A scoring tool to predict mortality and dependency after cerebral venous thrombosis.

BACKGROUND AND PURPOSE: A prognostic score was developed to predict dependency and death after cerebral venous thrombosis (CVT) to identify patients for targeted therapy in future clinical trials. METHODS: Data from the International CVT Consortium were used. Patients with pre-existent functional dependency were excluded. Logistic regression was used to predict poor outcome (modified Rankin Scale score 3-6) at 6 months and Cox regression to predict 30-day and 1-year all-cause mortality. Potential predictors derived from previous studies were selected with backward stepwise selection. Coefficients were shrunk using ridge regression to adjust for optimism in internal validation. RESULTS: Of 1454 patients with CVT, the cumulative number of deaths was 44 (3%) and 70 (5%) for 30 days and 1 year, respectively. Of 1126 patients evaluated regarding functional outcome, 137 (12%) were dependent or dead at 6 months. From the retained predictors for both models, the SI2 NCAL2 C score was derived utilizing the following components: absence of female-sex-specific risk factor, intracerebral hemorrhage, infection of the central nervous system, neurological focal deficits, coma, age, lower level of hemoglobin (g/l), higher level of glucose (mmol/l) at admission, and cancer. C-statistics were 0.80 (95% confidence interval [CI] 0.75-0.84), 0.84 (95% CI 0.80-0.88) and 0.84 (95% CI 0.80-0.88) for the poor outcome, 30-day and 1-year mortality model, respectively. Calibration plots indicated a good model fit between predicted and observed values. The SI2 NCAL2 C score calculator is freely available at www.cerebralvenousthrombosis.com. CONCLUSIONS: The SI2 NCAL2 C score shows adequate performance for estimating individual risk of mortality and dependency after CVT but external validation of the score is warranted.

Olfactory dysfunction in patients with cluster headache.

OBJECTIVE: Cluster headache (CH) is a primary headache characterized by strictly unilateral, short-lasting severe headache attacks accompanied by at least one ipsilateral autonomic symptom. Our study aimed to determine whether CH patients had olfactory dysfunction and to correlate it with clinical characteristics. MATERIALS AND METHODS: Twenty patients and 57 healthy volunteers were included in the study. All participants were examined in the otorhinolaryngology outpatient clinics to exclude other clinical problems causing olfactory dysfunction. The Sniffin' Sticks test was performed, and threshold (T), discrimination (D), identification (I) scores, and TDI global olfactory score were evaluated. RESULTS: The CH patients had significantly lower threshold scores than healthy controls (6.9 ± 1.70 vs. 7.8 ± 1.08, p = 0.007). The mean threshold scores of CH patients during in-bout (n = 9) were significantly lower than CH patients during out-of-bout (n = 11) in subgroup analysis (5.9 ± 1.16 vs. 7.6 ± 1.76, p = 0.038). CH patients with left-sided headache had significantly lower discrimination scores compared to CH patients with right-sided headache (12.8 ± 1.24 vs. 14.4 ± 1.51, p = 0.03). CONCLUSION: There is marked impairment in olfactory function in CH patients compared to healthy controls.

Serum glial fibrillary acidic protein (GFAP)-antibody in idiopathic intracranial hypertension.

AIM: Idiopathic intracranial hypertension (IIH), a disease of obscure origin, is characterized by headache and visual disturbances due to increased intracranial pressure. Recent line of evidence has suggested involvement of inflammation in IIH pathogenesis thus bringing forward anti-glial autoimmunity as a potential contributor of IIH. Glial fibrillary acidic protein (GFAP) is a major astrocytic autoantigen associated with a specific form of meningoencephalitis. MATERIALS AND METHODS: In this study, we investigated the presence of GFAP-antibody in 65 sera (49 obtained during active disease and 16 during remission) and in 15 cerebrospinal fluid (CSF) samples of 58 consecutively recruited IIH patients using cell based assay and indirect immunohistochemistry. RESULTS: GFAP-antibody was found in active period sera of 2 IIH patients with classical symptoms and good treatment response. Two remission period sera obtained at different time points from one of these cases showed lower titers of GFAP-antibody positivity. IgG from positive samples yielded an astrocytic immunoreactivity pattern. None of the CSF samples showed GFAP-antibodies. CONCLUSIONS: These results suggest that anti-astrocyte autoimmunity might be present in a fraction of IIH patients. Exact pathogenic significance of this association needs to be further studied.

Parkinson's Disease Dementia and Lewy Body Disease.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PD-D) are Lewy body-related neurodegenerative disorders sharing common clinical and neuropathological findings. The clinical features of both conditions include cognitive impairment, behavioral symptoms, autonomic dysfunction, sleep disorders, and parkinsonism. The cognitive profile of both disorders is characterized by particularly severe deficits in executive and visuospatial functions as well as attention. Clinical differentiation between DLB and PD-D is based on an arbitrary distinction between the time of onset of parkinsonism and cognitive symptoms; extrapyramidal symptoms precede dementia in PD-D, whereas it coincides with or follows dementia within 1 year in DLB. When the clinical picture is fully developed, DLB and PD-D are practically indistinguishable. Although the diagnosis is basically clinical, structural and functional neuroimaging as well as cerebrospinal fluid biomarkers may help the clinician in the diagnosis. Placebo-controlled randomized trials of the cholinesterase inhibitors have shown modest but significant benefits in cognition, global function, and neuropsychiatric symptoms in both disorders. Behavioral symptoms such as hallucinations and delusions should be treated with caution with antipsychotics, as they have the potential to worsen motor and cognitive symptoms.

Assessment of the Olfactory Function in Patients With Idiopathic Intracranial Hypertension Using the Sniffin' Sticks Test: A Case-Control Study.

OBJECTIVE: Despite the lack of recognition in clinical practice, there is increasing evidence that patients with idiopathic intracranial hypertension may suffer from hyposmia. The current case-control study aims to evaluate olfactory dysfunction in a large series of patients with idiopathic intracranial hypertension. METHODS: All subjects, 44 idiopathic intracranial hypertension patients and 57 healthy controls, underwent olfactory function assessment using standardized "Sniffin' Sticks" test at a tertiary referral center of a university hospital. Threshold, discrimination, identification, and total threshold-discrimination-identification scores have been determined and analyzed statistically. RESULTS: Idiopathic intracranial hypertension patients had significantly lower threshold (6.5 [3.69] vs 8 [1.88], P < .001, 95% CI [-2.250, -0.750]) and threshold-discrimination-identification scores (29.75 [5.56] vs 32.5 [5.25], P = .003, 95% CI [-4.250, -0.750]). Twenty-five patients (57%) were diagnosed with hyposmia. Test scores of patients with active idiopathic intracranial hypertension (n = 18) were not statistically different from patients with inactive disease (n = 26), except for discrimination score (14 [2.50] vs 11 [2.25], P = .005, 95% CI [-3.000, -1.000]). Although idiopathic intracranial hypertension patients with a cerebrospinal fluid opening pressure of ≥330 mmH2 O had lower test scores, the difference was significant only for total threshold-discrimination-identification scores (28.5 [5.50] vs 30.5 [4.38], P = .044, 95% CI [0.750, 5.500]). Multiple regression analysis revealed that test scores were related to disease activity, cerebrospinal fluid opening pressure, papilledema, headache, and medication. CONCLUSION: Our clinical study revealed significant olfactory dysfunction in patients with idiopathic intracranial hypertension compared with healthy controls. Future research should employ larger samples to search for usability of olfactory testing in clinical management of patients with idiopathic intracranial hypertension.

Follow-up of patients with epilepsy harboring antiglycine receptor antibodies.

OBJECTIVE: The long-term follow-up of patients with epilepsy harboring autoantibodies against the glycine receptor (also glycine receptor antibodies or GlyR-Ab) is not well-known. Our aim was to investigate the 5-year prognosis and treatment response of patients with epilepsy who were seropositive for GlyR-Ab. METHODS: Clinical features; electroencephalogram (EEG), neuroradiological, and neuropathological findings; and treatment responses of patients with epilepsy with GlyR-Ab seropositivity were investigated. RESULTS: Thirteen (5.46%) of 238 patients with epilepsy were GlyR-Ab positive: focal epilepsy of unknown cause (FEoUC) was diagnosed in four (7.27%) out of 55 patients, mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) in five (4.5%) out of 111 patients, epileptic encephalopathy (EE) in two (4%) out of 50 patients, and status epilepticus (SE) in two (9.09%) out of 22 patients. None of the patients developed any other neurological symptoms or cancer during the 5-year follow-up. Seven of them had seizures that were resistant to antiepileptic drug (AED). Immunotherapy was used in two patients (with FEoUC and EE) improving seizure control. Three patients with MTLE-HS benefited from epilepsy surgery, and another patient with EE showed spontaneous remission. CONCLUSION: Glycine receptor antibodies are detected in a wide spectrum of epileptic disorders with unclear pathogenic significance. Two GlyR-Ab seropositive patients with AED-resistant epilepsy treated with intravenous immunoglobulin (IVIg) showed clear benefit from immunotherapy. Future studies will be valuable in determining the role of screening patients with drug-resistant epilepsy for GlyR-Ab in order to identify patients who may benefit or respond to immunotherapy.

128 The Association Between Serum Levels of Glial Biomarkers, Clinical Severity and Electro-encephalography Features in Idiopathic West and Lennox-Gastaut Syndromes.

Introduction: Although the contribution of enhanced glial activity in seizure induction is increasingly recognized, the role of glia-induced neuroinflammation in the physiopathology of epileptic encephalopathy (EE) has been scarcely investigated. Methods: To delineate the contribution of glial activity in EE, we measured levels of glia-derived mediators with previously described biomarker value, including glial fibrillary acidic protein (GFAP), high mobility group box 1 (HMGB1), chitinase-3-like protein 1 (CHI3L1), soluble CD163 (sCD163) and triggering receptor expressed on myeloid cells 2 (TREM2) by ELISA in sera of patients with idiopathic West syndrome (WS, n=18), idiopathic Lennox-Gastaut syndrome (LGS, n=13) and healthy controls (n=31). Results: Patients with EE showed significantly higher CHI3L1 levels compared to healthy controls. Levels of HMGB1, CHI3L1, sCD163 and TREM2 were higher in LGS patients than WS patients and/or healthy controls. One or more of the investigated mediators were associated with treatment responsiveness, disease severity and presence of pathological features on electroencephalography (EEG). Conclusions: To our knowledge, our findings provide the initial patient-based evidence that astrocyte- and microglia-mediated neuroinflammation might be involved in the pathogenesis of LGS and WS. Moreover, glial mediators may serve as prognostic biomarkers in patients with idiopathic EE.

Medial medullary infarction: clinical, radiological findings and long-term prognosis.

BACKGROUND AND AIM: Medial medullary infarction (MMI) is a rare type of posterior circulation stroke. We aim to examine the clinical and radiological features, etiology, and prognosis of patients with MMI. METHOD: MMI patients registered consecutively in the stroke databank of the Istanbul Medical Faculty between January 1999 and April 2022 were included in the study. Medullary lesions were rostrocaudally classified as rostral, middle, and caudal, and ventrodorsally as ventral, middle, and dorsal. The etiological classification was performed, and functional outcome was assessed based on the modified Rankin Scale (mRS). Overall survival was estimated using the Kaplan-Meier technique. RESULTS: We examined 48 cases of MMI including 9 with bilateral MMI. There were 34 men (70%), and mean age was 62.9 (± 12.8) years. The median NIHSS score was 7 (IQR; 4.5-10.5). The most common symptom was motor dysfunction. The medullary lesions were located caudally in 4 patients, rostrally in 30, rostromedially in 10, and rostro-medio-caudally in 2 patients. On ventro-dorsal classification; unilateral lesions were found ventrally in 19, ventromedially in 11, and ventro-medio-dorsally in 4 patients. The median follow-up duration was 20 months (interquartile range (IQR); 1-60). According to the third-month mRS, 39% of the patients were considered to have a good prognosis. CONCLUSION: The most common etiology was distal vertebral artery atherosclerosis. More than 50% of the patients could walk unassisted in the long-term follow-up, and stroke recurrence was infrequent. Patients with bilateral MMI had poor outcomes.

Lesion probability map in cerebral vein thrombosis due to Behçet's disease.

AIM: Behçet's disease (BD) is a multisystemic inflammatory disease. Cerebral venous sinus thrombosis (CVST) is the second most common form of neuro-BD after parenchymal central nervous system involvement. The purpose of this study was to construct flow-void probability maps of patients with CVST with and without BD to visually illustrate the impacted cerebral venous sinuses, to compare the subgroups of patients, and investigate the effect of thrombus localization on clinical findings. METHODS: Seventeen patients with a diagnosis of BD-related CVST (CVST-BD) and 23 patients with a diagnosis of CVST related to other etiologies (CVST-O) were included. We collected data including gender, age at onset of BD and CVST, presenting symptoms, neurological findings, and the etiology. High-resolution magnetic resonance venographies obtained during CVST were used to mark and digitalize thrombosed areas. Thrombus probability and subtraction maps were created to reveal the differences between the subgroups. RESULTS: Remarkably, all patients with CVST-BD had thrombosis in the transverse sinus (TS). However, TS was affected in 73.9% of the CVST-O patients (17/17 in CVST-BD vs 17/23 in CVST-O, P = .03). Thrombosis developed mostly in the superior sagittal sinus (SSS) and TS in the CVST-O group (11/23, 47.8% and 17/23, 73.9%, respectively). The frequency of SSS thrombosis tended to be higher in the CVST-O (47.8% vs 23.5%, P = .19). CONCLUSION: Venous infarction and hemorrhage were less common in patients with CVST-BD. The only clinical symptom in most of the CSVT patients with BD was headache due to elevated intracranial pressure. TS thrombosis was more common in patients with BD.

Distinct neural circuits are associated with subclinical neuropsychiatric symptoms in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) can present with neuropsychiatric symptoms (here, anxiety, depression, and apathy) at any stage of the disease. We investigated the neural correlates of subclinical neuropsychiatric symptoms in relation to motor and cognitive symptoms in a high-functioning PD cohort. METHODS: Brain morphometry of the cognitively intact, early-stage (Hoehn & Yahr 2) PD group (n = 48) was compared to matched controls (n = 37). Whole-brain, pairwise, resting-state functional connectivity measures were correlated with neuropsychiatric symptom, motor exam, and global cognitive scores of the PD group. RESULTS: Factor analysis of highly collinear anxiety, depression, and apathy scores revealed a single principal component (i.e., composite neuropsychiatric symptom score) explaining 71.6% of variance. There was no collinearity between the neuropsychiatric, motor, and cognitive scores. Compared to controls, PD group showed only subcortical changes including amygdala and nucleus accumbens atrophy, and greater pallidal volume. Reduced functional connectivity in the limbic cortical-striatal circuits and increased functional connectivity between the cerebellum and occipito-temporal regions were associated with a more impaired neuropsychiatric profile. This functional connectivity pattern was distinct from those associated with motor deficits and global cognitive functioning. The individual components of the neuropsychiatric symptoms also exhibited unique connectivity patterns. LIMITATIONS: Patients were scanned in "on-medication" state only and a control group with similar neuropsychiatric symptoms was not included. CONCLUSION: Abnormal functional connectivity of distinct neural circuits is present even at the subclinical stage of neuropsychiatric symptoms in PD. Neuropsychiatric phenotyping is important and may facilitate early interventions to "reorganize" these circuits and delay/prevent clinical symptom onset.

Structural and functional brain changes in hepatic and neurological Wilson disease.

Wilson disease (WD) can manifest with hepatic or neuropsychiatric symptoms. Our understanding of the in vivo brain changes in WD, particularly in the hepatic phenotype, is limited. Thirty subjects with WD and 30 age- and gender-matched controls participated. WD group underwent neuropsychiatric assessment. Unified WD Rating Scale neurological exam scores were used to determine neurological (WDN, score > 0) and hepatic-only (WDH, score 0) subgroups. All subjects underwent 3 Tesla anatomical and resting-state functional MRI. Diffusion tensor imaging (DTI) and susceptibility-weighted imaging (SWI) were performed only in the WD group. Volumetric, DTI, and functional connectivity analyses were performed to determine between-group differences. WDN and WDH groups were matched in demographic and psychiatric profiles. The entire WD group compared to controls showed significant thinning in the bilateral superior frontal cortex. The WDN group compared to control and WDH groups showed prominent structural brain changes including significant striatal and thalamic atrophy, more subcortical hypointense lesions on SWI, and diminished white matter integrity in the bilateral anterior corona radiata and corpus callosum. However, the WDH group also showed significant white matter volume loss compared to controls. The functional connectivity between the frontostriatal nodes was significantly reduced in the WDN group, whereas that of the hippocampus was significantly increased in the WDH group compared to controls. In summary, structural and functional brain changes were present even in neurologically non-manifesting WD patients in this cross-sectional study. Longitudinal brain MRI scans may be useful as biomarkers for prognostication and optimization of treatment strategies in WD.

Functional Connectivity Analysis in Heterozygous Glucocerebrosidase Mutation Carriers.

BACKGROUND: There is evidence that alterations in functional connectivity (FC) of the striatocortical circuits may appear before the onset of clinical symptoms of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to investigate FC of the striatocortical circuitry in asymptomatic carriers of heterozygous glucocerebrosidase (GBA) mutations, which pose a significant risk for developing PD. METHODS: Twenty-one parents of confirmed Gaucher disease patients who were carrying heterozygous GBA mutations and 18 healthy individuals matched for age and gender were included. GBA mutation analysis was performed in all participants. Clinical evaluation included neurological examination, Mini Mental State Examination, and UPDRS Part III. Structural and functional MRI data of 18 asymptomatic GBA mutation carriers (asGBAmc) and 17 healthy controls (HC) were available. FC was analyzed with seed-based approach. RESULTS: Eleven asymptomatic mutation carriers had heterozygous p.L483P mutation, 6 subjects heterozygous p.N409S mutation and 1 subject heterozygous p.R392G mutation in GBA gene. Mini-Mental State Examination mean score was 28.77 (±1.16) and 29.64 (±0.70) in asGBAmc and HC groups, respectively (p = 0.012). Significant increased connectivityConclusion:Our results suggest that alterations in striatocortical FC can be detected in asymptomatic heterozygous GBA mutation carriers who are at risk of developing PD. These findings may provide insight into network changes during the asymptomatic phase of PD.

Investigation of neuronal auto-antibodies in children diagnosed with epileptic encephalopathy of unknown cause.

AIM: Cryptogenic forms of epileptic encephalopathies (EE) with their well-known features of drug-resistance, mental deterioration and partial response to immunotherapies are ideal candidates for screening for neuronal autoantibodies (NAA). METHOD: Fifty consecutive pediatric patients with a diagnosis of EE of unknown cause were included. Nine NAAs were tested by ELISA, RIA or cell-based assays. Clinical features of seronegative and seropositive patients were compared. RESULTS: NAAs were found in 7/50 (14%) patients. They were N-methyl-d-aspartate receptor in two (4%), glycine receptor in two (4%), contactin-associated protein-like 2 in one (2%), glutamic acid decarboxylase in one (2%) and type A gamma aminobutyric acid receptor in one patient (2%). Furthermore, serum IgGs of two patients negative for well-characterized NAAs, showed strong reactivity with the uncharacterized membrane antigens of live hippocampal neurons. There were no significant differences between seropositive and seronegative patients by means of epilepsy duration, anti-epileptic drug resistance, EE type, types of seizures, seizure frequencies, EEG features or coexisting autoimmune diseases. Some seropositive patients gave good-moderate response to immunotherapy. DISCUSSION: Potential clues for the possible role of autoimmunity in seropositive patients with EE were atypical prognosis of the classical EE type, atypical progression and unusual neurological findings like dyskinesia.

Insula as the Interface Between Body Awareness and Movement: A Neurofeedback-Guided Kinesthetic Motor Imagery Study in Parkinson's Disease.

Intentional movement is an internally driven process that requires the integration of motivational and sensory cues with motor preparedness. In addition to the motor cortical-basal ganglia circuits, the limbic circuits are also involved in the integration of these cues. Individuals with Parkinson's disease (PD) have a particular difficulty with internally generating intentional movements and maintaining the speed, size, and vigor of movements. This difficulty improves when they are provided with external cues suggesting that there is a problem with the internal motivation of movement in PD. The prevailing view attributes this difficulty in PD to the dysfunction of motor cortical-basal ganglia circuits. First, we argue that the standard cortical-basal ganglia circuit model of motor dysfunction in PD needs to be expanded to include the insula which is a major hub within the limbic circuits. We propose a neural circuit model highlighting the interaction between the insula and dorsomedial frontal cortex which is involved in generating intentional movements. The insula processes a wide range of sensory signals arising from the body and integrates them with the emotional and motivational context. In doing so, it provides the impetus to the dorsomedial frontal cortex to initiate and sustain movement. Second, we present the results of our proof-of-concept experiment demonstrating that the functional connectivity of the insula-dorsomedial frontal cortex circuit can be enhanced with neurofeedback-guided kinesthetic motor imagery using functional magnetic resonance imaging in subjects with PD. Specifically, we found that the intensity and quality of body sensations evoked during motor imagery and the emotional and motivational context of motor imagery determined the direction (i.e., negative or positive) of the insula-dorsomedial frontal cortex functional connectivity. After 10-12 neurofeedback sessions and "off-line" practice of the successful motor imagery strategies all subjects showed a significant increase in the insula-dorsomedial frontal cortex functional connectivity. Finally, we discuss the implications of these results regarding motor function in patients with PD and propose suggestions for future studies.

Neuronal autoantibodies in epilepsy patients with peri-ictal autonomic findings.

Autonomic dysfunction has frequently been reported in autoimmune encephalitis associated with seizures and there is growing evidence that epilepsy patients may display neuronal autoantibodies (NAAb). The aim of this study was to investigate the frequency of NAAb in epilepsy patients with peri-ictal autonomic findings. Fifty-eight patients (37 women/21 men; average age of 34.2 ± 9.9 years and epilepsy duration of 19.1 ± 9.6 years) who had at least one video-EEG recorded focal or secondary generalized seizure with clear-cut documented peri-ictal autonomic findings, or consistently reported seizures with autonomic semiology, were included. NAAb were tested by RIA or cell based assays. NAAb were present in 17 of 58 (29.3%) patients. Among seropositive patients, antibodies were directed against N-methyl-D-aspartate receptor (NMDAR) in 5 (29%), contactin-associated protein-like 2 (CASPR2) in 5 (29%), uncharacterized voltage gated potassium channel (VGKC)-complex antigens in 3 (18%), glutamic acid decarboxylase (GAD) in 2 (12%), glycine receptor (GLYR) in one (6%) and type A gamma aminobutyric acid receptor (GABAAR) in one patient (6%). Peri-ictal gastrointestinal manifestations, piloerection, ictal fever, urinary urge, and cough occurred more commonly in the seropositive group. The prevalences of psychotic attacks and status epilepticus were significantly increased in the seropositive group. Seropositivity prevalence in our patient group with peri-ictal autonomic findings is higher than other previously reported epilepsy cohorts. In our study, ictal fever-VGKC-complex antibody and pilomotor seizure-GABAAR antibody associations were documented for the first time. Chronic epilepsy patients with peri-ictal autonomic semiology, history of status epilepticus and psychotic disorder may benefit from autoantibody screening.