptoms of additional brainstem involvement in patients presenting with MOG-IgG-positive ON and/or myelitis.

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin.

BACKGROUND: Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders. OBJECTIVE: To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers. METHODS: 614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells. RESULTS: MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7 %) patients with a history of both ON and myelitis, 22/103 (21.4 %) with a history of ON but no myelitis and 6/45 (13.3 %) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67 %) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89 %) follow-up samples obtained over a median period of 16.5 months (range 0-123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment. CONCLUSIONS: To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status.

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome.

BACKGROUND: A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). OBJECTIVE: To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes. METHODS: Retrospective multicenter study. RESULTS: The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80 % (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40 % (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36 %) and markedly impaired ambulation due to paresis or ataxia (25 %) as the most common long-term sequelae. Functional blindess in one or both eyes was noted during at least one ON attack in around 70 %. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70 %). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44 %. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50 %; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70 %, oligoclonal bands in only 13 %, and blood-CSF-barrier dysfunction in 32 %. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9 %). Wingerchuk's 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28 %, 32 %, 15 %, 33 %, respectively; MS had been suspected in 36 %. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases. CONCLUSION: Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.

Brain activity underlying tool-related and imitative skills after major left hemisphere stroke.

Apraxia is a debilitating cognitive motor disorder that frequently occurs after left hemisphere stroke and affects tool-associated and imitative skills. However, the severity of the apraxic deficits varies even across patients with similar lesions. This variability raises the question whether regions outside the left hemisphere network typically associated with cognitive motor tasks in healthy subjects are of additional functional relevance. To investigate this hypothesis, we explored regions where functional magnetic resonance imaging activity is associated with better cognitive motor performance in patients with left hemisphere ischaemic stroke. Thirty-six patients with chronic (>6 months) large left hemisphere infarcts (age ± standard deviation, 60 ± 12 years, 29 male) and 29 control subjects (age ± standard deviation, 72 ± 7, 15 male) were first assessed behaviourally outside the scanner with tests for actual tool use, pantomime and imitation of tool-use gestures, as well as for meaningless gesture imitation. Second, functional magnetic resonance imaging activity was registered during the passive observation of videos showing tool-associated actions. Voxel-wise linear regression analyses were used to identify areas where behavioural performance was correlated with functional magnetic resonance imaging activity. Furthermore, lesions were delineated on the magnetic resonance imaging scans for voxel-based lesion-symptom mapping. The analyses revealed two sets of regions where functional magnetic resonance imaging activity was associated with better performance in the clinical tasks. First, activity in left hemisphere areas thought to mediate cognitive motor functions in healthy individuals (i.e. activity within the putative 'healthy' network) was correlated with better scores. Within this network, tool-associated tasks were mainly related to activity in supramarginal gyrus and ventral premotor cortex, while meaningless gesture imitation depended more on the anterior intraparietal sulcus and superior parietal lobule. Second, repeating the regression analyses with total left hemisphere lesion volume as additional covariate demonstrated that tool-related skills were further supported by right premotor, right inferior frontal and left anterior temporal areas, while meaningless gesture imitation was also driven by the left dorso-lateral prefrontal cortex. In summary, tool-related and imitative skills in left hemisphere stroke patients depend on the activation of spared left hemisphere regions that support these abilities in healthy individuals. In addition, cognitive motor functions rely on the activation of ipsi- and contralesional areas that are situated outside this 'healthy' network. This activity may explain why some patients perform surprisingly well despite large left brain lesions, while others are severely impaired.