Search

Objectives To describe the pharmacological treatments (2005-2017) and the healthcare utilization (1997-2016) for patients with narcolepsy in Sweden in order to create a framework for future organizational and economic analyses. Material & Methods Patients of all ages with a diagnosis of narcolepsy registered in the National Patient Registry in specialist care in Sweden were included and information on treatments for narcolepsy was retrieved from The Swedish Prescribed Drug Register. Results We collected 2508 patients with narcolepsy, 43,3% men and 56,7% women and 47,9% were prescribed modafenil, 33,8% metylphenidate and 26,2% amphetamine. In total, 3817 treatments were initiated. Patients treated with amphetamine had a higher mean age. More women than men used modafinil, methylphenidate, amphetamine and antidepressants. The narcolepsy population had more outpatient than inpatient healthcare. Patients treated with sodium oxybate had more outpatient visits than other narcolepsy patients, before and during treatment (p = .00). Conclusions This study gives valuable information on pharmaceutical treatments and healthcare utilization for patients with narcolepsy and can be used to estimate the healthcare cost in the future. Patients with sodium oxybate treatment had more outpatient visits than other patients before and during treatment which may be due to the need to monitor potentially severe side-effects or may indicate that patients with sodium oxybate treatment have a severe disease. The number of included patients was less than expected; however, this may depend on patients escaping our collection of data, which does not contain information from primary care. Funding Agencies|UCBUCB Pharma SA

Objectives Multiple sclerosis (MS) is a chronic neurodegenerative disease of the central nervous system. Identifying MS at the population level is important for disease surveillance and allocation of resources. The Swedish National Patient Registry (NPR) has been used to study the epidemiology of MS, but the accuracy of this resource is not known. We aimed to validate a definition of MS using the Swedish NPR in Varmland County using a longitudinal cohort design. Materials and Methods Data were extracted from the NPR, the Total Population Register, the Swedish MS Register, and medical records for the years 2001-2013. Fifteen algorithms of hospitalizations and clinic visits for MS were developed and compared with findings in medical records, which acted as the "gold standard" definition. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were estimated. Results Of 805 eligible persons identified in the NPR, 763 had MS (94.8%) according to medical records. Of these, 544 (71.3%) were also registered in the SMSreg. The case definition that had a well-balanced sensitivity and specificity required three or more clinic or hospital visits for MS (sensitivity of 85.3% (95% CI: 82.6-87.8) and specificity of 81.0% (95%CI: 65.9-91.4). Conclusions Multiple case definitions with high sensitivity and moderate specificity were found, suggesting that the NPR can be used to accurately identify persons with MS. Funding Agencies|Swedish Research Council for Health, Working Life and WelfareSwedish Research CouncilSwedish Research Council for Health Working Life & Welfare (Forte) [2019-00190]

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case.control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2= 0.15; P < 2.0 ∼ 10-22at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

Kleine-Levin Syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome wide association study in 673 KLS cases collected over 14 years, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (OR=1.48,rs71947865,p=8.6×10−9) with 20 single nucleotide polymorphisms encompassing a 35kb region located in the 3’ region ofTRANK1gene, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases withTRANK1rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 years, we further stratified our sample by birth years and found that recent cases had a significantly reducedTRANK1rs71947865 association. While theTRANK1rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, the TRANK1 rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR=1.54;p=0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo r2=0.15;p−22at p=0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, behavioral rhythmicity, and bipolar disorder, and indicates that theTRANK1polymorphisms in conjunction with reported birth difficulties may predispose to KLS.Significance StatementGenetic markers inTRANK1gene and its vicinity have been weakly associated with bipolar disorder and schizophrenia (10% increased risk). We found that the same polymorphisms are associated with Kleine-Levin Syndrome (50% increased risk), a rare sleep disorder characterized by recurrent episodes of severe hypersomnia and cognitive abnormalities. Response to lithium treatment are suggestive of a pathophysiological overlap between KLS and bipolar disorder. The study also shows that variants in theTRANK1gene region may predispose to KLS when patients have had a difficult birth, suggesting thatTRANK1gene region modulate newborns’ response to brain injury, with consequences for mental and neurological health in adulthood. Another possibility may be that the polymorphism impact birth and KLS.

Objective Identifying molecular changes that contribute to the onset and progression of Huntington's disease (HD) is of importance for the development and evaluation of potential therapies. Methods We conducted an unbiased mass‐spectrometry proteomic analysis on the cerebrospinal fluid of 12 manifest HD patients (ManHD), 13 pre‐manifest (preHD), and 38 controls. A biologically plausible and significant possible biomarker was validated in samples from a separate cohort of patients and controls consisting of 23 ManHD patients and 23 controls. Results In ManHD compared to preHD, 10 proteins were downregulated and 43 upregulated. Decreased levels of proenkephalin (PENK) and transthyretin were closely linked to HD symptom severity, whereas levels of 15 upregulated proteins were associated with symptom severity. The decreased PENK levels were replicated in the separate cohort where absolute quantitation was performed. Conclusions We hypothesize that declining PENK levels reflect the degeneration of medium spiny neurons (MSNs) that produce PENK and that assays for PENK may serve as a surrogate marker for the state of MSNs in HD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

n/a Funding Agencies|Alfred osterlunds Stiftelse; Anna och Edwin Bergers Stiftelse; Magnus Bergvalls Stiftelse; Crafoord Foundation; Filip Lundbergs Stiftelse; Fredrik och Ingrid Thurings Stiftelse; Royal Physiographic Society of Lund- Hedda; John Forssmans Foundation; Gunvor och Josef Aners Stiftelse; Gyllenstiernska Krapperupsstiftelsen; Jerringfonden; Kronprinsessan Lovisas Forening For Barnasjukvard/Stiftelsen Axel Tielmans Minnesfond; Linnea och Josef Carlssons Stiftelse; Neuro Sweden; Rune Ljungdahls Stiftelse; Stiftelsen Samariten; Stiftelsen till minne av Personalforeningarna i Holmia Forsakring AB; The Gun and Bertil Stohnes Foundation; Segerfalk Foundation; Svenska Lakaresallskapet; Tage Bluchers Stiftelse; Region Skane FoU; ALF grants; Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research [IRC15-0067]; Swedish Research Council, Linnaeus grantSwedish Research Council [349-2006-237]

PAX6 gene mutations cause a variety of eye and central nervous system (CNS) abnormalities. Aniridia is often accompanied by CNS abnormalities such as pineal gland atrophy or hypoplasia, leading to disturbed circadian rhythm and sleep disorders. Less is known on the coincidence of narcolepsy in this patient group. We aimed to find out whether the circadian rhythm or sleep-wake structure was affected in patients with aniridia. Four members of a family segregating with congenital aniridia in two generations were included in the study. The patients were subjected to genetic testing for a PAX6 mutation, multiple sleep latency test, whole-brain magnetic resonance imaging (MRI), hypocretin-1 in cerebrospinal fluid, and Human Leukocyte Antigen DQ beta1*06:02. All four members were heterozygous for the pathogenic c.959-1G>A mutation in the PAX6 gene. Sleep disturbance was observed in all family members. The index patient was diagnosed with narcolepsy. MRI showed a hypoplastic pineal gland in all members. We describe the first case of a patient with PAX6 haploinsufficiency, aniridia and pineal gland hypoplasia diagnosed with narcolepsy type-1, suggesting a complex sleep disorder pathogenesis.

Ecstatic seizures constitute a rare form of epilepsy, and the semiology is diverse. Previously, brain areas including the temporal lobe and the insula have been identified to be involved in clinical expression. The aim of this report is to review changes in ecstatic seizures in a patient before and after operation of a hypothalamic hamartoma, and to scrutinize the relation to gelastic seizures. In this case, the ecstatic seizures disappeared after surgery of the hamartoma but reappeared eleven years later. Clinical information was retrospectively obtained from medical records, interviews, and a questionnaire covering seizure semiology that pertained to ecstatic and gelastic seizures. Our findings imply a possible connection between gelastic and ecstatic seizures, originating from a hypothalamic hamartoma. To our knowledge, this location has not previously been described in ecstatic seizures. Gelastic seizures may in this case were associated with ecstatic seizures. We speclate patients with ecstatic seizures may have an ictal activation of neuronal networks that involves the insula. Our case may add information to the growing knowledge concerning ecstatic seizures., Highlights • Semiology of a seizure may be explained by the dynamic interaction of different areas. • There may be a connection between gelastic and ecstatic seizures. • Gelastic seizures may be a possible trigger of ecstatic seizures.

The study investigated brain activity changes during performance of a verbal working memory task in a population of adolescents with narcolepsy. Seventeen narcolepsy patients and twenty healthy controls performed a verbal working memory task during simultaneous fMRI and EEG acquisition. All subjects also underwent MRS to measure GABA and Glutamate concentrations in the medial prefrontal cortex. Activation levels in the default mode network and left middle frontal gyrus were examined to investigate whether narcolepsy is characterized by an imbalance in cognitive resources. Significantly increased deactivation within the default mode network during task performance was observed for the narcolepsy patients for both the encoding and recognition phases of the task. No evidence for task performance deficits or reduced activation within the left middle frontal gyrus was noted for the narcolepsy patients. Correlation analyses between the spectroscopy and fMRI data indicated that deactivation of the anterior aspect of the default mode in narcolepsy patients correlated more with increased concentrations of Glutamate and decreased concentrations of GABA. In contrast, deactivation in the default mode was correlated with increased concentrations of GABA and decreased concentrations of Glutamate in controls. The results suggested that narcolepsy is not characterized by a deficit in working memory but rather an imbalance of cognitive resources in favor of monitoring and maintaining attention over actual task performance. This points towards dysregulation within the sustained attention system being the origin behind self-reported cognitive difficulties in narcolepsy. Electronic supplementary material The online version of this article (doi:10.1007/s11682-017-9706-y) contains supplementary material, which is available to authorized users.

Background: The lifestyle factors smoking and obesity have been associated with the risk of multiple sclerosis (MS). Physical activity (PA) may also be of importance. Objective: To examine the association between PA and MS risk in Italy, Norway, and Sweden and to evaluate the possible influence by established risk factors. Methods: In this case–control study, 1904 cases and 3694 controls were asked to report their average weekly amounts of light and vigorous PA during adolescence on a scale ranging from none to more than 3 hours activity. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) and adjusted for potential confounders. Results: Vigorous PA was inversely associated with MS risk in the pooled analysis ( p-trend Conclusion: Our findings suggest that vigorous PA can modify the risk of developing MS independent of established risk factors.

Organic solvents exposure has for a long time been suspected as a risk factor for developing multiple sclerosis. The evidence, containing case reports, case-control studies and cohort studies has been contradictory. An early meta-analysis, however, pointed to a doubled risk for MS. Recent major case-control studies confirm this, but also have elucidated the risk pattern, being dependent on another risk factor, i.e. smoking.

n/a

Background: Intrathecal baclofen (ITB) treatment is considered a powerful tool in the management of severe spasticity in neurological conditions such as multiple sclerosis, cerebral palsy, and traumatic spinal cord and brain injury. Objectives: The objective of this study was to assess the effectiveness of the ITB in patients with inherited ataxia suffering from severe painful spasms and/or spasticity. Method: A total of 5 patients with spinocerebellar ataxia 3 or 7 or Friedreich’s ataxia were included in this observational multicenter study. The patients were interviewed and completed outcome measures assessing pain (The Brief Pain Inventory), fatigue (Fatigue Severity Scale), and life satisfaction (LiSAT-9) before and 1 year after the treatment. Spasticity (Modified Ashworth Scale) and spasm frequency (SPFS) were measured objectively for each patient. Results: The mean treatment time was 1.9 years. Evaluation of established standard forms revealed symptomatic relief from spasticity, spasms, pain, and fatigue in addition to improved body posture, sleep, and life satisfaction after ITB treatment. Conclusions: We report the potential beneficial effects of ITB treatment in patients with inherited ataxia who also suffer from spasticity/spasms. ITB treatment indication in neurological disorders allows for extension to the treatment of spasticity/ spasms in patients with hereditary ataxia.

Purpose of Review The purpose was to review the most recent literature on neuroimaging in the Kleine-Levin syndrome (KLS). We aimed to investigate if frontotemporal and thalamic dysfunction are key KLS signatures, and if recent research indicates other brain networks of interest that elucidate KLS symptomatology and aetiology. Recent Findings In a comprehensive literature search, we found 12 original articles published 2013–2018. Most studies report deviations related to cerebral perfusion, glucose metabolism, or blood-oxygen-level-dependent responses in frontotemporal areas and/or the thalamus. Studies also report dysfunction in the temporoparietal junction and the oculomotor network that also were related to clinical parameters. We discuss these findings based on recent research on thalamocortical networks and brain stem white matter tracts. Summary The hypothesis of frontotemporal and thalamic involvement in KLS was confirmed, and additional findings in the temporoparietal junction and the oculomotor system suggest a broader network involvement, which can be investigated by future high-resolution and multimodal imaging.

OBJECTIVES Off-label use of rituximab to treat MS patients in Sweden is high, and the need for long-term safety data may not be met. Our objectives were to assess the rate of rituximab prescription in patients with multiple sclerosis in Sweden and, in addition, to evaluate the safety of rituximab in a single centre for patients with multiple sclerosis. MATERIAL AND METHODS Review of the Swedish MS register was performed to study the number of MS patients treated with rituximab during the last 6 years. Investigation also included a retrospective review of medical files in search for possible side effects/adverse events in all adult patients with MS treated with rituximab at Uppsala University Hospital. RESULTS Presently, in Sweden the rate of rituximab prescriptions in relation to other annually started of disease- modifying drugs in MS is 53.5%. CONCLUSIONS The share of MS patients in Sweden who are treated with rituximab is very high, and also rapidly increasing. Taken into account the off-label use, cases with adverse medical conditions that could possibly be related to rituximab use should be reported thoroughly.

Helena Gauffin,1 Gullvi Flensner,2 Anne-Marie Landtblom1,3 1Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; 2Department of Nursing, Health and Culture, University West, Trollhättan, Sweden; 3Department of Neuroscience, Uppsala University, Uppsala, Sweden Objective: Parents with epilepsy can be concerned about the consequences of epilepsy affecting their children. The aim of this paper is to describe aspects of what it means being a parent having epilepsy, focusing the parents’ perspectives and their thoughts on having children.Methods: Fourteen adults aged 18–35 years with epilepsy and subjective memory decline took part in focus-group interviews. The interviews were conducted according to a semi-structured guideline. Material containing aspects of parenthood was extracted from the original interviews and a secondary analysis was done according to a content-analysis guideline. Interviews with two parents for the Swedish book Leva med epilepsi [To live with epilepsy] by AM Landtblom (Stockholm: Bilda ide; 2009) were analyzed according to the same method.Results: Four themes emerged: (1) a persistent feeling of insecurity, since a seizure can occur at any time and the child could be hurt; (2) a feeling of inadequacy – of not being able to take full responsibility for one’s child; (3) acknowledgment that one’s children are forced to take more responsibility than other children do; and (4) a feeling of guilt – of not being able to fulfill one’s expectations of being the parent one would like to be.Conclusion: The parents with epilepsy are deeply concerned about how epilepsy affects the lives of their children. These parents are always aware that a seizure may occur and reflect on how this can affect their child. They try to foresee possible dangerous situations and prevent them. These parents were sad that they could not always take full responsibility for their child and could not live up to their own expectations of parenthood. Supportive programs may be of importance since fear for the safety of the child increases the psychosocial burden of epilepsy. There were also a few parents who did not acknowledge the safety issue of their child – the authors believe that it is important to identify these parents and provide extra information and support to them. Keywords: focus group interviews, qualitative research, secondary analysis, guilt, feeling of inadequacy, insecurity

To determine drug utilization pathways from the incident healthcare visit due to epilepsy and three years onward.Anti-epileptic drug utilization was calculated using individual information on inpatient- and outpatient care utilization and drug sales. Throughout, we used national register information pertaining to pharmaceutical sales linked to diagnosis-related healthcare utilization. Information on pharmaceutical sales was collected for the 2007-2013 period.For the entire studied period, a majority of new patients with epilepsy were initiated on anti-epileptic drug treatment with a monotherapy (98%); most of these patients remained on that first treatment (64%). The three most frequently prescribed drugs accounted for 72% of the initiated AED treatments. Patients with epilepsy (ICD-10: G40/41) were most commonly prescribed carbamazepine, lamotrigine and valproate. The most common second-line monotherapy was levetiracetam. About 12% of new patients with epilepsy who were initiated on AED treatment during the period eventually switched to an add-on therapy. The proportion of patients who were initiated on treatment with carbamazepine or valproate decreased, and the proportion of patients who remained on their initial monotherapy increased between 2007 and 2013.A limited number of anti-epileptic drugs accounted for the treatment of a majority of new patients with epilepsy (carbamazepine, lamotrigine and valproate accounted for more than 70%). Add-on therapies showed the same pattern, as the most frequently prescribed add-on regimens were the same ones that accounted for most of the monotherapies. There was a tendency towards fewer patients being initiated on AED treatment with either carbamazepine or valproate.

Background: Results from previous studies on a possible interaction between smoking and Epstein–Barr virus (EBV) in the risk of multiple sclerosis (MS) are conflicting. Objectives: To examine the interaction between smoking and infectious mononucleosis (IM) in the risk of MS. Methods: Within the case–control study on Environmental Factors In Multiple Sclerosis (EnvIMS), 1904 MS patients and 3694 population-based frequency-matched healthy controls from Norway, Italy, and Sweden reported on prior exposure to smoking and history of IM. We examined the interaction between the two exposures on the additive and multiplicative scale. Results: Smoking and IM were each found to be associated with an increased MS risk in all three countries, and there was a negative multiplicative interaction between the two exposures in each country separately as well as in the pooled analysis ( p = 0.001). Among those who reported IM, there was no increased risk associated with smoking (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.66–1.37). The direction of the estimated interactions on the additive scale was consistent with a negative interaction in all three countries (relative excess risk due to interaction (RERI): −0.98, 95% CI: −2.05–0.15, p = 0.09). Conclusion: Our findings indicate competing antagonism, where the two exposures compete to affect the outcome.

Background: Obesity may be a risk factor for developing multiple sclerosis (MS). Objective: We examined if body size influences the risk of MS in a population-based, case control study. Methods: A total of 953 cases and 1717 controls from Norway and 707 cases and 1333 controls from Italy reported their body size by choosing a silhouette 1 to 9 (largest) every fifth year from age 5 to 30 and at time of study. The body size-related MS risk was defined by odds ratios (ORs) in logistic regression analyses adjusting for age, smoking and outdoor activity. Results: In Norway a large body size (silhouettes 6–9) compared to silhouette 3 increased the risk of MS, especially at age 25 (OR 2.21; 95% CI 1.09–4.46 for men and OR 1.43; 95% CI 0.90–2.27 for women). When comparing silhouette 9 to 1, we found a significant dose-response from age 10 until age 30 peaking at age 25 (sex-adjusted OR 2.83; 95% CI 1.68–4.78). The association was present for at least 15 years prior to disease onset. No significant associations were found in Italy. Conclusions: Obesity from childhood until young adulthood is a likely risk factor for MS with a seemingly stronger effect in Norway than in Italy.

BACKGROUND AND PURPOSE: The administration of gadolinium contrast agent is a common part of MR imaging examinations in patients with MS. The presence of gadolinium may affect the outcome of automated tissue classification. The purpose of this study was to investigate the effects of the presence of gadolinium on the automatic segmentation in patients with MS by using the synthetic tissue-mapping method. MATERIALS AND METHODS: A cohort of 20 patients with clinically definite multiple sclerosis were recruited, and the T1 and T2 relaxation times and proton density were simultaneously quantified before and after the administration of gadolinium. Synthetic tissue-mapping was used to measure white matter, gray matter, CSF, brain parenchymal, and intracranial volumes. For comparison, 20 matched controls were measured twice, without gadolinium. RESULTS: No differences were observed for the control group between the 2 measurements. For the MS group, significant changes were observed pre- and post-gadolinium in intracranial volume (−13 mL, P < .005) and cerebrospinal fluid volume (−16 mL, P < .005) and the remaining, unclassified non-WM/GM/CSF tissue volume within the intracranial volume (+8 mL, P < .05). The changes in the patient group were much smaller than the differences, compared with the controls, which were −129 mL for WM volume, −22 mL for GM volume, +91 mL for CSF volume, 24 mL for the remaining, unclassified non-WM/GM/CSF tissue volume within the intracranial volume, and −126 mL for brain parenchymal volume. No significant differences were observed for linear regression values against age and Expanded Disability Status Scale. CONCLUSIONS: The administration of gadolinium contrast agent had a significant effect on automatic brain-tissue classification in patients with MS by using synthetic tissue-mapping. The observed differences, however, were much smaller than the group differences between MS and controls.

The objective of this study was to investigate if combined measures of activation in the thalamus and working memory capacity could guide the diagnosis of Kleine-Levin Syndrome (KLS). A second objective was to obtain more insight into the neurobiological causes of KLS.Matched group and consecutive recruitment.University hospital neurology department and imaging center.Eighteen patients with KLS diagnosed according to the International Classification of Sleep Disorders and 26 healthy controls were included.N/A.Working memory capacity was assessed by the listening span task. A version of this task (reading span) was presented to the participants during functional magnetic resonance imaging (fMRI). Activation in the thalamus was measured in a region of interest analysis. A combination of the working memory capacity and the thalamic activation measures resulted in 80% prediction accuracy, 81% sensitivity, and 78% specificity regarding the ability to separate KLS patients from healthy controls. The controls had an inverse relation between working memory capacity and thalamic activation; higher performing participants had lower thalamic activation (r = -0.41). KLS patients showed the opposite relationship; higher performing participants had a tendency to higher thalamic activation (r = -0.35).This study shows that functional neuroimaging of the thalamus combined with neuropsychological assessment of working memory function provides a means to guide diagnosis of Kleine-Levin Syndrome. Results in this study also indicate that imaging of brain function and evaluation of cognitive capacity can give insights into the neurobiological mechanisms of Kleine-Levin Syndrome.

Background: Seasonal fluctuations in solar radiation and vitamin D levels could modulate the immune response against Epstein-Barr virus (EBV) infection and influence the subsequent risk of multiple sclerosis (MS). Methods: Altogether 1660 MS patients and 3050 controls from Norway and Italy participating in the multinational case-control study of Environmental Factors In Multiple Sclerosis (EnvIMS) reported season of past infectious mononucleosis (IM). Results: IM was generally reported more frequently in Norway ( p=0.002), but was associated with MS to a similar degree in Norway (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.64–2.73) and Italy (OR 1.72, 95% CI 1.17–2.52). For all participants, there was a higher reported frequency of IM during spring compared to fall ( pConclusions: IM is associated with MS independently of season, and the association is not stronger for IM during spring, when vitamin D levels reach nadir. The distribution of IM may point towards a correlation with solar radiation or other factors with a similar latitudinal and seasonal variation.

Narcolepsy is a chronic sleep disorder caused by a loss of hypocretin-1 producing neurons in the hypothalamus. Previous neuroimaging studies have investigated brain function in narcolepsy during rest using positron emission tomography (PET) and single photon emission computed tomography (SPECT). In addition to hypothalamic and thalamic dysfunction they showed aberrant prefrontal perfusion and glucose metabolism in narcolepsy. Given these findings in brain structure and metabolism in narcolepsy, we anticipated that changes in functional magnetic resonance imaging (fMRI) resting state network (RSN) dynamics might also be apparent in patients with narcolepsy. The objective of this study was to investigate and describe brain microstate activity in adolescents with narcolepsy and correlate these to RSNs using simultaneous fMRI and electroencephalography (EEG). Sixteen adolescents (ages 13-20) with a confirmed diagnosis of narcolepsy were recruited and compared to age-matched healthy controls. Simultaneous EEG and fMRI data were collected during 10 min of wakeful rest. EEG data were analyzed for microstates, which are discrete epochs of stable global brain states obtained from topographical EEG analysis. Functional fMRI data were analyzed for RSNs. Data showed that narcolepsy patients were less likely than controls to spend time in a microstate which we found to be related to the default mode network and may suggest a disruption of this network that is disease specific. We concluded that adolescents with narcolepsy have altered resting state brain dynamics. Funding Agencies|Research Council of South East Sweden (FORSS); Knut and Alice Wallenberg foundation (KAW); strategic research area of systems neurobiology at Linkoping University; Country council of Ostergotland Sweden

Previous studies have indicated involvement of the thalamus and the pons in Kleine-Levin syndrome. In the present study, functional connectivity of the thalamus and the pons was investigated in asymptomatic patients with Kleine-Levin syndrome and healthy controls. Twelve patients and 14 healthy controls were investigated by functional magnetic resonance imaging during rest. Resting state images were analysed using seed regions of interest in the thalamus and the pons. The results showed significantly lower functional connectivity between the pons and the frontal eye field in persons with Kleine-Levin syndrome compared with healthy controls. There were no connectivity differences involving the thalamus. Based on these findings, a relation is proposed between the sleep disorder Kleine-Levin syndrome and cerebral control of eye movements, which in turn is related to visual attention and working memory. This hypothesis has to be tested in future studies of oculomotor control in Kleine-Levin syndrome. Funding Agencies|KLS Foundation; Linkoping University; Linkoping University Hospital

Background: Sex ratio in multiple sclerosis has been reported from several geographical areas. The disease is more common in women. In Europe the female-to-male ratio varies from 1.1 to 3.4. A recent study from Canada has reported a significant increase, with time, in female-to-male ratio in multiple sclerosis over the last 100 years. Objective: The aim of this study was to analyse any change in sex ratio in multiple sclerosis in the Swedish population. Methods: Data from the Swedish MS Register and data from the Swedish National Statistics Office were used to estimate sex ratio by year of birth and year of onset. Results: In the analysis of sex ratio by year of birth there were 8834 patients (6271 women and 2563 men) born between 1931 and 1985. The mean women-to-men ratio was 2.62. No clear trend was noted for the women-to-men ratio by year of birth (Spearman’s rho = 0.345, p = 0.298, n = 11). The number of patients analysed by year of onset was 9098 during the time period 1946 until 2005. The mean women-to-men ratio was 2.57. No significant change in women-to-men ratio (Spearman’s rho = −0.007, p = 0.983, n = 12) with time was observed. Conclusion: There is no evidence for an increasing women-to-men ratio with time amongst Swedish multiple sclerosis patients.

Objective: Seizures with an aura of a "sensed presence," a religious emotion, or feelings of euphoria (ecstatic seizures) are characterized by heightened self-awareness. A previous case report on a patient with epilepsy and "sensed presence" as an aura described hypoperfusion in both temporal lobes and a local ictal increase in the left frontoparietal area. A reexamination of the data was suggested by a recent study of patients with ecstatic seizures, which proposed that hyperactivation of the left anterior insula might be a potential cause. Methods: We reanalyzed the laboratory data on the case with "sensed presence" aura using a fusion of SPECT and MR images of the brain, which had not previously been available, and a close examination of the subdural ictal EEG registrations. Results: Examination of the ictal EEG recordings from subdural strip electrodes implanted subtemporally and temporally on both sides showed that seizure activity occurred first at the most medial subtemporal electrode on the left side. From an anatomical point of view, this electrode position is close to the ventral aspect of the left anterior insula, and it is possible that the seizure activity was initiated there. Reexamination of the SPECT data after fusion with contemporary MR images clearly indicated that the region of strong hyperactivation overlies the left anterior insula. Hyperactive regions also appear on the midinsula bilaterally. Together with the neurophysiological ictal EEG, this evidence supports a reinterpretation that this aura of "sensed presence" can be attributed to hyperactivation of the left anterior insula. Conclusion: The present findings support the proposal that ecstatic seizures or "sensed presence" auras can originate from the left anterior insula, a region that has been suggested to engender self-awareness associated with positive feelings.

Background: In fMRI examinations, it is very important to select appropriate paradigms assessing the brain function of interest. In addition, the patients ability to perform the required cognitive tasks during fMRI must be taken into account. Purpose: To evaluate two language paradigms, word generation and sentence reading for their usefulness in examinations of aphasic patients and to make suggestions for improvements of clinical fMRI. Material and Methods: Five patients with aphasia after stroke or trauma sequelae were examined by fMRI. The patients language ability was screened by neurolinguistic tests and elementary pre-fMRI language tests. Results: The sentence-reading paradigm succeeded to elicit adequate language-related activation in perilesional areas whereas the word generation paradigm failed. These findings were consistent with results on the behavioral tests in that all patients showed very poor performance in phonemic fluency, but scored well above mean at a reading comprehension task. Conclusion: The sentence-reading paradigm is appropriate to assess language function in this patient group, while the word-generation paradigm seems to be inadequate. In addition, it is crucial to use elementary pre-fMRI language tests to guide the fMRI paradigm decision. Original Publication: Maria Engström, Marie Karlsson, Marie Crone, Mattias Ragnehed, Wolfram Antepohl, Anne-Marie Landtblom and Peter Lundberg, Clinical fMRI of language function in aphasic patients: Reading paradigm successful, while word generation paradigm fails, 2010, Acta Radiologica, (51), 6, 679-686. http://dx.doi.org/10.3109/02841851003753456 Copyright: Informa Healthcare http://informahealthcare.com/

Study Objectives: The objectives of this study were to investigate possible neuropathology behind the Kleine-Levin Syndrome (KLS), a severe form of hypersomnia with onset during adolescence. Design: Functional magnetic resonance imaging (fMRI) applying a verbal working memory task was used in conjunction with a paper-and-pencil version of the task. Participants: Eight patients with KLS and 12 healthy volunteers participated in the study. Results: The results revealed a pattern of increased thalamic activity and reduced frontal activity (involving the anterior cingulate and adjacent prefrontal cortex) while performing a reading span task. Discussion: This finding may explain the clinical symptoms observed in KLS, in that the thalamus is known to be involved in the control of sleep. Given the increasing access to fMRI, this investigation may aid clinicians in the diagnosis of patients suffering from severe forms of hypersomnia.

Fatigue is not only a complex phenomenon accompanying different illness conditions but is also a common complaint among individuals in the general population. Among individuals diagnosed with the chronic neurological disease multiple sclerosis (MS), one-third describe fatigue as the very first symptom, however it is invisible to others. When adopting an action-theoretic approach to health, fatigue may be considered to influence the individual's goals of life and subjectively perceived health. The aim of this study was to describe perceived fatigue in relation to perceived health among working-aged individuals diagnosed with MS (n = 155), and in a comparative group of individuals randomly selected from the general population living in the same geographical area (n = 190). A self-report questionnaire including the Fatigue Impact Scale, a checklist of six symptoms, questions covering perceived health and levels of and perceptions of fatigue was used for the data collection. The responses on perceived health were dichotomized into two categories: 'good health' and 'ill health'. Of the individuals with MS, 50% graded their perceived health as ill compared with 18% in the reference group (p0.001), and 68% graded fatigue as one of their worst symptoms compared with 21% in the reference group. In both groups, higher presence of symptoms and impact of fatigue in daily activities correlated negatively to perceived health. Compared with the individuals in the reference group, the individuals with MS reported higher impact of fatigue in physical areas in both the category of 'good health' (p0.001) and 'ill health' (p0.01). The perceived impact of fatigue was mirrored in increased problems in social and family activities. In conclusion, individuals with MS perceive fatigue as one of their worst symptoms three times as often as individuals in the general population. However, individuals with MS probably also adapt themselves or shift in their response to fatigue more than individuals in the general population.

A patient with paraneoplastic cerebellar degeneration due to anti-Purkinje cell antibodies (anti-Yo) arising from ovarian carcinoma with metastases was treated with three plasmapheresis (PP) series (a total of 22 PP treatments) over one year and was monitored by repeated otoneurological testing, balance tests and clinical investigations. Blood samples for antibody titers were checked on several occasions. Initially there was a weak clinical response and significantly improved test results regarding the caloric response, as well as a possible effect on visual suppression of the vestibulo-ocular reflex after caloric ear irrigation. After the first series of PP treatment, new metastases were found. A half year later there was a progressive course with increasing general symptoms. Serology tests showed continuously high titers of anti-Yo antibody, although somewhat lower after PP. We thus report a minor and short-lived effect of PP, possibly inhibited by the natural course of metastatic disease.

Sleep disorders are of increasing importance in the society and this is due to many reasons. Firstly, sleep disorder/disturbance in the young can have psychosocial consequences with an impact on education, work, and mental health, and may also underpin unemployment. One may suspect that the use of social media and nightly entertainment in young subjects may blur the clinical picture, and sometimes hinder a diagnosis of a real sleep disorder. Secondly, the impact of sleep disturbances is increasingly focused in the society with regard to traffic safety questions, where accidents can be related to reduced mental concentration due to sleepiness (1). Finally, the impact of sleep disturbance on the general outcome of a variety of diseases is increasingly highlighted, like for example in epilepsy, Alzheimer’s, and Parkinson’s disease (2). Sleep disorders can be hard to diagnose: they often have an onset in young ages, but young people are on the other hand also prone to a physiological sleepiness or delayed sleep phase, sometimes facilitated by the use of social media and nightly entertainment. The latter circumstances can hinder the diagnosing, which sometimes is difficult and needs laboratory support (3). In addition, the young cases with narcolepsy due to the Pandemrix vaccination against swine flu in Europe in 2009/2010 indeed put a focus on sleep disorders as a whole, with increasing awareness among physicians but also in the society, and an increasing research activity (4–6). This situation indicated clearly that narcolepsy is an autoimmune disease and in fact recent research has clarified the pathology to a big extent: the experience with the Pandemrix/H1N1-initiated cases gave evidence that there is a combined pathogenesis with a genetic component (HLA DQB1*0602) and an environmental factor like vaccination/virus working through molecular mimicry. The harmed site is a neuronal locus in the lateral hypothalamus, where hypocretin-producing cells are severely affected. The etiology and mechanisms of other sleep disorders like, for example, hypersomnias are far more unclear. The rare form of periodic hypersomnia, the Kleine–Levin syndrome (KLS), is important to recognize, since it can be mixed up with physiological sleepiness in teenagers or psychiatric conditions, again pointing at the importance of a proper differential diagnosing (3, 7–9). Another condition of particular interest for the young is the delayed sleep phase syndrome (DSPS) (3). Finally, in many countries, there is increasing interest to detect and treat the obstructive sleep apnea syndrome (OSAS), since it is a condition with substantial impact on the occupational life and also with severe cardiovascular risks in the long run (10). This research topic specifically aims at describing the progress of imaging sciences in sleep medicine. It is a rapidly developing instrument, both regarding pathological and physiological conditions in humans. Today’s knowledge of sleep physiology is founded on observations that are about 100 years old: the key components of the sleep–wake regulatory systems originates from von Economo’s studies on a specific hypersomnia disorder, encephalitis lethargica. Already in the early twentieth century, von Economy identified the specific areas of the brain where lesions caused abnormal sleep–wake behavior. Quite recently, these discoveries have been actualized and more details of the brain circuitries and the neurotransmitters involved in sleep–wake regulation have been described. Nevertheless, the neural substrates that regulate our diurnal regulation of sleep and wakefulness are not yet completely understood. Here, Larson-Prior and co-workers review the present knowledge about brain circuits involved in sleep and sleep disorders (11). In addition, the authors address the important relation between sleep and cognition. Sleep disorders can provide novel insights into the brain’s sleep–wake regulatory systems. Narcolepsy, which is characterized by sudden sleep attacks that can appear several times a day, is related to loss of hypocretin-producing neurons in the hypothalamus. The hypothalamus is one important node of one of the two major branches of the ascending arousal system. The other branch involves the thalamus, which might be affected in KLS. In a perspective article, Engstrom et al. suggest that functional magnetic resonance imaging (fMRI) can identify anatomical biomarkers of brain function related to narcolepsy and KLS and their concomitant symptoms (12). An interesting example is given in the case study that shows reduced thalamic and pontine connectivity during a hypersomnia period in KLS (13). A possible diagnostic method, single photon emission computed tomography (SPECT), is evaluated in the article by Vigren et al. (14). Neural circuits involved in sleep disorders could also be studied by pharmacological interventions. Sveinsson discusses this topic in his case study on lithium treatment in KLS (15), and Sarkanen and co-workers report on psychosis in narcolepsy patients treated by sodium oxybate (16). Another intervention, continuous positive airway pressure (CPAP) in OSAS, is reviewed by Huynh and co-workers, interestingly using a radiological volumetric outcome (17). A general clinical background is sketched in The Sleepy Teenager by Landtblom and Engstrom (3), aiming at building a structure for efficient diagnosing. Finally, a book review of Neuroimaging of Sleep and Sleep Disorders (18) concerning imaging methods in sleep medicine highlights the evolving investigation possibilities, from clinical and research aspects. This is a volume that we do recommend as a guide and inspiration.

Background: Multiple sclerosis (MS) is a chronic disease of the central nervous system, often resulting in significant neurological disability. The causes of MS are not known; however, the incidence of MS is increasing, thereby suggesting that changes in lifestyle and/or environmental factors may be responsible. On this background, the Environmental Risk Factors in MS Study or EnvIMS study was designed to further explore the etiology of MS. The design and methodology are described, providing details to enable investigators to (i) use our experiences to design their own studies; (ii) take advantage of, and build on the methodological work completed for, the EnvIMS study; (iii) become aware of this data source that is available for use by the research community. Methods: EnvIMS is a multinational case-control study, enrolling 2,800 cases with MS and 5,012 population-based controls in Canada, Italy, Norway, Serbia and Sweden. The study was designed to investigate the most commonly implicated risk factors for MS etiology using a self-report questionnaire. Results/Conclusions: The use of a common methodology to study MS etiology across several countries enhances the comparability of results in different geographic regions and research settings, reduces the resources required for study design and enhances the opportunity for data harmonization.

In several international studies, an increasing women-to-men (w/m) ratio in patients with multiple sclerosis (MS) has been reported. Such sex ratios have been analysed by year of onset or by year of birth. In a Swedish study, data from the Swedish MS register (SMSreg) were used to analyse the w/m ratio in Sweden. The sex ratio was analysed both by year of birth (8834 patients) and by year of onset (9098 patients). No increased w/m ratio was seen in this study. The age-specific sex ratio did not demonstrate any significant changes. However, a new investigation of the sex ratio in Sweden, based on data from all available data sources (19,510 patients), showed a significantly increased w/m ratio of MS in Sweden from 1.70 to 2.67. Environmental factors such as cigarette smoking, hormonal factors and nutrition are of interest in this context, but the cause of the increasing w/m ratio in MS is yet not possible to explain.

Several famous religious personalities have been discussed as possibly having had epilepsy. Partial epileptic fits can be accompanied by religious experiences. The Swedish St Birgitta of Vadstena is focused on from this perspective as the exterior of the skull thought to belong to her has a prominent tuberculum with a corresponding interior indentation possibly indicating the previous existence of a meningioma, a well known cause of epilepsy. This article scrutinises arguments for and against the possibility of epileptic features in the revelations of the saint, as well as in her life story.

Background - A previous investigation at our department of a young man with typical Kleine-Levin syndrome revealed short-term memory dysfunction as well as hypoperfusion of the temporal lobes on single photon emission tomography (SPECT) (CERETECR) examination, 6 and 7 years after recovery, suggesting long lasting or even permanent cerebral dysfunction. Patients and methods - We investigated four cases with classical adolescent Kleine-Levin syndrome characterized by hypersomnia and typical associated symptoms. We used neuropsychological testing and SPECT (CERETECR) of the brain. The results from the previous report related to above is included. Results - Examination with SPECT (CERETECR) during remission revealed hypoperfusion of the temporal lobes and fronto-temporal region in two of four cases. There were normal findings in two. Neuropsychological testing performed during remission showed reduction in the short-term memory capacity in all four cases. Conclusion - It is striking that all the cases investigated showed short-term memory dysfunction. One patient who had recovered from paroxysmal symptoms (hypersomnia attacks and bulimia) 6 years earlier showed progress in the short-term memory dysfunction. A pathologic condition in the temporal lobes may be suspected in Kleine-Levin syndrome.

Bent spine syndrome : a phenotype of dysferlinopathy or a symptomatic DYSF gene mutation carrier

A case of Kleine-Levin syndrome with typical periodic hypersomnia and bulemia was diagnosed. On examination with single photo emission tomography (SPECT) (CERETEC«) during a relapse period and 2 weeks later there was marked cortical hypoperfusion of the frontal and temporal lobes, especially on the left side as well as in the right parietal lobe. Neuropsychological testing performed 1 week after a relapse showed a reduction in encoding to memory function of verbal learning indicating neocortical damage of the left fronto-temporal region. A follow-up 2 months later after the patient had spontaneously recovered showed only a slight left fronto-temporal disturbance. CT and MRI of the brain were normal although the MRI showed a large and asymmetric mamillary body. Neuropsychological testing 6 years after recovery showed pronounced reduction in short-time verbal and visual memory. Seven years after recovery SPECT demonstrated a normalized frontal perfusion but still a slight hypoperfusion in the left temporal lobe. Our results correlate to autopsy findings in two cases described previously.

The objective of this study was to evaluate the safety and efficacy of the humanized antibody ATM-027 in a baseline versus treatment magnetic resonance imaging-monitored study. Expansion of Vbeta5.2/5.3(+) T cells has been demonstrated in the peripheral blood, cerebrospinal fluid, and brain lesions of MS patients. In a phase I study, ATM-027 depleted these cells in peripheral blood and, in parallel, T-cell MBP reactivity and IFN-gamma expression were reduced. We studied 59 patients with relapsing-remitting MS (47 on ATM-027 and 12 on placebo) stratified for HLA-DR2 status. Monthly intravenous injections were given for 6 months. Individual dose titration was employed to obtain depletion of the target T-cell level and downregulation of antigen receptor density as monitored by flow cytometry. Five monthly magnetic resonance imaging scans were performed before treatment to establish baseline activity, six during treatment, and three during follow-up. Additional immunological assessments were performed to elucidate the mechanism of action of ATM-027. The treatment was safe and well tolerated, inducing consistent suppression of the target cell population. During run-in, active lesions were found in 78.7% (37/47) of patients treated with ATM-027. During treatment, the median number of lesions was reduced by 33% (p = 0.13) independent of DR2 status. The corresponding volume of enhancement was 221 mm(3) at baseline, with a reduction of 10% during treatment. Decreased numbers of cells expressing interferon-gamma messenger RNA, and decreased T-cell reactivity to several myelin antigens were found in ATM-027 treated patients. In conclusion, consistent suppression of Vbeta 5.2/5.3(+) T cells was achieved. However, the effect size on magnetic resonance imaging was considerably less than the targeted 60%.

Previous studies have shown the Fennoscandian region to be a high-risk area for multiple sclerosis (MS). In order to investigate the distribution of MS in Sweden, mortality (1952–1992) and disability pensioning statistics (1971–1994) were studied. A total of 11,414 cases with a disability pension and 5,421 cases with MS on their death certificate were analysed according to county and time period and the results were compared with the mortality figures for amyotrophic lateral sclerosis (ALS) and disability pensioning statistics for Parkinson’s disease. We found increasing rates of both MS mortality and disability pensioning. Disability pensioning correlated well with mortality 10 years later (r = 0.42, p = 0.04). We also found a marked geographical variation. Värmland county had the highest mortality, with 14 out of its 16 municipalities having higher rates than the national mean. Unexpectedly, we found a high correlation between mortality due to MS and ALS (r = 0.60, p = 0.002).

Sleep physiology is a field of increasing importance because the recent awareness of how sleep affects us all, whether it is good or bad. Sleep disorders have a big impact on daily life and functioning, but this is true, also for other disorders that are not primarily associated with sleep disturbances. Subsequently, several disorders should be investigated and treated for sleep symptoms because these can be frequent. Examples here are Parkinson’s disease with frequent daytime sleepiness and insomnia. Also, epilepsy is frequently connected to disturbed night sleep in a complex way: antiepileptic drugs can be sedative, but seizures can also occur at night and disturb the night sleep. A focus on increased sleep health for persons with epilepsy can improve seizure control and should be included in future follow up of such patients. Of course, the impact of sleep deprivation on driving is a well-known problem that often concerns doctors, for example, in common diseases like obstructive sleep apnea syndrome, OSAS, as well as other chronic conditions, also regarding medications, with an impact on alertness. Naturally, sleep effects in healthy persons are of great importance in the society, concerning both safety and quality of life. Besides medicine, new fields also have emerged that do not primarily link to pathological conditions. The effects of sleep deprivation on economic decision making constitute an example of research that reveals how sleep can affect human behavior.

To estimate the prevalence of epilepsy, costs associated with in- and outpatient care, drug utilization and productivity losses due to epilepsy in Sweden for the years 2005 and 2011.Cost components were calculated using registry data on inpatient- and outpatient-care utilization, drug sales and early pensions granted due to permanent disability and mortality. Moreover, by cross-identification of information in healthcare and pharmaceutical registries, we were able to distinguish between pharmaceuticals prescribed for epilepsy and non-epilepsy indications.The prevalence of epilepsy was estimated at 0.62% in 2005 and 0.88% in 2011. The total cost of epilepsy increased during the same period, while the per-patient cost decreased from €2929 to €1729. Direct medical costs accounted for about 36% of the estimated total cost in 2005 and 60% in 2011. The estimated healthcare cost due to epilepsy as a share of total healthcare costs for all illnesses was about the same in 2005 as in 2011 (0.2%), while the corresponding pharmaceutical cost increased from about 0.5% in 2005 to almost 1% in 2011.The per-patient cost of epilepsy is substantial, implying a significant aggregated cost incurred on society (despite a prevalence1%). Our results suggest that the per-patient pharmaceutical utilization increased, while the per-patient physician visits and hospitalizations decreased, between 2005 and 2011. Moreover, we demonstrate that the 2005 prevalence measure was underestimated the true prevalence in 2005.

The aim of the study was to explore the possibilities of multi-parametric representations of voxel-wise quantitative MRI data to objectively discriminate pathological cerebral tissue in patients with brain disorders. For this purpose, we recruited 19 patients with Multiple Sclerosis (MS) as benchmark samples and 19 age and gender matched healthy subjects as a reference group. The subjects were examined using quantitative Magnetic Resonance Imaging (MRI) measuring the tissue structure parameters: relaxation rates, R-1 and R-2, and proton density. The resulting parameter images were normalized to a standard template. Tissue structure in MS patients was assessed by voxel-wise comparisons with the reference group and with correlation to a clinical measure, the Expanded Disability Status Scale (EDSS). The results were visualized by conventional geometric representations and also by multi-parametric representations. Data showed that MS patients had lower R-1 and R-2, and higher proton density in periventricular white matter and in wide-spread areas encompassing central and sub-cortical white matter structures. MS-related tissue abnormality was highlighted in posterior white matter whereas EDSS correlation appeared especially in the frontal cortex. The multi-parameter representation highlighted disease-specific features. In conclusion, the proposed method has the potential to visualize both high-probability focal anomalies and diffuse tissue changes. Results from voxel-based statistical analysis, as exemplified in the present work, may guide radiologists where in the image to inspect for signs of disease. Future clinical studies must validate the usability of the method in clinical practice. Funding Agencies|National Research Council [VR/NT 2008-3368]; Linkoping University; County Council of Ostergotland

Background: An increasing women-to-men ratio in later birth cohorts of patients with multiple sclerosis (MS) has been observed in several populations and has been hypothesised to be due to one or several environmental factors of importance for disease aetiology. However, in a study based on data from the Swedish MS registry (SMSreg) this ratio was recently reported to be rather stable during the 20th century. Objective: The purpose of this study was to reinvestigate the women-to-men ratio in Sweden based on data from all available data sources, including deceased patients. Method: We combined data from the SMSreg with data from national patient registers. Results: In total we obtained information on 19,510 MS patients born 1931–1985, 13,321 women and 6189 men. The women-to-men ratio increased from 1.70 for patients born in the 1930s to 2.67 for patients born in the 1980s. When comparing the coverage of SMSreg to the full data set, a significantly higher proportion of women born 1931–1935 compared to men born in the same period were found in SMSreg, resulting in a sampling bias hiding the increasing sex ratio in the full material. Conclusion: The women-to-men ratio in MS has increased in Sweden during the 20th century similarly to observations in other western countries.

Helena Gauffin1,2 Anne-Marie Landtblom1–4 1Department of Neurology, Linköping University, Linköping, Sweden; 2Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; 3Neurology Unit, Department of Medical Specialist, General Hospital, Department of Medicine and Health Sciences, IMM, County Council, Linköping University, Motala, Sweden; 4Department of Neuroscience, Uppsala University, Uppsala, Sweden Abstract: Historically, epilepsy has been associated with violence, but more recent studies have emphasized genetic and psychosocial factors as more important. The case series presented here aim to highlight the difficult situation the affected children are in. We report on three cases when children have been traumatized and, in one case, even been killed by their parent who was diagnosed with epilepsy. In the first case, we describe a woman with juvenile myoclonic epilepsy who was sentenced to forensic psychiatry care for killing her child. She lived under difficult psychosocial circumstances and a suicide attempt contributed to what happened. The second case describes a man with post-traumatic seizures who was sentenced for child abuse. Ictal or postictal violence was considered in these two cases but a causal link between the violence and epilepsy has not been established. In the third case, we describe a woman with focal epilepsy and psychogenic non-epileptic seizures (PNESs). Her child was hurt and frightened in relation to violent seizures, which were regarded as PNESs. This case series demonstrates that children of parents with epilepsy can be in a vulnerable situation. No causality has been established between the seizures and these events, so consequently other factors such as psychosocial stress, low cognitive function, and a suicide attempt must also be considered as important. When a child is hurt by a parent with epilepsy the patient must be closely examined to determine the role of the seizures. Children can also be affected by PNESs. It is essential to notice especially those children of parents with epilepsy who live under difficult psychosocial circumstances and offer extra support when necessary. Keywords: homicide, epilepsy, child abuse, children, psychosocial, crime, law&nbsp

Objective: Physical disability explains only part of the reduced quality of life found among multiple sclerosis (MS) patients. Bladder dysfunction and sexual disturbance are frequent and distressing problems for MS patients. We therefore estimated the relationship between the presence and degree of sexual disturbance/bladder dysfunction and the patients' quality of life as measured by the SF-36 Health Survey. Methods: We performed a cross-sectional study of all individuals with the onset of MS between 1976 and 1986 in Hordaland County, Norway. The disease duration at examination was 9-19 years; 194 patients (94%) participated. Results: Fifty-three per cent of the patients with low physical disability (Expanded Disability Status Scale (EDSS)≤44.0) reported disease-related sexual disturbance and 44% had bladder dysfunction according to the Incapacity Status Scale. The corresponding figures for the patients with a high physical disability (EDSS>44.0) were 86 and 81% respectively. The patients with sexual disturbance had markedly and significantly reduced scores on all eight SF-36 scales, this was after adjustment for disease development measured by the EDSS. The patients without sexual disturbance scored 0.5 s.d. lower than a normal population on the social functioning scale, whereas those with marked sexual disturbance scored 1.5 s.d. lower. Similar results were found for the patients with bladder dysfunction. Conclusion: Bladder and sexual problems are associated with a marked reduction in the quality of life, also among patients with otherwise low disability. This underlines the need for identifying and treating these problems.

The etiology of multiple sclerosis (MS) may involve exposure to infectious, chemical or physical agents damaging the blood-brain barrier and an autoimmune reaction against myelin breakdown products. Here we report a pooled analysis of 174 MS cases and 815 population controls from two case-control studies with regard to such a potentially damaging exposure, namely X-ray examinations, radiological work and treatment with ionizing radiation. Exposure was assessed by questionnaires to the subjects. We obtained odds ratios of 4.4 (95% confidence interval, CI, 1.6–11.6) and 1.8 (95% CI 1.2–2.6) for radiological work and X-ray examinations, respectively; 5 cases, but no controls, in one of the studies had been treated with ionizing radiation. Our data and some other observations reported in the literature suggest a contributory role for ionizing radiation to the development of MS in some cases.

Several genetic factors are likely to play a role in the etiology of multiple sclerosis (MS). We used a candidate gene strategy in a study of polymorphic markers within or close to genes encoding cytokines (interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-4, IL-4 receptor (IL-4R), IL-10, transforming growth factor-beta1 and -beta2) and myelin proteins (2',3'-cyclic-nucleotide 3'-phosphohydrolase (CNP:ase), myelin associated glycoprotein, oligodendrocyte myelin glycoprotein, proteolipid protein) in 34 Swedish multiplex MS families and in 147 sporadic MS patients and 95 healthy controls. No evidence for linkage was observed in two-point linkage analysis. However, a slightly positive LOD score of 0.88 (theta = 0.01) for IFN-gamma was found. Affected pedigree member (APM) analysis indicated a possible linkage with TGF-beta2 (p = 0.008) and IL-4R (p = 0.043). None of the cytokine markers were associated with MS in case-control analysis. Our results suggest a possible importance of the TGF-beta2, IL-4R and IFN-gamma genes in MS.