Distinct hemodynamic and functional connectivity features of fatigue in clinically isolated syndrome and multiple sclerosis: accounting for the confounding effect of concurrent depression symptoms.

PURPOSE: This study aims to identify common and distinct hemodynamic and functional connectivity (FC) features for self-rated fatigue and depression symptoms in patients with clinically isolated syndrome (CIS) and relapsing-remitting multiple sclerosis (RR-MS). METHODS: Twenty-four CIS, 29 RR-MS patients, and 39 healthy volunteers were examined using resting-state fMRI (rs-fMRI) to obtain whole-brain maps of (i) hemodynamic response patterns (through time shift analysis), (ii) FC (via intrinsic connectivity contrast maps), and (iii) coupling between hemodynamic response patterns and FC. Each regional map was correlated with fatigue scores, controlling for depression, and with depression scores, controlling for fatigue. RESULTS: In CIS patients, the severity of fatigue was associated with accelerated hemodynamic response in the insula, hyperconnectivity of the superior frontal gyrus, and evidence of reduced hemodynamics-FC coupling in the left amygdala. In contrast, depression severity was associated with accelerated hemodynamic response in the right limbic temporal pole, hypoconnectivity of the anterior cingulate gyrus, and increased hemodynamics-FC coupling in the left amygdala. In RR-MS patients, fatigue was associated with accelerated hemodynamic response in the insula and medial superior frontal cortex, increased functional role of the left amygdala, and hypoconnectivity of the dorsal orbitofrontal cortex, while depression symptom severity was linked to delayed hemodynamic response in the medial superior frontal gyrus; hypoconnectivity of the insula, ventromedial thalamus, dorsolateral prefrontal cortex, and posterior cingulate; and decreased hemodynamics-FC coupling of the medial orbitofrontal cortex. CONCLUSION: There are distinct FC and hemodynamic responses, as well as different magnitude and topography of hemodynamic connectivity coupling, associated with fatigue and depression in early and later stages of MS.

Nonparaneoplastic Anti-GAD Limbic Encephalitis: Seizure Outcome and Long-term Neuropsychological Follow-up After Immunotherapy.

Antibodies against glutamate decarboxylase (GAD-Abs), especially GAD65 antibodies, are associated with limbic encephalitis (LE) manifested by temporal lobe epilepsy and neuropsychological deficits. We present the case of a 42-year-old Greek woman with nonparaneoplastic anti-GAD LE, discussing the therapeutic management and highlighting the role of neuropsychological assessment. The patient underwent functional and structural brain studies and was investigated longitudinally over a 6-year period with a battery of neuropsychological tests that were designed to document her intellectual function and verbal and visual memory. The patient suffered from refractory temporal-impaired awareness seizures and memory impairment that was mediated by autoimmune nonparaneoplastic LE and comorbid autoimmune disorders (ie, Hashimoto thyroiditis and vitiligo). Neuroimaging studies demonstrated hyperintensities in the medial temporal lobes bilaterally on T2WI MRI sequences. Serial EEGs showed bitemporal intermittent delta activity as well as epileptiform discharges. Tumor blood markers and onconeural antibodies were negative. Immunological screening revealed extremely high GAD-Abs titers in both serum and CSF, as well as the presence of CSF oligoclonal bands. Neuropsychological testing revealed anterograde amnesia with relative preservation of more remote, premorbid memories. The patient underwent first-line immunotherapy followed by immunosuppressive maintenance treatment that led to a reduction of seizures, EEG improvement, and a significant decline in GAD-Abs titers. Neuropsychological evaluations at 5 months, 1 year, and 6 years posttreatment demonstrated improvement, particularly in recent memory and everyday functionality. In this case of anti-GAD LE, the long-term seizure reduction and the improvement of neuropsychological deficits were most likely related to the immunotherapy.

T2 Relaxometry Evidence of Microstructural Changes in Diffusely Abnormal White Matter in Relapsing-Remitting Multiple Sclerosis and Clinically Isolated Syndrome: Impact on Visuomotor Performance.

BACKGROUND: Although diffusely abnormal white matter (DAWM) is commonly seen in multiple sclerosis (MS), it is rarely considered in clinical/imaging studies. PURPOSE: To evaluate quantitative markers of microstructural changes in DAWM of patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RR-MS) in relation to MS lesions and degree of neurocognitive impairment, by using a multi-echo spin echo (MESE) Proton Density PD-to-T2 sequence. STUDY TYPE: Prospective, cross-sectional. POPULATION: Thirty-seven RR-MS patients, 33 CIS patients, and 52 healthy controls. FIELD STRENGTH/SEQUENCE: 1.5 T/T1-, T2-weighted, fluid-attenuated inversion recovery, and MESE sequences. ASSESSMENT: Long T2, short T2, and myelin water fraction (MWF) values were estimated as indices of intra/extracellular water content and myelin content, respectively, in DAWM, posterior periventricular normal appearing white matter (NAWM), and focal MS lesions, classified according to their signal intensity on T1 sequences. Patients were, also, administered a battery of neuropsychological tests. STATISTICAL TESTS: Comparisons of T2 and MWF values in DAWM, NAWM, and MS lesions were examined, using two-way mixed analyses of variance. Associations of Grooved Pegboard performance with T2 and MWF values in DAWM and NAWM were assessed using Pearson correlation coefficients. RESULTS: T2 and MWF values of DAWM were intermediate between the respective values of NAWM and T1 hypointense focal lesions, while there was no difference between the respective values of DAWM and T1-isointense lesions. T2 values in DAWM were strongly associated with visuomotor performance in CIS patients. DATA CONCLUSION: Intra/extracellular water and myelin water content of DAWM are similar to those of T1-isointense lesions and predict visuomotor performance in CIS patients. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Regional MRI perfusion measures predict motor/executive function in patients with clinically isolated syndrome.

BACKGROUND: Patients with clinically isolated syndrome (CIS) demonstrate brain hemodynamic changes and also suffer from difficulties in processing speed, memory, and executive functions. OBJECTIVE: To explore whether brain hemodynamic disturbances in CIS patients correlate with executive functions. METHODS: Thirty CIS patients and forty-three healthy subjects, matched for age, gender, education level, and FSIQ, were administered tests of visuomotor learning and set shifting ability. Cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) values were estimated in normal-appearing white matter (NAWM) and normal-appearing deep gray Matter (NADGM) structures, using a perfusion MRI technique. RESULTS: CIS patients showed significantly elevated reaction time (RT) on both tasks, while their CBV and MTT values were globally increased, probably due to inflammatory vasodilation. Significantly, positive correlation coefficients were found between error rates on the inhibition condition of the visuomotor learning task and CBV values in occipital, periventricular NAWM and both thalami. On the set shifting condition of the respective task significant, positive associations were found between error rates and CBV values in the semioval center and periventricular NAWM bilaterally. CONCLUSION: Impaired executive function in CIS patients correlated positively with elevated regional CBV values thought to reflect inflammatory processes.

Early signs of memory impairment among multiple sclerosis patients with clinically isolated syndrome.

The study investigates primary and secondary verbal memory and motor/executive functions (response inhibition and strategy shifting ability) in multiple sclerosis (MS) patients with clinically isolated syndrome (CIS). We studied 44 CIS patients and compared them to 49 patients with relapsing remitting MS (RR-MS) displaying mild disability and to a large cohort of age- and education level-matched healthy volunteers(n=230). Results showed that both CIS and RR-MS patients evidenced a disproportionate impairment in the immediate and delayed recall of the second (as compared to the first) of two short narratives of the Logical Memory WMS-III subtest, and reduced performance on the Memory for Digits-Forward. Performance of either group on the executive tasks was not impaired, showing evidence of a reversed speed-accuracy trade-off. Illness duration emerged as a significant predictor of memory and executive task performance. Clinical, psychoemotional, and brain imaging findings were also examined as potential correlates of memory deficits and disease progression among CIS patients. These findings may signify early-onset decline of specific cognitive functions in CIS, which merits regular follow-up assessments and monitoring of psychoemotional adaptation and everyday functioning.

Oxcarbazepine monotherapy in benign childhood epilepsy with centrotemporal spikes: a clinical and cognitive evaluation.

We report on 70 patients (aged 5.2-11.6 years) newly diagnosed with benign childhood epilepsy with centrotemporal spikes (BECTS) who were assigned to oxcarbazepine (OXC) monotherapy. All of them underwent clinical and electroencephalographic examination at baseline and at 3- to 6-month intervals during the study. Psychometric assessment was performed at baseline and after 18 months of treatment with the WISC-III, Illinois Test of Psychomotor Abilities, DSM-IV, and Bender-Santucci test. The Mann-Whitney U test was used to describe differences in the frequency of abnormal findings: (1) at initial evaluation, comparing patients with a matched group of 45 healthy controls, and (2) after 18 months of OXC monotherapy, as an individual follow-up in the patient group. Cognitive assessment at baseline revealed mild learning disabilities in 9% of patients and 7% of controls; all participants had a normal intelligence quotient. During the follow-up, sustained cessation of seizures under medication was observed in 53% of patients; an additional 21% had some relapse but were subsequently rendered seizure free, 21% experienced a >50% improvement, and 5% showed no improvement. Normalization of interictal epileptiform activity was observed in 58% of patients, 35% showed an improvement in the grade of electroencephalographic pathology, and 7% manifested no change at all. The initial mildly weak scores in isolated cognitive domains did not deteriorate, and even improved in some cases, during the course of the study, with concomitant electroencephalographic improvement or normalization and effective seizure control. The results of this study suggest that OXC is effective in preventing seizures and normalizing electroencephalograms and seems to preserve cognitive functions and behavioral abilities as long-term monotherapy in children with typical BECTS.