Microstates in multiple sclerosis: an electrophysiological signature of altered large-scale networks functioning?

Multiple sclerosis has a highly variable course and disabling symptoms even in absence of associated imaging data. This clinical-radiological paradox has motivated functional studies with particular attention to the resting-state networks by functional MRI. The EEG microstates analysis might offer advantages to study the spontaneous fluctuations of brain activity. This analysis investigates configurations of voltage maps that remain stable for 80-120 ms, termed microstates. The aim of our study was to investigate the temporal dynamic of microstates in patients with multiple sclerosis, without reported cognitive difficulties, and their possible correlations with clinical and neuropsychological parameters. We enrolled fifty relapsing-remitting multiple sclerosis patients and 24 healthy subjects, matched for age and sex. Demographic and clinical data were collected. All participants underwent to high-density EEG in resting-state and analyzed 15 min free artefact segments. Microstates analysis consisted in two processes: segmentation, to identify specific templates, and back-fitting, to quantify their temporal dynamic. A neuropsychological assessment was performed by the Brief International Cognitive Assessment for Multiple Sclerosis. Repeated measures two-way ANOVA was run to compare microstates parameters of patients versus controls. To evaluate association between clinical, neuropsychological and microstates data, we performed Pearsons' correlation and stepwise multiple linear regression to estimate possible predictions. The alpha value was set to 0.05. We found six templates computed across all subjects. Significant differences were found in most of the parameters (global explained variance, time coverage, occurrence) for the microstate Class A (P < 0.001), B (P < 0.001), D (P < 0.001), E (P < 0.001) and F (P < 0.001). In particular, an increase of temporal dynamic of Class A, B and E and a decrease of Class D and F were observed. A significant positive association of disease duration with the mean duration of Class A was found. Eight percent of patients with multiple sclerosis were found cognitive impaired, and the multiple linear regression analysis showed a strong prediction of Symbol Digit Modalities Test score by global explained variance of Class A. The EEG microstate analysis in patients with multiple sclerosis, without overt cognitive impairment, showed an increased temporal dynamic of the sensory-related microstates (Class A and B), a reduced presence of the cognitive-related microstates (Class D and F), and a higher activation of a microstate (Class E) associated to the default mode network. These findings might represent an electrophysiological signature of brain reorganization in multiple sclerosis. Moreover, the association between Symbol Digit Modalities Test and Class A may suggest a possible marker of overt cognitive dysfunctions.

Lost diagnoses in not otherwise specified headache in Emergency Department.

 The diagnosis of Not Otherwise Specified (NOS) headaches in the Emergency Department (ED) is frequent despite many specialist visits performed. The aim of the study was to examine specialist visits carried out in the patients discharged from ED with diagnosis of NOS headache to evaluate discrepancies between specialist and ED diagnosis at discharge. We retrospectively (1.6.2018-31.12.2018) analyzed all the patients admitted with non-traumatic headache to the ED of the tertiary-care University Hospital of Trieste. We evaluated the patients discharged from ED with a final diagnosis of NOS headache and who underwent at least one specialist examination. Demographic data, specialist and ED diagnosis were analyzed.  One hundred twenty-four patients (93 F, 31 M, mean age 44 ± 15 years) were included. 71.8% of patients were examined only by a neurologist, 12.9% by non-neurologists, 15.3% by both neurologist and non-neurologist. Only 37% of the patients received a precise diagnosis. Neurologist made a diagnosis slightly more frequently than the other consultants (40.5% vs 37.5%). Neurologists diagnosed primary headaches, headaches secondary to neurological diseases, and facial neuralgia, instead non-neurologists diagnosed only headaches secondary to non-neurological diseases. Primary headaches were diagnosed in 25.7% of cases, migraine being the most frequent. Physicians did not report any specialist diagnoses in the ED discharge sheet. Specialist consultants made specific diagnoses in about one-third of patients that were not reported as final in the discharge records by the ED physician. This leads to a loss of diagnoses and to an overestimation of NOS headache.

Unveiling the relationship between autonomic involvement, fatigue, and cognitive dysfunction in early relapsing-remitting multiple sclerosis.

BACKGROUND: Fatigue is a common, yet disabling, symptom in patients with multiple sclerosis (PwMS). Fatigue has shown to be associated with self-reported autonomic nervous system (ANS) symptoms, particularly for cognitive fatigue; however, the question whether ANS involvement is related to cognitive impairment has never been addressed. We performed a study to unveil the complex relationship between fatigue, ANS symptoms, and cognitive impairment. METHODS: We prospectively recruited early PwMS that were tested with Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Modified Fatigue Impact Scale (MFIS) and Composite Autonomic Symptoms Scale-31 (COMPASS-31) scale. We performed a comparison between fatigued and non-fatigued patients and between cognitive unimpaired and impaired patients. We evaluated the association of COMPASS-31, MFIS, BDI, STAI, and BICAMS scores, and the analysis was repeated for each scale's sub-scores. A multivariable analysis was performed to elucidate predictors of fatigue. RESULTS: Forty-four patients were recruited. Fatigued patients had higher COMPASS-31 total, orthostatic intolerance, secretomotor, and pupillomotor scores. No differences in fatigue and ANS symptoms were found between cognitive impaired and unimpaired patients. MFIS total score correlated with STAI state (p = 0.002) and trait (p < 0.001), BDI (p < 0.001), COMPASS-31 total (p < 0.001), orthostatic intolerance (p < 0.001), pupillomotor scores (p = 0.006). Multivariable analysis showed that BDI (p < 0.001) and COMPASS-31 (p = 0.021) predicted MFIS score. Sub-scores analysis showed that orthostatic intolerance has a relevant role in fatigue. CONCLUSION: ANS symptoms are closely related with fatigue. Orthostatic intolerance may have a predominant role. Cognitive impairment seems not to be associated with ANS symptoms.

Nabiximols and botulinum toxin injections for patients with multiple sclerosis: efficacy on spasticity and spasms in a single-centre experience.

BACKGROUND: Spasticity is a common and disabling symptom in patients with multiple sclerosis (PwMS): as highlighted by many epidemiological studies, it is often a severe and not well treated. Despite the availability of evidence-based spasticity management guidelines, there is still great variability in everyday therapeutic approach, especially for the most complex cases. METHODS: In our single-centre study, we retrospectively evaluated PwMS-treated nabiximols and botulinum toxin injections (BTI) from July 2015 to April 2019. Clinical and demographic data were collected. The severity of spasticity and spasms was recorded by modified Ashworth Scale (mAS) and Penn Spasm Frequency Scale (PSFS) at baseline and after 1 month of treatment. RESULTS: We evaluated 64 treatments for MS-related spasticity: 28 patients were treated with BTI and 36 patients with nabiximols. We found that both BTI and nabiximols are effective in reducing mAS (nabiximols, BTI: p < 0.001), PSFS frequency (nabiximols: p = 0.001, BTI: p = 0.008) and intensity (nabiximols: p = 0.001, BTI p = 0.016). No differences were found when directly comparing the efficacy of the two treatments, except for a statistical trend favouring BTI on spasms intensity (p = 0.091). Eleven patients were treated with both BTI and nabiximols, and only four patients continued both treatments. All dropouts were due to inefficacy of at least one of the two therapies. CONCLUSIONS: Our single-centre experience highlights that both BTI and nabiximols are effective in treating multiple sclerosis-related spasticity; however, BTI treatment may be more effective on spasms intensity. Combined nabiximols and BTI treatment could represent a therapeutic option for severe spasticity.

Effects of a cooling vest with sham condition on walking capacity in heat-sensitive people with Multiple Sclerosis.

PURPOSE: Heat sensitivity is a common contraindication in people with Multiple Sclerosis (pwMS), and physical fatigue is one of the most frequently reported symptoms that can affect quality of life. Increases in body temperature may exacerbate fatigue and heat-related symptoms. Decreasing body temperature via cooling devices may mitigate disease symptoms and improve physical abilities and quality of life. This study evaluates the effects of a cooling vest with sham condition on walking capacity using a commercially-available cooling vest specifically designed for pwMS. METHODS: A counter-balanced, cross-over design was used to assess the effects of a cooling vest (CryoVest Comfort, CryoInnov, France) (COLD) from a menthol-induced sham condition (CON) on ground walking time to exhaustion (Tex, s) and distance at exhaustion (Dex, m) in ambulatory pwMS. Secondary outcomes were heart rate (HR, bpm), thermal sensation (Tsens), skin chest (Tchest) and back (Tback) temperature. RESULTS: Ten females with Multiple Sclerosis (59 ± 9 years, EDSS 3.0-5.5) participated to the study. During COLD, pwMS walked significantly longer (1896 ± 602 vs. 1399 ± 404 s, p < 0.001) and farther (1879 ± 539 vs. 1302 ± 318 m, p < 0.001) than CON. Importantly, Tsens and HR at exhaustion were not significantly different between conditions, although Tchest (- 2.7 ± 1.8 °C, p < 0.01) and Tback (- 3.9 ± 1.8 °C, p < 0.001) were lower at volitional fatigue during COLD. CONCLUSION: The lightweight cooling vest improved total walking time and distance in heat-sensitive pwMS. These physiological improvements were likely due to feeling perceptually cooler in the COLD trial, compared to the corresponding point of fatigue in the CON condition.

Early putamen hypertrophy and ongoing hippocampus atrophy predict cognitive performance in the first ten years of relapsing-remitting multiple sclerosis.

BACKGROUND: The first years of relapsing-remitting multiple sclerosis (RRMS) constitute the most vulnerable phase for the progression of cognitive impairment (CImp), due to a gradual decrease of compensatory mechanisms. In the first 10 years of RRMS, the temporal volumetric changes of deep gray matter structures must be clarified, since they could constitute reliable cognitive biomarkers for diagnostic, prognostic, and therapeutic purposes. METHODS: Forty-five cognitively asymptomatic patients with RRMS lasting ≤ 10 years, and with a brain MRI performed in a year from the neuropsychological evaluation (Te-MRI), were included. They performed the Brief International Cognitive Assessment battery for MS. Thirty-one brain MRIs performed in the year of diagnosis (Td-MRI) and 13 brain MRIs of age- and sex-matched healthy controls (HCs) were also included in the study. The relationships between clinical features, cognitive performances, and Te- and Td-MRI volumes were statistically analyzed. RESULTS: Cognitively preserved (CP) patients had significantly increased Td-L-putamen (P = 0.035) and Td-R-putamen volume (P = 0.027) with respect to cognitively impaired (CI) ones. CI patients had significantly reduced Te-L-hippocampus (P = 0.019) and Te-R-hippocampus volume (P = 0.042) compared, respectively, with Td-L-hippocampus and Td-R-hippocampus volume. Td-L-putamen volume (P = 0.011) and Te-L-hippocampus volume (P = 0.023) were independent predictors of the Symbol Digit Modalities Test score in all patients (r2 = 0.31, F = 6.175, P = 0.001). CONCLUSION: In the first years of RRMS, putamen hypertrophy and hippocampus atrophy could represent promising indices of cognitive performance and reserve, and become potentially useful tools for diagnostic, prognostic, and therapeutic purposes.

Adherence to guidelines of treatment of non-traumatic headache in the emergency department.

To evaluate therapies employed in patients presenting to the emergency department (ED) with a chief complaint of non-traumatic headache to check if guidelines are followed. A 6-month retrospective analysis of the ED records of all the patients who referred to the ED of the University Hospital of Trieste for non-traumatic headache was performed. Out of 37.335 admissions, 336 patients were selected (0.9%). Diagnosis at discharge was primary headache (25.6%), secondary headache (40.5%), and headache "not otherwise specified" (33.9%). One-hundred-ninety-three patients were treated in mono- (51.8%) or poly-therapy (48.2%), with NSAIDs (46.5%), benzodiazepines (13.4%), antiemetics (10.7%), analgesics (8.3%), opioids (1.6%), triptans (1.5%), and other drugs (17.7%). NSAIDs, particularly ketorolac, are the class of drugs most often prescribed in ED, independently of the discharge diagnosis. Metoclopramide is rarely used in monotherapy (4%), but it is the drug most frequently used in association with NSAIDs (19.3%). Only two migraineurs received triptans. Mean time spent in ED was 231 ± 130 min, which was significantly longer in patients who received treatment (272 ± 141 vs. 177 ± 122 min; p = 0.003). No drugs had any side effects. In accordance with the current guidelines, NSAIDs monotherapy or in association with antiemetics were the drugs most often prescribed in ED. Opioids were rarely used probably because of potential sedative side effects. Only very few patients received triptans. Special attention should be drawn also in ED to apply the International Classification of Headache Disorders criteria, which can lead to clarify the diagnosis and receive the specific treatment.

Comfortable walking speed and energy cost of locomotion in patients with multiple sclerosis.

Comfortable walking speed and energy cost of walking are physiological markers of metabolic activity during gait. People with multiple sclerosis are characterized by altered gait biomechanics and energetics, related to the degree of disability and spasticity, which lead to an increased energy cost of walking. Several studies concerning the energy cost of walking in multiple sclerosis have been published. Nevertheless, differences in protocols and characteristics of the sample have led to different outcomes. The aim of the present meta-analysis is to summarize results from studies with specific inclusion characteristics, and to present data about the comfortable walking speed and the energy cost of walking at that speed. Moreover, a detailed discussion of the potential mechanisms involved in the altered metabolic activity during exercise was included. A total of 19 studies were considered, 12 of which were also part of the quantitative analysis. Despite the strict selection process, high between-group heterogeneity was found for both outcomes. Nevertheless, the overall results suggest a pooled mean comfortable walking speed of 1.12 m/s (95% CI 1.05-1.18) and energy cost of 0.19 mLO2/kg/m (95% CI 0.17-0.21). These findings support the results of previous studies suggesting that energy cost of walking may be increased by 2-3 times compared to healthy controls (HC), and encourage the use of this marker in association with other parameters of the disease.

Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact.

It is widely known that vitamin D receptors have been found in neurons and glial cells, and their highest expression is in the hippocampus, hypothalamus, thalamus and subcortical grey nuclei, and substantia nigra. Vitamin D helps the regulation of neurotrophin, neural differentiation, and maturation, through the control operation of growing factors synthesis (i.e., neural growth factor [NGF] and glial cell line-derived growth factor (GDNF), the trafficking of the septohippocampal pathway, and the control of the synthesis process of different neuromodulators (such as acetylcholine [Ach], dopamine [DA], and gamma-aminobutyric [GABA]). Based on these assumptions, we have written this review to summarize the potential role of vitamin D in neurological pathologies. This work could be titanic and the results might have been very fuzzy and even incoherent had we not conjectured to taper our first intentions and devoted our interests towards three mainstreams, demyelinating pathologies, vascular syndromes, and neurodegeneration. As a result of the lack of useful therapeutic options, apart from the disease-modifying strategies, the role of different risk factors should be investigated in neurology, as their correction may lead to the improvement of the cerebral conditions. We have explored the relationships between the gene-environmental influence and long-term vitamin D deficiency, as a risk factor for the development of different types of neurological disorders, along with the role and the rationale of therapeutic trials with vitamin D implementation.