Superhuman performance on sepsis MIMIC-III data by distributional reinforcement learning.

We present a novel setup for treating sepsis using distributional reinforcement learning (RL). Sepsis is a life-threatening medical emergency. Its treatment is considered to be a challenging high-stakes decision-making problem, which has to procedurally account for risk. Treating sepsis by machine learning algorithms is difficult due to a couple of reasons: There is limited and error-afflicted initial data in a highly complex biological system combined with the need to make robust, transparent and safe decisions. We demonstrate a suitable method that combines data imputation by a kNN model using a custom distance with state representation by discretization using clustering, and that enables superhuman decision-making using speedy Q-learning in the framework of distributional RL. Compared to clinicians, the recovery rate is increased by more than 3% on the test data set. Our results illustrate how risk-aware RL agents can play a decisive role in critical situations such as the treatment of sepsis patients, a situation acerbated due to the COVID-19 pandemic (Martineau 2020). In addition, we emphasize the tractability of the methodology and the learning behavior while addressing some criticisms of the previous work (Komorowski et al. 2018) on this topic.

Impact of Dietary Intervention on Serum Neurofilament Light Chain in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Adapted ketogenic diet (AKD) and caloric restriction (CR) have been suggested as alternative therapeutic strategies for multiple sclerosis (MS), but information on their impact on neuroaxonal damage is lacking. Thus, we explored the impact of diets on serum neurofilament light chain (sNfL) levels in patients with relapsing-remitting MS. METHODS: We retrospectively evaluated a prospective randomized controlled trial of 60 patients with MS who were on a common diet or ketogenic diet or fasting. We examined sNfL levels of 40 participants at baseline and at the end of the study after 6 months using single molecule array assay. RESULTS: sNfL levels were investigated in 9 controls, 14 participants on CR, and 17 participants on AKD. Correlation analysis showed an association of sNfL with age and disease duration; an association was also found between sNfL and the Multiple Sclerosis Functional Composite. AKD significantly reduced sNfL levels at 6 months compared with the common diet group (p = 0.001). DISCUSSION: For clinical or study use, consider that AKD may incline sNfL levels independent of relapse activity up to 3 months after initiation. At 6 months, AKD, which complements current therapies, reduced sNfL levels, therefore suggesting potential neuroprotective effects in MS. A single cycle of seven-day fasting did not affect sNfL. AKD may be an addition to the armamentarium to help clinicians support patients with MS in a personalized manner with tailored diet strategies. TRIAL REGISTRATION INFORMATION: Clinical trial registration number NCT01538355.

[Osteitis/Osteomyelitis of the Hand and Wrist]. / Osteitis/Osteomyelitis an Hand und Handgelenk.

Osteomyelitis of the hand and wrist is uncommon compared to the infections of the long bones but not rare. There is poor evidence on many answers to questions concerning this disease. This includes careful consideration of the prevalence, pathogenesis, microbiology, diagnostic methods and the conservative, medical and surgical treatment. The emergence of the disease can subdivided in post-traumatic, postoperative, spread from contiguous infections and hematogenous. The individual patient-specific risk must be considered. Early diagnosis and correct management are essential to preserve bony structures and the articular function of the hand. A two-step surgical procedure is usually necessary, but uncertainties about the optimal treatment are still existing. Satisfactory control rates of the infection and successful bone reconstructions can be achieved. But complications, a limited range of motion and amputations of finger parts can still not be avoided in all cases.

Study of Medical Ultrasound for Rhizarthrosis (SUR): study protocol for a randomized controlled single-center pilot-trial.

BACKGROUND: Rhizarthrosis (trapeziometacarpal osteoarthritis) is the second most common site of osteoarthritis in the hand affecting 10-30% of adults over the age of 50. Up to four times as many women as men have rhizarthrosis. Clinical symptoms include functional disability of the thumb, pain, joint swelling, and reduced strength. The first carpometacarpal joint is pivotal in the opposition of the thumb and allows a high degree in flexibility to humans. Current therapies focus mainly on surgical strategies, which should be considered in advanced, therapy-resistant stages to relieve pain and improve function. However, conservative treatment methods are urgently required in presurgical stages. The efficacy of conservative treatment options for rhizarthrosis, which are intended to preserve function, joint integrity and to relieve pain, has not been adequately studied. In the clinical study protocol presented here, we investigate the efficacy of multimodal hand therapy versus therapeutic ultrasound versus combination therapy with both hand therapy and therapeutic ultrasound. METHODS: This study is a single-center, randomized, controlled, parallel-group pilot trial. One hundred fifty patients with rhizarthrosis and current disease activity will be randomized to one of three conservative interventions over 6 months. Interventions are (1) multimodal hand therapy (2) therapeutic ultrasound, and (3) combination therapy with both hand therapy and ultrasound therapy. The primary outcome measure is the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire score after 6 months. Secondary endpoints are changes in pain, quality of life, disability progression, and changes of hand function. Safety will also be assessed. DISCUSSION: Clinical data suggest that multimodal hand therapy may improve functionality and reduce pain in rhizarthrosis. Clinical data regarding therapeutic ultrasound are not available. Clinical evidence is lacking. This study is the first clinical study investigating the effects of multimodal hand therapy in direct comparison to therapeutic ultrasound and to a combination therapy with both hand therapy and ultrasound therapy for rhizarthrosis. TRIAL REGISTRATION: ClinicalTrials.gov; NCT04115085; Registered on September 30, 2019.

Ketogenic diet and fasting diet as Nutritional Approaches in Multiple Sclerosis (NAMS): protocol of a randomized controlled study.

BACKGROUND: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adults that may lead to progressive disability. Since pharmacological treatments may have substantial side effects, there is a need for complementary treatment options such as specific dietary approaches. Ketone bodies that are produced during fasting diets (FDs) and ketogenic diets (KDs) are an alternative and presumably more efficient energy source for the brain. Studies on mice with experimental autoimmune encephalomyelitis showed beneficial effects of KDs and FDs on disease progression, disability, cognition and inflammatory markers. However, clinical evidence on these diets is scarce. In the clinical study protocol presented here, we investigate whether a KD and a FD are superior to a standard diet (SD) in terms of therapeutic effects and disease progression. METHODS: This study is a single-center, randomized, controlled, parallel-group study. One hundred and eleven patients with relapsing-remitting MS with current disease activity and stable immunomodulatory therapy or no disease-modifying therapy will be randomized to one of three 18-month dietary interventions: a KD with a restricted carbohydrate intake of 20-40 g/day; a FD with a 7-day fast every 6 months and 14-h daily intermittent fasting in between; and a fat-modified SD as recommended by the German Nutrition Society. The primary outcome measure is the number of new T2-weighted MRI lesions after 18 months. Secondary endpoints are safety, changes in relapse rate, disability progression, fatigue, depression, cognition, quality of life, changes of gut microbiome as well as markers of inflammation, oxidative stress and autophagy. Safety and feasibility will also be assessed. DISCUSSION: Preclinical data suggest that a KD and a FD may modulate immunity, reduce disease severity and promote remyelination in the mouse model of MS. However, clinical evidence is lacking. This study is the first clinical study investigating the effects of a KD and a FD on disease progression of MS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03508414. Retrospectively registered on 25 April 2018.

[Dementia and Metabolic-Vascular Risk Factors: Strategies for Prevention]. / Demenz und metabolisch-vaskuläre Risikofaktoren: Möglichkeiten der Prävention.

The prevalence of dementias is on the rise, increases exponentially with age and constitutes a major healthcare burden nationally and worldwide. Dementias are clinically heterogeneous and encompass numerous etiologies. Noteworthy, late onset dementias are closely related to vascular and metabolic risk factors in midlife. Cardiometabolic risk factors commonly precede the onset of cognitive decline for decades. This opens a huge window for prevention. Given the lack of established pharmacological options for treatment of most dementias, preventive strategies are of utmost importance. Several factors have been identified that have the potential to preserve a healthy metabolic phenotype and to attenuate the onset of late onset dementias. Evidence exists for low-risk lifestyle factors including a real food dietary pattern, an adequate supply with long chain omega-3 fatty acids, regular physical activity and restorative sleep, with multimodal concepts showing the greatest cumulative benefit.

Ketogenic diets attenuate cyclooxygenase and lipoxygenase gene expression in multiple sclerosis.

BACKGROUND: Adapted ketogenic diet (AKD) and caloric restriction (CR) have been suggested as alternative therapeutic strategies for inflammatory, hyperproliferative and neurodegenerative diseases. Pro-inflammatory eicosanoids have been implicated in the pathogenesis of multiple sclerosis since they augment vascular permeability and induce leukocyte migration into the brain. We explored the impact of ketogenic diets on gene expression of biosynthetic enzymes for pro- (ALOX5, COX1, COX2) and anti-inflammatory (ALOX15) eicosanoids in patients with relapsing-remitting multiple sclerosis. METHODS: 60 adults were prospectively recruited for this six months randomized controlled trial and the impact of dietary treatment on the Multiple Sclerosis Quality of Life-54 index (ClinicalTrials.gov (NCT01538355) has previously been published. Here we explored 24 patients (8 controls, 5 on CR and 11 on AKD). For statistical analysis we combined the two diet groups to a single pooled treatment group. FINDINGS: Inter-group comparison indicated that expression of the pro-inflammatory ALOX5 in the pooled treatment group was significantly (p < 0.05) reduced when compared with the control group. Moreover, intra-group comparison (same individuals before and after dietary treatment) suggested significantly impaired expression of other pro-inflammatory enzymes, such as COX1 (p < 0.001) and COX2 (p < 0.05). Finally, pretreatment cross-group analysis revealed a significant positive correlation between expression of pro-inflammatory ALOX5 and COX2 and an inverse correlation of ALOX5 and COX1 expression with the MSQoL-54 index. INTERPRETATION: Ketogenic diets can reduce the expression of enzymes involved in the biosynthesis of pro-inflammatory eicosanoids. Pharmacological interference with eicosanoid biosynthesis might constitute a strategy supplementing current therapeutic approaches for MS.

Peptide receptor radionuclide therapy as a new tool in treatment-refractory sarcoidosis - initial experience in two patients.

Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that can involve virtually all organ systems. Whereas most patients present without symptoms, progressive and disabling organ failure can occur in up to 10% of subjects. Somatostatin receptor (SSTR)-directed peptide receptor radionuclide therapy (PRRT) has recently received market authorization for treatment of SSTR-positive neuroendocrine tumors. Methods: We describe the first case series comprising two patients with refractory multi-organ involvement of sarcoidosis who received 4 cycles of PRRT. Results: PRRT was well-tolerated without any acute adverse effects. No relevant toxicities could be recorded during follow-up. Therapy resulted in partial response accompanied by a pronounced reduction in pain (patient #1) and stable disease regarding morphology as well as disease activity (patient #2), respectively. Conclusion: Peptide receptor radionuclide therapy in sarcoidosis is feasible and might be a new valuable tool in patients with otherwise treatment-refractory disease. Given the long experience with and good tolerability of PRRT, further evaluation of this new treatment option for otherwise treatment-refractory sarcoidosis in larger patient cohorts is warranted.

Reduced Mass and Diversity of the Colonic Microbiome in Patients with Multiple Sclerosis and Their Improvement with Ketogenic Diet.

Background: Colonic microbiome is thought to be involved in auto-immune multiple sclerosis (MS). Interactions between diet and the colonic microbiome in MS are unknown. Methods: We compared the composition of the colonic microbiota quantitatively in 25 MS patients and 14 healthy controls.Fluorescence in situ hybridization (FISH) with 162 ribosomal RNA derived bacterial FISH probes was used. Ten of the MS patients received a ketogenic diet for 6 months. Changes in concentrations of 35 numerically substantial bacterial groups were monitored at baseline and at 2, 12, and 23/24 weeks. Results: No MS typical microbiome pattern was apparent.The total concentrations and diversity of substantial bacterial groups were reduced in MS patients (P < 0.001). Bacterial groups detected with EREC (mainly Roseburia), Bac303 (Bacteroides), and Fprau (Faecalibacterium prausnitzii) probes were diminished the most. The individual changes were multidirectional and inconsistent. The effects of a ketogenic diet were biphasic. In the short term, bacterial concentrations and diversity were further reduced. They started to recover at week 12 and exceeded significantly the baseline values after 23-24 weeks on the ketogenic diet. Conclusions: Colonic biofermentative function is markedly impaired in MS patients.The ketogenic diet normalized concentrations of the colonic microbiome after 6 months.

A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms.

Dietary interventions have not been effective in the treatment of multiple sclerosis (MS). Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely reversed symptoms in 20% of animals. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cell numbers and reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs). Moreover, the FMD promoted oligodendrocyte precursor cell regeneration and remyelination in axons in both EAE and cuprizone MS models, supporting its effects on both suppression of autoimmunity and remyelination. We also report preliminary data suggesting that an FMD or a chronic ketogenic diet are safe, feasible, and potentially effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) patients (NCT01538355).

Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation.

The functional dynamics and cellular sources of oxidative stress are central to understanding MS pathogenesis but remain elusive, due to the lack of appropriate detection methods. Here we employ NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX enzymes) in vivo to identify inflammatory monocytes, activated microglia, and astrocytes expressing NOX1 as major cellular sources of oxidative stress in the central nervous system of mice affected by experimental autoimmune encephalomyelitis (EAE). This directly affects neuronal function in vivo, indicated by sustained elevated neuronal calcium. The systemic involvement of oxidative stress is mirrored by overactivation of NOX enzymes in peripheral CD11b(+) cells in later phases of both MS and EAE. This effect is antagonized by systemic intake of the NOX inhibitor and anti-oxidant epigallocatechin-3-gallate. Together, this persistent hyper-activation of oxidative enzymes suggests an "oxidative stress memory" both in the periphery and CNS compartments, in chronic neuroinflammation.

Metabolic response to epigallocatechin-3-gallate in relapsing-remitting multiple sclerosis: a randomized clinical trial.

BACKGROUND: Muscle weakness and fatigue are common symptoms in multiple sclerosis (MS). Green tea catechins such as (-)epigallocatechin-3-gallate (EGCG) are known to improve energy metabolism at rest and during exercise. OBJECTIVE: We tested the hypothesis that EGCG improves energy metabolism and substrate utilization in patients with MS. DESIGN: Eighteen patients (8 men) with relapsing-remitting MS (expanded disability status scale score <4.5, all receiving glatiramer acetate) participated in this randomized, double-blind, placebo-controlled, crossover trial at a clinical research center. All patients received EGCG (600 mg/d) and placebo over 12 wk (4-wk washout in between). After each intervention, fasting and postprandial energy expenditure (EE), as well as fat oxidation (FAOx) and carbohydrate oxidation (CHOx) rates, were measured either at rest or during 40 min of exercise (0.5 W/kg). At rest, blood samples and microdialysates from adipose tissue and skeletal muscle were also taken. RESULTS: At rest, postprandial EE and CHOx, as well as adipose tissue perfusion and glucose supply, were significantly lower in men but higher in women receiving EGCG compared with placebo. During exercise, postprandial EE was lower after EGCG than after placebo, indicating an increased working efficiency (men > women). After placebo, exercise EE was mainly fueled by FAOx in both men and women. After EGCG, there was a shift to a higher and more stable CHOx during exercise in men but not in women. CONCLUSIONS: Our data indicate that EGCG given to patients with MS over 12 wk improves muscle metabolism during moderate exercise to a greater extent in men than in women, possibly because of sex-specific effects on autonomic and endocrine control.

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.

Is metabolic flexibility altered in multiple sclerosis patients?

OBJECTIVES: Metabolic flexibility is defined as ability to adjust fuel oxidation to fuel availability. Multiple sclerosis (MS) results in reduced muscle strength and exercise intolerance. We tested the hypothesis that altered metabolic flexibility contributes to exercise intolerance in MS patients. METHODS: We studied 16 patients (all on glatiramer) and 16 matched healthy controls. Energy expenditure (EE), and carbohydrate (COX) and lipid oxidation (LOX) rates were determined by calorimetry, before and after an oral glucose load. We made measurements either at rest (canopy device) or during 40 min low-grade (0.5 W/kg) exercise (metabolic chamber). We also obtained plasma, and adipose tissue and skeletal muscle dialysate samples by microdialysis to study tissue-level metabolism under resting conditions. RESULTS: At rest, fasting and postprandial plasma glucose, insulin, and free fatty acid levels did not differ between patients and controls. Fasting and postprandial COX was higher and LOX lower in patients. In adipose, fasting and postprandial dialysate glucose, lactate, and glycerol levels were higher in patients vs. controls. In muscle, fasting and postprandial dialysate metabolite levels did not differ significantly between the groups. During exercise, EE did not differ between the groups. However, COX increased sharply over 20 min in patients, without reaching a steady state, followed by an immediate decrease within the next 20 min and fell even below basal levels after exercise in patients, compared to controls. CONCLUSIONS: Glucose tolerance is not impaired in MS patients. At rest, there is no indication for metabolic inflexibility or mitochondrial dysfunction in skeletal muscle. The increased adipose tissue lipolytic activity might result from glatiramer treatment. Autonomic dysfunction might cause dysregulation of postprandial thermogenesis at rest and lipid mobilization during exercise.

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 ß=0.277, p<0.001, and ß=0.262, p<0.001, respectively; AUC Night: ß=0.202, p=0.009 and ß=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.

Association of retinal and macular damage with brain atrophy in multiple sclerosis.

Neuroaxonal degeneration in the central nervous system contributes substantially to the long term disability in multiple sclerosis (MS) patients. However, in vivo determination and monitoring of neurodegeneration remain difficult. As the widely used MRI-based approaches, including the brain parenchymal fraction (BPF) have some limitations, complementary in vivo measures for neurodegeneration are necessary. Optical coherence tomography (OCT) is a potent tool for the detection of MS-related retinal neurodegeneration. However, crucial aspects including the association between OCT- and MRI-based atrophy measures or the impact of MS-related parameters on OCT parameters are still unclear. In this large prospective cross-sectional study on 104 relapsing remitting multiple sclerosis (RRMS) patients we evaluated the associations of retinal nerve fiber layer thickness (RNFLT) and total macular volume (TMV) with BPF and addressed the impact of disease-determining parameters on RNFLT, TMV or BPF. BPF, normalized for subject head size, was estimated with SIENAX. Relations were analyzed primarily by Generalized Estimating Equation (GEE) models considering within-patient inter-eye relations. We found that both RNFLT (p = 0.019, GEE) and TMV (p = 0.004, GEE) associate with BPF. RNFLT was furthermore linked to the disease duration (p<0.001, GEE) but neither to disease severity nor patients' age. Contrarily, BPF was rather associated with severity (p<0.001, GEE) than disease duration and was confounded by age (p<0.001, GEE). TMV was not associated with any of these parameters. Thus, we conclude that in RRMS patients with relatively short disease duration and rather mild disability RNFLT and TMV reflect brain atrophy and are thus promising parameters to evaluate neurodegeneration in MS. Furthermore, our data suggest that RNFLT and BPF reflect different aspects of MS. Whereas BPF best reflects disease severity, RNFLT might be the better parameter for monitoring axonal damage longitudinally. Longitudinal studies are necessary for validation of data and to further clarify the relevance of TMV.

Metabolic changes in the visual cortex are linked to retinal nerve fiber layer thinning in multiple sclerosis.

OBJECTIVE: To investigate the damage to the retinal nerve fiber layer as part of the anterior visual pathway as well as an impairment of the neuronal and axonal integrity in the visual cortex as part of the posterior visual pathway with complementary neuroimaging techniques, and to correlate our results to patients' clinical symptoms concerning the visual pathway. DESIGN, SUBJECTS AND METHODS: Survey of 86 patients with relapsing-remitting multiple sclerosis that were subjected to retinal nerve fiber layer thickness (RNFLT) measurement by optical coherence tomography, to a routine MRI scan including the calculation of the brain parenchymal fraction (BPF), and to magnetic resonance spectroscopy at 3 tesla, quantifying N-acetyl aspartate (NAA) concentrations in the visual cortex and normal-appearing white matter. RESULTS: RNFLT correlated significantly with BPF and visual cortex NAA, but not with normal-appearing white matter NAA. This was connected with the patients' history of a previous optic neuritis. In a combined model, both BPF and visual cortex NAA were independently associated with RNFLT. CONCLUSIONS: Our data suggest the existence of functional pathway-specific damage patterns exceeding global neurodegeneration. They suggest a strong interrelationship between damage to the anterior and the posterior visual pathway.

Correlation of self-assessed fatigue and alertness in multiple sclerosis.

BACKGROUND: Fatigue is the most common symptom in multiple sclerosis patients, but is difficult to measure; quantification thus relies on self-assessed questionnaires. OBJECTIVE: To evaluate a battery of neuropsychological tests regarding their capacity to objectify self-reported fatigue. METHODS: We assessed the correlation between age, gender, education, Kurtzke's Expanded Disability Status Scale, depression, fatigue and neuropsychological testing using a cross-sectional approach in 110 multiple sclerosis patients. Fatigue was measured with the Fatigue Severity Scale. Cognition was measured using a series of neuropsychological tests including three subtests of the Test of Attentional Performance, the Brief Repeatable Battery of Neuropsychological Tests and the Faces Symbol Test. RESULTS: According to the Fatigue Severity Scale 51.4% of the cohort were fatigued (scores > or =4). Age, education and depression showed a significant correlation with the Fatigue Severity Scale. Only 5.5% of the cohort exhibited cognitive impairment in the Brief Repeatable Battery of Neuropsychological Tests scores. After correction for age, education, Expanded Disability Status Scale and depression, Fatigue Severity Scale scores were an independent predictor of performance in the alertness subtest of the Test of Attentional Performance (standardized coefficient beta = 0.298, p = 0.014). CONCLUSION: The alertness subtest of the Test of Attentional Performance may offer an objective method of evaluating self-reported fatigue, and may therefore - in addition to the Fatigue Severity Scale - be a suitable tool for the assessment of multiple sclerosis patients complaining of fatigue.

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.