Christian Veauthier

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.

Sleep disorders in multiple sclerosis and their relationship to fatigue

Treatment of multiple sclerosis (MS)-related fatigue is still a challenging task, given that no proven therapies exist and its mechanisms are not known. Our review highlights the relationship between MS-related fatigue and sleep disorders (SD). Although many studies suggest a higher overall prevalence of SD in MS, there are no valid and robust data to confirm this hypothesis until now except for restless legs syndrome (RLS): the prevalence of RLS in MS patients-especially in those with severe pyramidal and sensory disability-seems to be four times higher than in controls subjects. RLS is sometimes difficult to distinguish from spasticity and in case of doubt, probatory dopaminergic therapy or polysomnographic (PSG) investigations may be helpful. Nocturia may impact MS-related fatigue and should be considered. The treatment of underlying SD led to an improvement of MS-related fatigue. From a scientific point of view, SD should be examined in all studies investigating MS-related fatigue and be considered as a relevant confounder.

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.

Fatigue in multiple sclerosis: which patient should be referred to a sleep specialist?

Recently we published the results of a previous study, the first cross-sectional polysomnographic investigation with consecutive unselected MS patients in this journal. We found a significant association between relevant sleep disorders according to the International Classification of Sleep Disorders second edition and fatigue, measured with the Modified Fatigue Impact Scale (MFIS) and the Fatigue Severity Scale (FSS). However, there was no relationship between sleep disorders and the values in the Epworth Sleepiness Scale (ESS). In order to find a screening instrument for sleep disorders in MS-related fatigue we investigated retrospectively the usefulness of the Pittsburgh Sleep Quality Index (PSQI) and the MFIS, both applied in our previously reported polysomnographic investigation, to predict the presence of a sleep disorder. In our recent study 66 MS patients (21 male, 45 female, mean age 43.2 years, standard deviation 10.0, range 20–66; mean disease duration 137.4 months, standard deviation 108.2, range 13–469; median Expanded Disability Status Scale [EDSS] 2.0, range 0–7.5) were examined with two overnight polysomnographies and completed, amongst other measures, the MFIS and PSQI. In our previously published study we did not calculate the values of the PSQI. Now we report for the first time the findings of a retrospective analysis of these PSQI values and we compare them with the polysomnography. A receiver operating characteristic (ROC) analysis was performed (SPSS 13, SPSS Inc., Chicago, IL, USA). A global PSQI score greater than 5 yielded a diagnostic sensitivity of 75% and 64.7% specificity (positive predictive value 85.7%; negative predictive value 47.8%). In line with the original paper from Buysse et al., a threshold value of >5 in the PSQI appeared to be the best cut-off-point to predict sleep disturbances. A MFIS score of >34 yielded a diagnostic sensitivity of 71.4% and a specificity of 82.4% for predicting sleep disorders as detected by polysomnography (positive predictive value 92.1%; negative predictive value 50%). By jointly applying the MFIS cut-off of 34 and the PSQI cut-off of 5 (either MFIS >34 or PSQI >5), a higher sensitivity of 89.8% was achieved (specificity 58.8%, positive predictive value 86.3%, negative predictive value 66.7%). Our data show that the combination of two selfrating questionnaires which can easily be filled out within a few minutes are a good screening instrument for sleep disorders in MS-related fatigue and can predict sleep disorders with a good sensitivity, with a good positive predictive value and with sufficient specificity. The treatment of MS-related fatigue remains difficult, because no specific drug therapy exists. As there are, in contrast to fatigue, specific and efficacious treatment options for the majority of sleep disorders, an early diagnosis of these conditions is warranted. Therefore, in all fatigued MS patients, a careful medical history which may point to sleep disturbances should be performed; of course symptomatic causes such as hypothyroidism and anemia should also be excluded. In the case of insomnia, complaints indicating restless legs syndrome, nocturia and pain, these sleep disorders should already be treated without polysomnographic investigations. However, it is MS patients in particular who may be denied access to sleep diagnostic procedures, as the treating physician may attribute daytime tiredness to MS-related fatigue and thus regard a polysomnography as unnecessary. In this context, it is important to point out that periodic limb movement disorders, sleep-related breathing disorders and some other dyssomnias are in many cases not recognized by the patients themselves or their bed partners. Therefore, in order not to misdiagnose sleep disorders, all fatigued MS patients with MFIS values greater than 34 or PSQI values greater than 5 should be referred to a sleep specialist and undergo subsequent polysomnography.

The Berlin Treatment Algorithm: recommendations for tailored innovative therapeutic strategies for multiple sclerosis-related fatigue

More than 80% of multiple sclerosis (MS) patients suffer from fatigue. Despite this, there are few therapeutic options and evidence-based pharmacological treatments are lacking. The associated societal burden is substantial (MS fatigue is a major reason for part-time employment or early retirement), and at least one out of four MS patients view fatigue as the most burdensome symptom of their disease. The mechanisms underlying MS-related fatigue are poorly understood, and objective criteria for distinguishing and evaluating levels of fatigue and tiredness have not yet been developed. A further complication is that both symptoms may also be unspecific indicators of many other diseases (including depression, sleep disorders, anemia, renal failure, liver diseases, chronic obstructive pulmonary disease, drug side effects, recent MS relapses, infections, nocturia, cancer, thyroid hypofunction, lack of physical exercise). This paper reviews current treatment options of MS-related fatigue in order to establish an individualized therapeutic strategy that factors in existing comorbid disorders. To ensure that such a strategy can also be easily and widely implemented, a comprehensive approach is needed, which ideally takes into account all other possible causes and which is moreover cost efficient. Using a diagnostic interview, depressive disorders, sleep disorders and side effects of the medication should be identified and addressed. All MS patients suffering from fatigue should fill out the Modified Fatigue Impact Scale, Epworth Sleepiness Scale, the Beck Depression Inventory (or a similar depression scale), and the Pittsburgh Sleep Quality Index (or the Insomnia Severity Index). In some patients, polygraphic or polysomnographic investigations should be performed. The treatment of underlying sleep disorders, drug therapy with alfacalcidol or fampridine, exercise therapy, and cognitive behavioral therapy-based interventions may be effective against MS-related fatigue. The objectives of this article are to identify the reasons for fatigue in patients suffering from multiple sclerosis and to introduce individually tailored treatment approaches. Moreover, this paper focuses on current knowledge about MS-related fatigue in relation to brain atrophy and lesions, cognition, disease course, and other findings in an attempt to identify future research directions.

Perioperative fluctuations of lamotrigine serum levels in patients undergoing epilepsy surgery

UNLABELLED Some patients undergoing epilepsy surgery suffer from early postoperative seizures which may have a negative impact on later outcome. Factors contributing to these seizures have not to date been examined systematically. We hypothesized that reduction of postoperative serum levels of antiepileptic drugs (AED) may be one risk factor for early postoperative seizures. METHODS We retrospectively reviewed medical records from 20 patients treated with lamotrigine (LTG) who underwent epilepsy surgery between January 1997 and February 2004. Demographic data, anaesthesiological and surgical procedures, co-medication, and pre- as well as one or more postoperative LTG serum levels were evaluated. RESULTS We found a significant decrease in LTG serum levels, amounting to more than 20% (mean 46%, range 21.9-69.1%), in 16 of 20 patients (80%). Six patients (30%) suffered from seizures in the first 2 weeks after surgery. In three patients, postoperative seizures occurred isochronically with the LTG serum level nadir. The magnitude of the reduction in serum levels was not influenced by age, sex, duration of the operation, the type of anaesthetic drugs or the postoperative co-medication. DISCUSSION Reductions in LTG serum levels are a relevant contributing factor for early postoperative seizures. Postoperative alteration of the gastrointestinal motility and transient time leading to delayed absorption and reduced bioavailability of AED may be a major risk factor. Therefore, close monitoring of postoperative LTG serum levels is necessary and should lead to a temporary dose augmentation and/or anticonvulsant co-medication with benzodiazepines in case of a pronounced reduction of serum levels.

Contribution of spinal cord biopsy to diagnosis of aquaporin-4 antibody positive neuromyelitis optica spectrum disorder

Longitudinally extensive transverse myelitis is characteristic but not pathognomonic for neuromyelitis optica spectrum disorders (NMOSDs) and may mimic local tumors. In this retrospective study based on a cohort of 175 NMOSD patients we identified seven patients who initially presented with a longitudinally extensive spinal cord lesion and underwent spinal cord biopsy due to magnetic resonance imaging (MRI)-suspected malignancies. Remarkably, routine neuropathology was inconclusive and did not guide the diagnostic process to anti-aquaporin-4 (AQP4)-seropositive NMOSD. Serious postoperative complications occurred in 5/7 patients and persisted during follow-up in 2/7 patients (29%). Considering these sequelae, AQP4-antibody testing should be mandatory in patients with inconclusive longitudinally extensive spinal cord lesions prior to biopsy.

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.

Sleep Disorders in Multiple Sclerosis. Review

Sleep disorders are common in patients with multiple sclerosis (MS) and play a crucial role in health and quality of life; however, they are often overlooked. The most important sleep disorders in this context are as follows: insomnia, restless legs syndrome, periodic limb movement disorders, and sleep-related breathing disorders (SRBD). It is unclear if MS-related processes (lesions, brain atrophy) can cause symptomatic forms of sleep apnea. MS-related narcolepsy-like symptoms are described in the literature and, in some cases, have resolved with methylprednisolone pulse therapy. Similarly, REM sleep behavior disorder (RBD) is very rare in MS, but it can be an initial sign of MS where cortisone therapy may be helpful and can be taken into account in this specific context. Independent diagnosis and treatment is required for all of the abovementioned conditions. Treating physicians and neurologists should be aware of these comorbidities and initiate specific therapy. Highly fatigued or sleepy MS patients should have polysomnography in order not to overlook these diagnoses.

Fatigue in multiple sclerosis: a diagnostic and therapeutic challenge

Multiple sclerosis (MS) is the most frequent autoimmune CNS condition in young adults in Western countries. It leads to demyelination and neuroaxonal damage. Classic neurological deficits include -amongst others -motor disability, sensory and gait disturbances, impairment of vision, bladder and bowel dysfunction, and cognitive dysfunction and fatigue. Fatigue is one of the most frequent symptoms; it is often disabling and is a major cause of unemployment [1,2]. Fatigue in MS is characterized by an overwhelming sense of tiredness, lack of energy or feeling of exhaustion [3]. One widely used definition of fatigue is ‘a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities’ [4]. The term ‘fatigue’ encompasses several clinical aspects such as mental and muscle fatigue. One widely used self-rating questionnaire, the Modified Fatigue Impact Scale (MFIS), aims to display the impact of fatigue on physical, cognitive and psychosocial functioning [5]. Fatigue overlaps with both cognitive dysfunction and depression in a complex way [6,7]. Many underlying conditions can influence and worsen MS-related fatigue; for example, side effects from medication or drug interactions, sleep disorders, spasticity, pain syndromes or depression and affective disorders [8-11]. Thus, it is challenging to differentiate between ‘primary’ fatigue related to CNS injury in the autoimmune disease MS and ‘secondary’ fatigue associated with other conditions because it is not possible to objectify and quantify pure primary fatigue. To date, owing to the lack of adequate biomarkers or physiological measures of fatigue, the estimation of symptom severity is highly dependent on patients’ reports and self-assessed questionnaires [12,13]. Despite the substantial individual burden for the affected patient and the high socioeconomic importance of MSrelated fatigue our knowledge on pathophysiology, diagnosis and treatment is still strikingly sparse. Fatigue is a multifactorial phenomenon. Associations with neuroimaging findings such as brain lesion load or atrophy, neuroendocrine dysregulation, proinflammatory cytokines, sympathetic vasomotor dysfunction, xenotropic murine leukemia virus-related virus (XMRV) infections and melatonin dysregulation have been reported [14-19]. With respect to treatment options, the situation is at least as unsatisfactory. Several pharmaceutical and nonpharmaceutical interventions have been proposed. However, none of these measures has reached a sufficiently high level of evidence and no drug has received approval by the USFDA (FDA), the European Medicines Agency (EMA) or other authorities. To improve the situation for affected patients, the nihilistic attitude that they face when reporting their symptoms to their treating neurologist must be challenged. Fatigue is often seen as an inevitable and intractable side effect that patients must learn to live with and neurologists often do not ask whether fatigue is a burden to the patient.