Effectiveness, Safety and Patients' Satisfaction of Nabiximols (Sativex®) on Multiple Sclerosis Spasticity and Related Symptoms in a Swiss Multicenter Study.

Background: Cannabinoid oro-mucosal spray nabiximols is approved for patients with moderate to severe multiple sclerosis spasticity (MSS) resistant to other antispastic medications. Few real-world data are available on the effectiveness, safety and patients' satisfaction in MS patients treated with nabiximols as monotherapy. Methods: To investigate the effectiveness, tolerability and satisfaction of nabiximols in a real-life multicentric Swiss cohort as monotherapy or with stable doses of other antispastic medications, and explore clinical features which may predict treatment response. The following data were collected at treatment start (baseline) and 12 weeks thereafter: Modified Ashworth scale (MAS), scores at numerical rating scales ranging from 0 (absent) to 10 (considerable) for effect on spasticity (sNRS), pain (pNRS), gait (gNRS), urinary symptoms (uNRS), tolerability (tNRS) as assessed by the treating neurologist, and overall treatment satisfaction (TsNRS) and tolerability (tNRS) as assessed by the patient. Results: Ninety-five patients (44 relapsing remitting, 37 secondary progressive and 14 primary progressive MS; median age = 53 (IQR 45-62); female 70%; median EDSS 6 (IQR 4-6), concomitant antispastic treatments in 54% of patients) were included. From baseline to week 12, median MAS score decreased from 3.0 to 2.0 (p < 0.001). Median scores of the each NRS also significantly decreased (p < 0.001 for all comparisons). At week 12, the median TsNRS and tTS scores were 8/10 (IQR: 6-9) and 9/10 (IQR: 7-10), respectively, and 93.7% of patients continued to use nabiximols at the average dose of six sprays/day. No clinical factors, including use of nabiximols as add on vs. monotherapy, were associated with responder status. Conclusions: Our first Swiss, multicentric, observational, real-life study supports and enhances previous finding of nabiximols as monotherapy and as add-on therapy, being an effective, safe and well-tolerated treatment option for resistant MS spasticity and spasticity-related symptoms (pain, bladder dysfunction and gait).

Fatigue, sleepiness and depression in multiple sclerosis: defining the overlaps for a better phenotyping.

BACKGROUND AND OBJECTIVES: To define the boundaries and the overlaps between fatigue, sleepiness and depression in patients with multiple sclerosis (MS) by using different tools for each dimension, including instrumental sleep analysis. METHODS: In this cross-sectional, observational study, 71 MS patients (males/females: 20/51; mean age: 48.9 ± 10.5 years) filled in clinical questionnaires and performed polysomnography followed by maintenance of wakefulness test (MWT). Frequency and reciprocal overlap of sleepiness, fatigue and depression in MS were expressed by Eulero-Venn diagrams; standard multiple regression was used to assess the ability of symptoms to predict each other. RESULTS: There was a high percentage of fatigued (70%), somnolent (45%) and depressed (27%) patients. Fatigue had the strongest overlap and correlated with both depression (beta: 0.52, p < 0.001) and sleepiness (beta: 0.74, p < 0.001). Somnolence and depression were nearly always accompanied by fatigue and were well differentiated from each other by MWT. Four MS subgroups were identified that had: (1) fatigue only; (2) fatigue and sleepiness (3) fatigue and depression; (4) fatigue, sleepiness and depression. DISCUSSION: The subjective and objective tools are not able to clearly distinguish fatigue from sleepiness and depression, while only a test of vigilance can be helpful in separating somnolence and depression from each other.

Sleep-Related Breathing Disorders in Multiple Sclerosis: Prevalence, Features and Associated Factors.

Background: Multiple sclerosis (MS) represents a risk factor for sleep disorders, but there are conflicting results about the prevalence and severity of sleep-related breathing disorders (SRBD) in MS. Most available data come from self-administered questionnaires. Objective: To conduct a polysomnographic study in MS focused on SRBD, compared to a group of healthy controls (HC), also considering the neuroimaging findings. To evaluate the impact of SRBD on vigilance, fatigue and depression in MS. Methods: In this cross-sectional, observational, instrumental study, 67 MS patients (men/women: 20/47; mean age: 50.6±8.2 years) underwent PSG and maintenance of wakefulness test. Findings were compared to 67 age-, sex-, BMI-matched HC, by using parametric (Student's t-test) and nonparametric statistics (chi-squared test). A subgroup analysis was then performed, evaluating the influence of brainstem (mesencephalic, pontine and medullary) lesions at neuroimaging on instrumental and clinical data: MS patients with at least one brainstem lesion vs MS patients without vs HC. Results: The frequency of SRBD was comparable in MS patients and HC. No MS patient had a central apnea index ≥2/h. The respiratory disturbance index (RDI) did not correlate to clinical parameters such as fatigue and depression. Patients with MS were drowsier than HC (47% vs 26%, p = 0.019) and showed a worse sleep pattern, in terms of duration, efficiency and architecture. Conclusion: Our study does not provide evidence of an association between MS-specific symptoms such as fatigue, sleepiness, depression and central or obstructive apneas, even in the presence of brainstem lesions.

Clinic and genetic predictors in response to erenumab.

BACKGROUND AND PURPOSE: Erenumab (ERE) is the first anticalcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. A proportion of patients do not adequately respond to ERE. METHODS: Prospective multicenter study involving 110 migraine patients starting ERE 70 mg monthly. Baseline socio-demographics and migraine characteristics, including mean monthly migraine days (MMDs), migraine-related burden (MIDAS [Migraine Disability Assessment scale] and Headache Impact Test-6), and use of abortive medications, during 3 months before and after ERE start were collected. Real-time polymerase chain reaction was used to determine polymorphic variants of calcitonin receptor-like receptor and receptor activity-modifying protein-1 genes. Logistic regression models were used to identify independent predictors for 50% responder patients (50-RESP) and 75% responder patients (75-RESP). RESULTS: At month 3, MMDs decreased from 17.2 to 9.2 (p < 0.0001), 59/110 (53.6%) patients were 50-RESP, and 30/110 (27.3%) were 75-RESP. Age at migraine onset (odds ratio [OR] [95% confidence interval (95% CI)]: 1.062 [1.008-1.120], p = 0.024), number of failed preventive medications (0.753 [0.600-0.946], p = 0.015), and MIDAS score (1.011 [1.002-1.020], p = 0.017) were associated with 75-RESP. Among the genetic variants investigated, RAMP1 rs7590387 was found associated with a lower probability of being 75-RESP (per G allele OR [95% CI]: 0.53 [0.29-0.99], p = 0.048]), but this association did not survive adjustment for confounding clinical variables (per G allele, 0.55 [0.28-1.10], p = 0.09]). CONCLUSIONS: In this real-word study, treatment with ERE significantly reduced MMDs. The number of failed preventive medications, migraine burden, and age at migraine onset predicted response to ERE. Larger studies are required to confirm a possible role of RAMP1 rs7590387 as genetic predictor of ERE efficacy.

Leg movement activity during sleep in multiple sclerosis with and without restless legs syndrome.

STUDY OBJECTIVES: To carry out an analysis of leg movement activity during sleep in a polysomnography dataset of patients with multiple sclerosis (MS) in comparison to idiopathic restless legs syndrome (iRLS) and healthy controls. METHODS: In this cross-sectional, observational, instrumental study, 57 patients (males/females: 11/46; mean age 46.2 ± 10.2 years) with a diagnosis of MS underwent a telephone interview assessing the 5 standard diagnostic criteria for RLS and polysomnography. Sleep architecture and leg movement activity during sleep were subsequently compared: 1) 40 patients with MS without RLS (MS-RLS) vs 28 healthy controls; 2) 17 patients with MS with RLS (MS+RLS) vs 35 patients with iRLS; 3) MS+RLS vs MS-RLS. RESULTS: MS-RLS and MS+RLS presented increased sleep latency, percentage of sleep stage N1, and reduced total sleep time compared to healthy controls and iRLS, respectively. The periodic limb movements during sleep (PLMS) index was higher in MS-RLS than in healthy controls (P = .035) and lower in MS+RLS compared to iRLS (P = .024). PLMS in MS+RLS were less periodic, less often bilateral, and with shorter single movements compared to the typical PLMS in iRLS. CONCLUSIONS: MS is a risk factor for RLS, PLMS, and for a lower sleep quality in comparison to healthy patients. PLMS in MS+RLS are fewer and shorter if compared to iRLS. Our results suggest a dissociation between motor (PLMS) and sensory symptoms (RLS sensory component) in RLS secondary to MS, with possible treatment implications. CITATION: Ferri R, Sparasci D, Castelnovo A, et al. Leg movement activity during sleep in multiple sclerosis with and without restless legs syndrome. J Clin Sleep Med. 2022;18(1):11-20.

Hyperconnectivity of the dorsolateral prefrontal cortex following mental effort in multiple sclerosis patients with cognitive fatigue.

OBJECTIVE: To investigate the dynamic temporal changes of brain resting-state functional connectivity (RS-FC) following mental effort in multiple sclerosis (MS) patients with cognitive fatigue (CF). METHODS: Twenty-two MS patients, 11 with (F) and 11 without CF, and 12 healthy controls were included. Separate RS-FC scans were acquired on a 3T MR scanner immediately before (t0), immediately after (t1) and 30 minutes after (t2) execution of the paced auditory serial addition test (PASAT), a cognitively demanding task. Subjectively perceived CF after PASAT execution was also assessed. RS-FC changes were investigated by using a data-driven approach (the Intrinsic Connectivity Contrast-power), complemented by a priori defined regions of interest analyses. RESULTS: The F-group patients experienced stronger RS-FC at t2 between the left superior frontal gyrus (L-SFG) and occipital, frontal and temporal areas, which increased over time after PASAT execution. In the F-group patients, the L-SFG was hyperconnected at t1 with the left caudate nucleus and hypoconnected at t2 with the left anterior thalamus. These variations were correlated with both subjectively perceived and clinically assessed CF, and-for the left thalamus-with PASAT performance. CONCLUSION: The development of cortico-cortical and cortico-subcortical hyperconnectivity following mental effort is related to CF symptoms in MS patients.