Harlequin syndrome in a pediatric population: a case series.

Harlequin syndrome is a rare condition, presenting with unilateral facial flushing and hyperhidrosis in response to physical exercise, heat or emotional stressors and has scarcely been reported in pediatric patients. It is caused by a dysfunction of vasomotor and sudomotor sympathetic fiber activity inhibiting the ability to flush on the affected side, causing the neurologically intact side to appear red. We present three pediatric cases of this uncommon syndrome, each of them of different origin and displaying distinct associated (neurological) symptoms, and review medical literature. Insight into the anatomical structure of the thoracocervical and facial sympathetic nervous system is pivotal as it dictates symptomatology. About half of Harlequin syndrome cases are complicated with ocular symptoms and a minority may be part of more extensive partial dysautonomias affecting facial sudomotor, vasomotor and pupillary responses, such as Holmes-Adie syndrome and Ross syndrome. Etiology is generally idiopathic, however, cases secondary to surgery, trauma or infection have been described. Considering its predominantly self-limiting nature, treatment is usually unnecessary and should be restricted to incapacitating cases.

Perceived neuropsychological impairment inversely related to self-reported health and employment in multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients frequently report cognitive difficulties which impact daily functioning. The objective was to investigate the relationship between patient-reported cognitive impairment and depression, demographic and MS-related variables, and to clarify its impact on self-reported health measures and employment. METHOD: A large two-centre survey included the MS Neuropsychological Screening Questionnaire (MSNQ), the two-question screening tool for depression, vitality, health-related quality of life, the Health-Promoting Lifestyle Profile II and questions assessing social network satisfaction and employment status. RESULTS: Of the 751 respondents (median age 54 years, median Expanded Disability Status Scale 5, 66.2% female), two-thirds reported perceived neuropsychological impairment or depressive symptoms. Whilst depressive symptoms were related to higher MSNQ scores, the MSNQ poorly predicted depression. After correcting for confounders, higher MSNQ scores and depressive symptoms decreased vitality, health-related quality of life and health-promoting behaviours and increased the probability of being socially dissatisfied. In participants below retirement age, higher MSNQ and Expanded Disability Status Scale scores increased the probability of unemployment, whilst depression did not. CONCLUSION: The contribution of the MSNQ to self-reported health measures and its unique explanatory power regarding unemployment suggest that subjective cognitive complaints are connected to subtle, yet meaningful, neuropsychological dysfunction.

Electronic visual analogue scales for pain, fatigue, anxiety and quality of life in people with multiple sclerosis using smartphone and tablet: a reliability and feasibility study.

OBJECTIVE: To explore the reliability and feasibility of electronic visual analogue scales in people with multiple sclerosis (MS) and healthy individuals. DESIGN: Cross-sectional observational study Setting: Clinical setting Subjects: Convenience sample of 52 people with MS and 52 matched healthy controls Interventions: NA Main measures: Participants scored 15 statements assessing fatigue, pain, anxiety and quality of life on an electronic visual analogue scale (eVAS), either using a smartphone or a tablet (randomly allocated). To check for test-retest reliability, statements were administered in two separate randomly ordered groups. Subjects completed a feasibility questionnaire. RESULTS: Mean (SD) eVAS scores ranged from 35 (28.1) to 80 (22.1) in MS group, and from 57 (28.0) to 86 (13.2) in controls. Intra Class Correlations ranged from 0.73 to 0.95 in MS sample; 0.61 to 0.92 in controls. For most statements, Bland-Altman plots indicated no systematic error, but relatively large random error of the eVAS scores (exceeding 20mm). Considerable ceiling effects (i.e. better health) were found in healthy controls. Similar reliability was found among smartphone or tablet, different demographic groups and the experience-groups. CONCLUSION: Electronic visual analogue scales are reliable and useful for people with MS to register fatigue, pain, anxiety and quality of life.

Self-reported levels of education and disability progression in multiple sclerosis.

OBJECTIVES: The purpose of our study is to investigate whether socioeconomic indicators such as education, financial concerns, employment, and living status are associated with disease progression in relapsing-onset and progressive-onset Multiple Sclerosis (MS). MATERIALS AND METHODS: We performed a cross-sectional survey among individuals with MS, registered by the Flemish MS society and included socioeconomic indicators. A Cox proportional hazard regression was performed with the time from MS onset and from birth to reach an ambulatory disability milestone corresponding to Expanded Disability Status Scale (EDSS) 6 (requiring a cane) as outcome measure, adjusted for gender, age at MS onset, and immunomodulatory treatment. RESULTS: Among the participants with relapsing-onset MS, subjects reporting education for more than 12 years had a reduced risk of reaching EDSS 6 compared to subjects reporting education for less than 12 years [HR from onset 0.68 (95% CI 0.49-0.95); HR from birth 0.71 (95% CI 0.51-0.99)]. In progressive-onset MS, longer education was associated with an increased hazard to reach EDSS 6 [HR from onset 1.25 (95% CI 0.91-1.70); HR from birth 1.39 (95% CI 1.02-1.90)]. CONCLUSIONS: Our study shows an association of self-reported levels of education with disability progression in MS, with the highest level being protective in relapsing-onset MS.

A 10-year follow-up of the European multicenter trial of interferon ß-1b in secondary-progressive multiple sclerosis.

OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.

The Symbol Digit Modalities Test as sentinel test for cognitive impairment in multiple sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment (CI) is found in about half of the multiple sclerosis (MS) population and is an important contributor to employment status and social functioning. CI is encountered in all disease stages and correlates only moderately with disease duration or Expanded Disability Status Scale scores. Most present neuropsychological test batteries are time-demanding and expensive. The Symbol Digit Modalities Test (SDMT) has been suggested as a screening tool for CI in MS. In this paper, we aim to assess the performance of the SDMT in predicting the outcome of an extensive battery. METHODS: Neuropsychological test results from 359 patients were assessed in a multidisciplinary MS center (National MS Center Melsbroek, Belgium). Using receiver operating characteristic curves, the performance of the SDMT in predicting the general cognitive outcome of the extensive Neuropsychological Screening Battery for MS (NSBMS) could be assessed. The performance of the SDMT was assessed for different levels of CI and compared with other cognitive tests. Finally, useful covariates were included in a logistic regression model. RESULTS: At a specificity of 0.60 a high sensitivity (0.91) was obtained indicating the potential of the SDMT as a sentinel test for CI in MS. The SDMT outperformed the individual tests included in the NSBMS, used as benchmark. As the logistic regression model did not result in a relevant improvement, it is concluded that most clinical variables influence both the SDMT and the NSBMS in a similar way. Excluding patients with possible practice effects, an optimal cutoff of 40 was found for the SDMT. CONCLUSION: As the SDMT is an easy, low-cost and fast test, this result may help to detect CI in everyday clinical practice.

Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.

BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.

Female gender and reproductive factors affecting risk, relapses and progression in multiple sclerosis.

Multiple sclerosis (MS), a chronic inflammatory demyelina-ting and degenerative disease of the central nervous system, is a frequent cause of neurological disability in young adults. Female predominance has increased over the last decades. Although female gender carries a higher risk of developing relapsing remitting MS, being female and at child-bearing age also appears to provide some protection against cognitive decline and against progressive onset MS, an adverse predictive factor when considering long-term disability in MS. The risk of MS in women has been associated with an earlier age at menarche. In most studies, parity did not impact MS risk. However, the recently published association of higher parity and offspring number with a reduced risk of a first demyelinating event suggests a potential suppressive effect. Pregnancy in MS patients has been associated with a reduced relapse rate and a reduction of neurological symptoms, especially in the third trimester. Despite the increased relapse risk in the postpartum period, there is no indication of an adverse effect of childbirth on the long-term course of MS. Fertility treatment in MS has been associated with an increased relapse risk in the following 3-month period, especially when the procedure did not result in pregnancy and gonadotrophin-releasing hormone agonists were used. Altogether, there is substantial evidence to support a regulatory role of sex steroid hormones in MS. In the absence of correlations with single hormone blood levels, we can only speculate about the underlying mechanisms. In conclusion, the increased MS risk in women and the changes in relapse and progression risk in association with reproductive events suggest significant and complex interactions between immune, neuroendocrine and reproductive systems in MS.

Alcohol, coffee, fish, smoking and disease progression in multiple sclerosis.

BACKGROUND: Certain lifestyle factors might influence disease activity in multiple sclerosis (MS). OBJECTIVES: To investigate the consumption of alcoholic beverages, caffeinated drinks, fish and cigarette smoking in relation to disability progression in relapsing onset and progressive onset MS. METHODS: We conducted a cross-sectional survey amongst individuals with MS, registered by the Flemish MS society in Belgium. A time-to-event analysis and Cox proportional-hazard regression were performed with time to Expanded Disability Status Scale (EDSS) 6 (requiring a cane or support to walk for a distance of 100 m) as outcome measure. Hazard ratios for the time from onset and from birth were adjusted for age at onset, gender and immunomodulatory treatment. RESULTS: Data of 1372 persons with definite MS were collected. In the relapsing onset group, a decreased risk for reaching EDSS 6 was found in regular consumers of alcohol, wine, coffee and fish compared with those who never consumed these substances. Cigarette smoking was associated with an enhanced risk for reaching EDSS 6. In the progressive onset group, no association with the risk of reaching EDSS 6 was found, except for the type of fish. Preference for fatty fish was associated with an increased risk to reach EDSS 6, when lean fish was taken as the reference category. CONCLUSION: Consumption of alcoholic beverages, coffee and fish were inversely associated with progression of disability in relapsing onset MS, but not in progressive onset MS. These findings allow to support the hypothesis that different mechanisms might underlie progression of disability in relapsing and progressive onset MS.

Menarche, oral contraceptives, pregnancy and progression of disability in relapsing onset and progressive onset multiple sclerosis.

Female gender and hormones have been associated with disease activity in multiple sclerosis (MS). We investigated age at menarche, use of oral contraceptives and pregnancy in relation to progression of disability in relapsing onset and progressive onset MS. We conducted a cross-sectional survey among individuals with MS, registered by the Flemish MS Society in Belgium. A time-to-event analysis and Cox proportional hazard regression were performed with time to Expanded Disability Status Score (EDSS) of 6 (requires a cane) as outcome measure. Hazard ratios for the time from onset and the time from birth were adjusted for age at onset and immunomodulatory treatment. Data on 973 women with definite MS were collected. In the relapsing onset group, women with at least two pregnancies had a reduced risk to reach EDSS 6 compared with nulliparous women. In the progressive onset group, later age at menarche was associated with a reduced risk to reach EDSS 6, whereas oral contraceptive use was associated with a higher risk of reaching EDSS 6. Our study corroborates the association of pregnancies with a reduced progression of disability in relapsing onset MS. In progressive onset MS, a slower progression was found in women with a later onset of menarche and a more rapid progression occurred when women reported the use of oral contraceptives.

Sunlight exposure and sun sensitivity associated with disability progression in multiple sclerosis.

BACKGROUND: Sunlight and vitamin D have been inversely associated with the risk of multiple sclerosis (MS). OBJECTIVE: We investigated sunlight exposure and sun sensitivity in relation to disability progression in MS. METHODS: We conducted a survey among persons with MS, registered by the Flemish MS society, Belgium, and stratified data according to relapsing-onset and progressive-onset MS. We used Kaplan-Meier survival and Cox proportional hazard regression analyses with time to Expanded Disability Status Scale (EDSS) 6 as outcome measure. Hazard ratios for the time from onset and from birth were calculated for the potentially predictive variables, adjusting for age at onset, gender and immunomodulatory treatment. RESULTS: 704 (51.3%) of the 1372 respondents had reached EDSS 6. In relapsing-onset MS, respondents reporting equal or higher levels of sun exposure than persons of the same age in the last 10 years had a decreased risk of reaching EDSS 6. In progressive-onset MS, increased sun sensitivity was associated with an increased hazard of reaching EDSS 6. CONCLUSION: The association of higher sun exposure with a better outcome in relapsing-onset MS may be explained by either a protective effect or reverse causality. Mechanisms underlying sun sensitivity might influence progression in progressive-onset MS.

Nutritional intake evolution in adolescent sporting boys over the last two decades.

UNLABELLED: The AIM of the study was to evaluate the nutritional trends in young elite male soccer players, attending national soccer league at RFC Bruges over the last two decades. At the start of each season, players and parents are instructed about normal healthy nutrition and fluid intake by dieticians. METHODS: Since 1983, dieticians perform dietary habit surveys in the adolescent player groups. They instruct players and parents how to record all food and fluid intake during 3 days, a training-day, a match-day and an off -day. It is asked to do the recordings when players and parents are together and parents are asked to supervise the recording. Intakes are calculated using the Becel institute nutrition software (BINS), Becel, 2003. RESULTS: A significant decrease of energy intake/m2 is observed over the last 20 years. Body composition, measured as age-matched body mass index remained at median levels for the population during this period. An important modification of dietary content towards the recommended daily intakes is observed. Fat, saturated fat and cholesterol intake decreased dramatically. Carbohydrate intake increased. CONCLUSIONS: A positive evolution towards the recommended dietary composition is observed over the years. However, the decrease in caloric intake without influence on the body mass index could suggest that these elite male footballers have a decreased physical activity as compared to 20 years ago.

Replication of KIF21B as a susceptibility locus for multiple sclerosis.

BACKGROUND: Knowledge of genetic susceptibility to autoimmune disorders is growing exponentially. One of the messages emerging from these data is the growing overlap in genetic susceptibility to different autoimmune disorders. KIF21B is a member of the kinesin superfamily and was recently established as a susceptibility locus for inflammatory bowel disease and for multiple sclerosis. RESULTS: We here replicate the association with multiple sclerosis in a Belgian study population of 791 patients and 1098 controls. CONCLUSION: As SNPs in KIF21B increase risk for both inflammatory bowel disease and multiple sclerosis, this suggests a common pathway in the pathogenesis of these diseases.

Modifiable factors influencing relapses and disability in multiple sclerosis.

A growing body of literature indicates that the natural course of multiple sclerosis can be influenced by a number of factors. Strong evidence suggests that relapses can be triggered by infections, the postpartum period and stressful life events. Vaccinations against influenza, hepatitis B and tetanus appear to be safe. Surgery, general and epidural anaesthesia, and physical trauma are not associated with an increased risk of relapses. Factors that have been associated with a reduced relapse rate are pregnancy, exclusive breastfeeding, sunlight exposure and higher vitamin D levels. A number of medications, including hormonal fertility treatment, seem to be able to trigger relapses. Factors that may worsen progression of disability include stressful life events, radiotherapy to the head, low levels of physical activity and low vitamin D levels. Strong evidence suggests that smoking promotes disease progression, both clinically and on brain magnetic resonance imaging. There is no evidence for an increased progression of disability following childbirth in women with multiple sclerosis. Moderate alcohol intake and exercise might have a neuroprotective effect, but this needs to be confirmed.

Long-term effects of childbirth in MS.

BACKGROUND: The uncertainty about long-term effects of childbirth presents MS patients with dilemmas. METHODS: Based on clinical data of 330 female MS patients, the long-term effects of childbirth were analysed, using a cross-sectional study design. Four groups of patients were distinguished: (1) without children (n = 80), (2) with children born before MS onset (n = 170), (3) with children born after MS onset (n = 61) and (4) with children born before and after MS onset (n = 19). A time-to-event analysis and Cox proportional hazard regression were performed with time from onset to EDSS 6 and age at EDSS 6 as outcome measure. RESULTS: After a mean disease duration of 18 years, 55% had reached EDSS 6. Survival curves show a distinct shift in the time to EDSS 6 between patients with no children after MS onset and patients with children after MS onset in favour of the latter. Cox regression analysis correcting for age at onset shows that patients with children only after MS onset had a reduced risk compared with patients without children (HR 0.61; 95% CI 0.37 to 0.99, p = 0.049). Also, patients who gave birth at any point in time had a reduced risk compared with patients without children (HR 0.66; 95% CI 0.47 to 0.95, p = 0.023). A similar pattern was seen for age at EDSS 6 (HR 0.57, p = 0.027 and HR 0.68, p = 0.032 respectively) CONCLUSION: Although a bias cannot fully be excluded, these results seem to support a possible favourable long-term effect of childbirth on the course of MS.

Expanding CEP290 mutational spectrum in ciliopathies.

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

The effect of levetiracetam on tremor severity and functionality in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) intention tremor is a disabling symptom, which is difficult to treat. OBJECTIVES: To investigate the effects of levetiracetam, an antiepileptic drug, on tremor severity and related functionality in MS. METHODS: A randomized, double-blind, placebo-controlled, cross-over study examined the effects of 6 weeks of oral levetiracetam administration (starting dose=250 mg/day, maximal dose=2000 mg/day) in 18 MS patients with disabling intention tremor. Primary outcome was Fahn's Tremor Rating Scale (FTRS) A&B. Secondary outcome measures were the nine-hole peg test, patient's opinion rated with the visual analog scale, FTRS C, and an activities of daily life questionnaire and validated tremor indexes derived during the performance of a digitized spiral drawing task and a wrist step-tracking task. Repeated measures analysis of variance and Friedman tests were applied. RESULTS: In all, 14 patients completed the trial. Maximal dose intake ranged from 1000 to most commonly 2000 mg, depending on patients' tolerance level. No significant effects of levetiracetam were found for any outcome measure. Further analyses on subgroups with different tremor severity showed no differential effects. Eight patients reported adverse events such as fatigue and stomach ache. CONCLUSIONS: Levetiracetam intake of 2000 mg/day did not affect tremor severity or functionality in patients with MS.

Proxy ratings from multiple sources: disagreement on the impact of multiple sclerosis on daily life.

BACKGROUND AND PURPOSE: The use of self-report measurements may be problematic in patients with limitations that interfere with reliable self-assessment like cognitive impairment, as may be the case in multiple sclerosis (MS). In these situations proxy respondents, such as close relatives or healthcare providers, may provide valuable information. To examine the accuracy and value of healthcare providers and close relatives to assess disease impact of MS. METHODS: MS patients, close relatives and healthcare providers completed the Multiple Sclerosis Impact Scale (MSIS-29) before and after a rehabilitation program. Agreement between outcomes was assessed by calculating mean absolute and directional differences and intraclass correlation coefficients. RESULTS: Comparison of ratings between patients and proxy respondents revealed low levels of agreement. Close relatives appeared to significantly overestimate the disease impact of MS whereas healthcare providers tended to underestimate the disease impact of MS. CONCLUSION: Caution is advised when incorporating close relatives and healthcare providers as proxy respondents in a rehabilitation setting. However, when close relatives are consulted, one should expect a certain level of overestimation of disease impact. When consulting healthcare providers, one should expect a certain level of underestimation of disease impact.

Within-session practice effect on paced auditory serial addition test in multiple sclerosis.

The paced auditory serial addition test (PASAT) is increasingly used in multiple sclerosis (MS) studies. Since these studies rely on repeated assessments with relatively short inter-test intervals, practice effects can be a confounding factor. We examined intra-session PASAT practice effects in 70 relapsing remitting (RR) and 40 secondary progressive (SP) patients. The average number of correct answers increased from 39.6+/-11.7 in the first PASAT run to 43.8+/-11.4 in the second run for the RR group, and from 39.1+/-11.6 to 41.8+/-13.3 in the SP group. PASAT scores showed a consistent decrease when comparing the second half of each test to the first half for both patient groups, and for both runs. Items for which the answer was a number greater than 9 had the same discrimination ability as other test items, but were significantly more difficult. A simulation of ;single-button' responses supported the use of the simplified scoring method which is currently used in fMRI studies. Our results demonstrate a within-session PASAT practice effect in MS, as well as a fatigability effect for both patient groups.