Gunnar Gaede

Fatigue in multiple sclerosis is closely related to sleep disorders: a polysomnographic cross-sectional study:

Background: Sleep disorders can cause tiredness. The relationship between sleep disorders and fatigue in patients with multiple sclerosis (MS) has not yet been investigated systematically. Objective: To investigate the relationship between fatigue and sleep disorders in patients with MS. Methods: Some 66 MS patients 20 to 66 years old were studied by overnight polysomnography. Using a cut-off point of 45 in the Modified Fatigue Impact Scale (MFIS), the entire cohort was stratified into a fatigued MS subgroup (n = 26) and a non-fatigued MS subgroup (n = 40). Results: Of the fatigued MS patients, 96% (n = 25) were suffering from a relevant sleep disorder, along with 60% of the non-fatigued MS patients (n = 24) (p = 0.001). Sleep-related breathing disorders were more frequent in the fatigued MS patients (27%) than in the non-fatigued MS patients (2.5%). Significantly higher MFIS values were detected in all (fatigued and non-fatigued) patients with relevant sleep disorders (mean MFIS 42.8; SD 18.3) than in patients without relevant sleep disorders (mean MFIS 20.5; SD 17.0) (p < 0.001). Suffering from a sleep disorder was associated with an increased risk of fatigue in MS (odds ratio: 18.5; 95% CI 1.6–208; p = 0.018). Conclusion: Our results demonstrate a clear and significant relationship between fatigue and sleep disorders.

Optic neuritis interferes with optical coherence tomography and magnetic resonance imaging correlations

Background: Retinal nerve fibre layer (RNFL) thinning is associated with brain atrophy in multiple sclerosis (MS). An influence of optic neuritis is well documented but sparsely investigated. Recently, the retinal ganglion cell layer (GCL) has been shown to provide superior information regarding visual function and retinal neurodegeneration as compared with RNFL. Objective: To investigate the association of white and grey matter brain volume with peripapillary RNFL and macular GCL in MS patients with and without a history of optic neuritis. Methods: 63 patients with relapsing–remitting MS were included in a two-centre cross-sectional prospective study. All patients underwent retinal examination with spectral domain optical coherence tomography and 1.5 T MRI for determination of normalized brain volume (NBV), white matter volume (NWMV) and grey matter volume (NGMV). Results: Both RNFL and GCL were associated with NBV, NWMV and NGMV in eyes without previous optic neuritis. This association is disrupted in the case of NGMV following optic neuritis. Conclusions: Both RNFL and GCL as parameters of neuro-axonal damage are comparably linked to whole brain as well as white and grey matter atrophy. An event of optic neuritis interferes with this relation, adding further damage to the optic nerve and disrupting especially an association with grey matter.

Patterns of retinal nerve fiber layer loss in multiple sclerosis patients with or without optic neuritis and glaucoma patients

OBJECTIVE Optical coherence tomography (OCT) has gained increasing attention in multiple sclerosis (MS) research and has been suggested as outcome measure for neuroprotective therapies. However, to date it is not clear whether patterns of retinal nerve fiber layer thickness (RNFLT) loss are different in MS compared to other diseases such as glaucoma and data on RNFLT loss in MS patients with or without optic neuritis (ON/NON) have remained inconsistent or even contradictory. METHODS In this large cross-sectional study we analyzed the patterns of axonal loss of retinal ganglion cells in MS eyes (n=262) with and without history of ON (MS/ON: 73 eyes; MS/NON: 189 eyes) and patients eyes with glaucomatous optic disc atrophy (GA: n=22; 39 eyes) in comparison to healthy control eyes (HC: n=406 eyes). RESULTS We found that significant average and quadrant RNFLT loss is detectable by OCT in both MS and GA patients compared to healthy controls (p<0.01). The age- and gender adjusted average and quadrant RNFLT did not differ significantly between MS and GA patients (p>0.05). Average (p<0.0001) and quadrant (p<0.05) RNFL thinning is significantly more severe in MS/ON versus MS/NON eyes, and the extent of RNFL thinning varies across quadrants in MS/ON eyes with the highest degree of RNFLT loss in the temporal quadrant (p<0.001). CONCLUSION RNFLT reduction across all four quadrants in MS patients as a whole as well as in MS/NON eyes argues for a diffuse neurodegenerative process. Superimposed inflammatory attacks to the optic nerve may cause additional axonal damage with a temporal preponderance. Future studies are necessary to further evaluate the capacity of OCT to depict disease specific damage patterns.

Impairment of contrast visual acuity as a functional correlate of retinal nerve fibre layer thinning and total macular volume reduction in multiple sclerosis

Objectives To analyse the association between retinal nerve fibre layer thickness (RNFLT) and total macular volume (TMV) as measured by optical coherence tomography, and contrast sensitivity (CS) measured by Functional Acuity Contrast Testing (FACT) in relapsing-remitting multiple sclerosis; and to investigate whether FACT testing by a contrast box device is feasible in multiple sclerosis (MS). Methods fact was performed using the Optec 6500 P vision testing system with best correction under photopic and mesopic conditions without glare. The Area Under the Log Contrast Sensitivity Function (AUC) was calculated. RNFLT and TMV were assessed by Stratus optical coherence tomography. All participants underwent visual acuity testing (Snellen), spherical refractive error testing and cylindrical refractive error testing. Results 85 relapsing-remitting multiple sclerosis patients (170 eyes) and 35 healthy controls (HC, 70 eyes) were measured. AUC Day and Night were lower in MS than in HC (p<0.001) when correcting for age, as were mean RNFLT and TMV (p<0.001 and p=0.018, respectively). Both RNFLT and TMV predicted contrast sensitivity in MS (AUC Day: standardised coefficient β=0.277, p<0.001, and β=0.262, p<0.001, respectively; AUC Night: β=0.202, p=0.009 and β=0.222, p=0.004, respectively, linear regressions). In HC, there was no correlation between RNFLT or TMV and contrast sensitivity. Conclusion (1) Contrast sensitivity is reduced in MS versus HC; (2) RNFL and TMV as morphological measures of retinal axonal loss are predictors of contrast sensitivity as a functional visual parameter in MS but not in HC; and (3) FACT with the contrast box is a novel, feasible and rapid method to assess contrast sensitivity in MS.

Treatment of sleep disorders may improve fatigue in multiple sclerosis

OBJECTIVE In a previous polysomnographic cross-sectional study we found a significant relationship between sleep disorders and multiple sclerosis (MS) related fatigue. The purpose of this open follow-up observation was to compare the impact of treatment of sleep disorders on MS related fatigue measured with the Modified Fatigue Impact Scale (MFIS). METHODS Non-randomized follow-up observation: treated versus untreated patients, subgroups according to compliance with sleep medical treatment recommendations (univariate, multivariate analysis, multiple logistic regression). 66 MS patients were followed after polysomnography, 49 patients with relevant sleep disorders and 17 without. RESULTS Mean MFIS scores decreased from 41.2 to 26.2 (p=0.025) in patients with good compliance (GC; n=18), from 42.4 to 32.1 (p=0.12) in patients with moderate compliance (MC; n=12), and from 41.6 to 35.5 (p=0.17) in non-compliant patients (NC; n=17). Mean MFIS values increased in patients without sleep disorders from 22.9 to 25.4 (NSD; n=12, p=0.56). In multiple logistic regression, treatment of sleep disorders predicted decrease of MFIS-values (GC versus NSD odds ratio 13.4; p=0.015; 95% confidence interval (CI) 1.7-107.2, MC versus NSD odds ratio 13.8; p=0.028; 95% CI 1.3-143.3). CONCLUSIONS Sleep medical treatment may improve MS related fatigue when patients adhere to treatment recommendations.

Sleep Disorders Reduce Health-Related Quality of Life in Multiple Sclerosis (Nottingham Health Profile Data in Patients with Multiple Sclerosis)

Quality of Life (QoL) is decreased in multiple sclerosis (MS), but studies about the impact of sleep disorders (SD) on health-related quality of Life (HRQoL) are lacking. From our original cohort, a cross-sectional polysomnographic (PSG) study in consecutive MS patients, we retrospectively analysed the previously unpublished data of the Nottingham Health Profile (NHP). Those MS patients suffering from sleep disorders (n = 49) showed significantly lower HRQoL compared to MS patients without sleep disorders (n = 17). Subsequently, we classified the patients into four subgroups: insomnia (n = 17), restless-legs syndrome, periodic limb movement disorder and SD due to leg pain (n = 24), obstructive sleep apnea (n = 8) and patients without sleep disorder (n = 17). OSA and insomnia patients showed significantly higher NHP values and decreased HRQoL not only for the sleep subscale but also for the “energy” and “emotional” area of the NHP. In addition, OSA patients also showed increased NHP values in the “physical abilities” area. Interestingly, we did not find a correlation between the objective PSG parameters and the subjective sleep items of the NHP. However, this study demonstrates that sleep disorders can reduce HRQoL in MS patients and should be considered as an important confounder in all studies investigating HRQoL in MS.

Periodic limb movements during REM sleep in multiple sclerosis: a previously undescribed entity.

Background There are few studies describing periodic limb movement syndrome (PLMS) in rapid eye movement (REM) sleep in patients with narcolepsy, restless legs syndrome, REM sleep behavior disorder, and spinal cord injury, and to a lesser extent, in insomnia patients and healthy controls, but no published cases in multiple sclerosis (MS). The aim of this study was to investigate PLMS in REM sleep in MS and to analyze whether it is associated with age, sex, disability, and laboratory findings. Methods From a study of MS patients originally published in 2011, we retrospectively analyzed periodic limb movements (PLMs) during REM sleep by classifying patients into two subgroups: PLM during REM sleep greater than or equal to ten per hour of REM sleep (n=7) vs less than ten per hour of REM sleep (n=59). A univariate analysis between PLM and disability, age, sex, laboratory findings, and polysomnographic data was performed. Results MS patients with more than ten PLMs per hour of REM sleep showed a significantly higher disability measured by the Kurtzke expanded disability status scale (EDSS) (P=0.023). The presence of more than ten PLMs per hour of REM sleep was associated with a greater likelihood of disability (odds ratio 22.1; 95% confidence interval 3.5–139.7; P<0.0001), whereas there were no differences in laboratory and other polysomnographic findings. Conclusion PLMs during REM sleep were not described in MS earlier, and they are associated with disability measured by the EDSS.

Poor Sleep in Multiple Sclerosis Correlates with Beck Depression Inventory Values, but Not with Polysomnographic Data

Objectives. Pittsburgh Sleep Quality Index (PSQI) values correlate with depression, but studies investigating the relationship between PSQI values and polysomnographic (PSG) data showed inconsistent findings. Methods. Sixty-five consecutive patients with multiple sclerosis (MS) were retrospectively classified as “good sleepers” (GS) (PSQI ≤ 5) and “poor sleepers” (PS) (PSQI > 5). The PSG data and the values of the Visual Analog Scale (VAS) of fatigue, Modified Fatigue Impact Scale (MFIS), Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), and the Beck Depression Inventory (BDI) were compared. Results. No significant differences were found either for PSG data or for ESS, MFIS, and FSS values; but PS showed significantly increased BDI and VAS values. Conclusions. Poor sleep is associated with increased depression and fatigue scale values.

Safety and preliminary efficacy of deep transcranial magnetic stimulation in MS-related fatigue

Objective: To conduct a randomized, sham-controlled phase I/IIa study to evaluate the safety and preliminary efficacy of deep brain H-coil repetitive transcranial magnetic stimulation (rTMS) over the prefrontal cortex (PFC) and the primary motor cortex (MC) in patients with MS with fatigue or depression (NCT01106365). Methods: Thirty-three patients with MS were recruited to undergo 18 consecutive rTMS sessions over 6 weeks, followed by follow-up (FU) assessments over 6 weeks. Patients were randomized to receive high-frequency stimulation of the left PFC, MC, or sham stimulation. Primary end point was the safety of stimulation. Preliminary efficacy was assessed based on changes in Fatigue Severity Scale (FSS) and Beck Depression Inventory scores. Randomization allowed only analysis of preliminary efficacy for fatigue. Results: No serious adverse events were observed. Five patients terminated participation during treatment due to mild side effects. Treatment resulted in a significant median FSS decrease of 1.0 point (95%CI [0.45,1.65]), which was sustained during FU. Conclusions: H-coil rTMS is safe and well tolerated in patients with MS. The observed sustained reduction in fatigue after subthreshold MC stimulation warrants further investigation. ClinicalTrials.gov identifier: NCT01106365. Classification of evidence: This study provides Class III evidence that rTMS of the prefrontal or primary MC is not associated with serious adverse effects, although this study is underpowered to state this with any precision.