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1.  Epilepsy and violence: case series concerning physical trauma in children of persons with epilepsy 
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.
doi:10.2147/NDT.S68438
PMCID: PMC4238791  PMID: 25484586
homicide; epilepsy; child abuse; children; psychosocial; crime; law
2.  Multi-Parametric Representation of Voxel-Based Quantitative Magnetic Resonance Imaging 
PLoS ONE  2014;9(11):e111688.
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 and R, 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 and R, 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.
doi:10.1371/journal.pone.0111688
PMCID: PMC4230947  PMID: 25393722
3.  Neuroimaging of Sleep and Sleep Disorders 
doi:10.3389/fneur.2014.00151
PMCID: PMC4179551
imaging; narcolepsy; hypersomnia; neuronal circuitry; sleep disorders; physiology
4.  SPECT in the Kleine–Levin Syndrome, a Possible Diagnostic and Prognostic Aid? 
Introduction: Kleine–Levin syndrome (KLS) is a rare syndrome of periodic hypersomnia and behavioral and cognitive symptoms based on clinical criteria. In the setting of differential diagnosis of hypersomnia disorders, an objective diagnostic aid is desirable. A promising modality is single photon emission computed tomography (SPECT). As intraepisodal investigations are difficult to perform, an interepisodal investigation would be very helpful. Another aim of the study was to correlate SPECT findings to prognosis.
Methods and Materials: Twenty-four KLS-patients were categorized as severe or non-severe based on clinical characteristics. The clinical characteristics were analyzed in relation to SPECT-examinations performed between hypersomnia periods (interepisodal) or after remission, as a clinical routine investigation.
Results: Forty-eight percent of the KLS-patients have hypoperfusion in the temporal or fronto-temporal regions. In patients that have undergone remission, 56% show that pattern. There were no specific findings related to prognosis.
Discussion/Conclusion: SPECT might be a diagnostic aid, in a setting of hypersomnia experience. With a sensitivity of 48%, interepisodal SPECT alone cannot be used for diagnosing KLS.
doi:10.3389/fneur.2014.00178
PMCID: PMC4172011  PMID: 25295028
single photon emission tomography; sleep disorders; brain perfusion; Kleine–Levin syndrome; sleep
5.  Psychosis in Patients with Narcolepsy as an Adverse Effect of Sodium Oxybate 
Aim: Hypnagogic and hypnopompic hallucinations are characteristic symptoms of narcolepsy, as are excessive daytime sleepiness, cataplexy, and sleep paralysis. Narcolepsy patients may also experience daytime hallucinations unrelated to sleep–wake transitions. The effect of medication on hallucinations is of interest since treatment of narcolepsy may provoke psychotic symptoms. We aim to analyze the relation between sodium oxybate (SXB) treatment and psychotic symptoms in narcolepsy patients. Furthermore, we analyze the characteristics of hallucinations to determine their nature as mainly psychotic or hypnagogic and raise a discussion about whether SXB causes psychosis or if psychosis occurs as an endogenous complication in narcolepsy.
Method: We present altogether four patients with narcolepsy who experienced psychotic symptoms during treatment with SXB. In addition, we searched the literature for descriptions of hallucinations in narcolepsy and similarities and differences with psychotic symptoms in schizophrenia.
Results: Three out of four patients had hallucinations typical for psychosis and one had symptoms that resembled aggravated hypnagogic hallucinations. Two patients also had delusional symptoms primarily associated with mental disorders. Tapering down SXB was tried and helped in two out of four cases. Adding antipsychotic treatment (risperidone) alleviated psychotic symptoms in two cases.
Conclusion: Psychotic symptoms in narcolepsy may appear during SXB treatment. Hallucinations resemble those seen in schizophrenia; however, the insight that symptoms are delusional is usually preserved. In case of SXB-induced psychotic symptoms or hallucinations, reducing SXB dose or adding antipsychotic medication can be tried.
doi:10.3389/fneur.2014.00136
PMCID: PMC4138489  PMID: 25191304
xyrem; sodium oxybate; gamma hydroxybutyrate; psychosis; hallucinations; narcolepsy; schizophrenia; sleep disorders
6.  A 2-year observational study of patients with relapsing-remitting multiple sclerosis converting to glatiramer acetate from other disease-modifying therapies: the COPTIMIZE trial 
Journal of Neurology  2014;261(11):2101-2111.
Studies suggest that patients with relapsing-remitting multiple sclerosis (RRMS) who do not benefit from other disease-modifying treatments (DMTs) may benefit from converting to glatiramer acetate (GA). COPTIMIZE was a 24-month observational study designed to assess the disease course of patients converting to GA 20 mg daily from another DMT. Eligible patients had converted to GA and had received prior DMT for 3–6 months, depending on the reasons for conversion. Patients were assessed at baseline and at 6, 12, 18, and 24 months. In total, 672 patients from 148 centers worldwide were included in the analysis. Change of therapy to GA was prompted primarily by lack of efficacy (53.6 %) or intolerable adverse events (AEs; 44.8 %). Over a 24-month period, 72.7 % of patients were relapse free. Mean annual relapse rate decreased from 0.86 [95 % confidence interval (CI) 0.81–0.91] before the change to 0.32 (95 % CI 0.26–0.40; p < 0.0001) at last observation, while the progression of disability was halted, as the Kurtzke Expanded Disability Status Scale (EDSS) scores remained stable. Patients improved significantly (p < 0.05) on measures of fatigue, quality of life, depression, and cognition; mobility scores remained stable. The results indicate that changing RRMS patients to GA is associated with positive treatment outcomes.
doi:10.1007/s00415-014-7446-0
PMCID: PMC4221652  PMID: 25119836
Disease-modifying therapy; Glatiramer acetate; Multiple sclerosis; RRMS
7.  The Sleepy Teenager – Diagnostic Challenges 
The sleepy teenager puts the doctor in a, often tricky, situation where it must be decided if we deal with normal physiology or if we should suspect pathological conditions. What medical investigations are proper to consider? What differential diagnoses should be considered in the first place? And what tools do we actually have? The symptoms and problems that usually are presented at the clinical visit can be both of medical and psychosocial character – and actually they are often a mixture of both. Subsequently, the challenge to investigate the sleepy teenager often includes the examination of a complex behavioral pattern. It is important to train and develop diagnostic skills and to realize that the physiological or pathological conditions that can cause the symptoms may have different explanations. Research in sleep disorders has shown different pathological mechanisms congruent with the variations in the clinical picture. There are probably also different patterns of involved neuronal circuits although common pathways may exist. The whole picture remains to be drawn in this interesting and challenging area.
doi:10.3389/fneur.2014.00140
PMCID: PMC4120676  PMID: 25136329
adolescent; narcolepsy; hypersomnia; delayed sleep phase syndrome; computer gaming; fatigue; cognition disorders; Kleine–Levin syndrome
8.  Functional Magnetic Resonance Imaging in Narcolepsy and the Kleine–Levin Syndrome 
This work aims at reviewing the present state of the art when it comes to understanding the pathophysiology of narcolepsy and the Kleine–Levin syndrome (KLS) from a neuroimaging point of view. This work also aims at discussing future perspectives of functional neuroimaging in these sleep disorders. We focus on functional magnetic resonance imaging (fMRI), which is a technique for in vivo measurements of brain activation in neuronal circuitries under healthy and pathological conditions. fMRI has significantly increased the knowledge on the affected neuronal circuitries in narcolepsy and the Kleine–Levin syndrome. It has been shown that narcolepsy is accompanied with disturbances of the emotional and the closely related reward systems. In the Kleine Levin syndrome, fMRI has identified hyperactivation of the thalamus as a potential biomarker that could be used in the diagnostic procedure. The fMRI findings in both narcolepsy and the Kleine–Levin syndrome are in line with previous structural and functional imaging studies. We conclude that fMRI in combination with multi-modal imaging can reveal important details about the pathophysiology in narcolepsy and the Kleine–Levin syndrome. In the future, fMRI possibly gives opportunities for diagnostic support and prediction of treatment response in individual patients.
doi:10.3389/fneur.2014.00105
PMCID: PMC4069720  PMID: 25009530
functional magnetic resonance imaging; narcolepsy; hypersomnia; Kleine–Levin syndrome; sleep; ascending arousal system; hypothalamus; thalamus
9.  Normal Appearing and Diffusely Abnormal White Matter in Patients with Multiple Sclerosis Assessed with Quantitative MR 
PLoS ONE  2014;9(4):e95161.
Introduction: Magnetic Resonance Imaging is a sensitive technique for detecting white matter (WM) MS lesions, but the relation with clinical disability is low. Because of this, changes in both ‘normal appearing white matter’ (NAWM) and ‘diffusely abnormal white matter’ (DAWM) have been of interest in recent years. MR techniques, including quantitative magnetic resonance imaging (qMRI) and quantitative magnetic resonance spectroscopy (qMRS), have been developed in order to detect and quantify such changes. In this study, qMRI and qMRS were used to investigate NAWM and DAWM in typical MS patients and in MS patients with low number of WM lesions. Patient data were compared to ‘normal white matter’ (NWM) in healthy controls. Methods: QMRI and qMRS measurements were performed on a 1.5 T Philips MR-scanner. 35 patients with clinically definite MS and 20 healthy controls were included. Twenty of the patients fulfilled the ‘Barkhof-Tintoré criteria’ for MS, (‘MRIpos’), whereas 15 showed radiologically atypical findings with few WM lesions (‘MRIneg’). QMRI properties were determined in ROIs of NAWM, DAWM and lesions in the MS groups and of NWM in controls. Descriptive statistical analysis and comparisons were performed. Correlations were calculated between qMRI measurements and (1) clinical parameters and (2) WM metabolite concentrations. Regression analyses were performed with brain parenchyma fraction and MSSS. Results: NAWM in the MRIneg group was significantly different from NAWM in the MRIpos group and NWM. In addition, R1 and R2 of NAWM in the MRIpos group correlated negatively with EDSS and MSSS. DAWM was significantly different from NWM, but similar in the MS groups. N-acetyl aspartate correlated negatively with R1 and R2 in MRIneg. R2 of DAWM was associated with BPF. Conclusions: Changes in NAWM and DAWM are independent pathological entities in the disease. The correlation between qMRI and clinical status may shed new light on the clinicoradiological paradox.
doi:10.1371/journal.pone.0095161
PMCID: PMC3991609  PMID: 24747946
10.  Reduced Thalamic and Pontine Connectivity in Kleine–Levin Syndrome 
The Kleine–Levin syndrome (KLS) is a rare sleep disorder, characterized by exceptionally long sleep episodes. The neuropathology of the syndrome is unknown and treatment is often inadequate. The aim of the study was to improve understanding of the underlying neuropathology, related to cerebral networks, in KLS during sleep episodes. One patient with KLS and congenital nystagmus was investigated by resting state functional magnetic resonance imaging during both asymptomatic and hypersomnic periods. Fourteen healthy subjects were also investigated as control samples. Functional connectivity was assessed from seed regions of interest in the thalamus and the dorsal pons. Thalamic connectivity was normal in the asymptomatic patient whereas the connectivity between the brain stem, including dorsal pons, and the thalamus was diminished during hypersomnia. These results suggest that the patient’s nystagmus and hypersomnia might have their pathological origin in adjacent dorsal pontine regions. This finding provides additional knowledge of the cerebral networks involved in the neuropathology of this disabling disorder. Furthermore, these findings regarding a rare syndrome have broad implications, and results could be of interest to researchers and clinicians in the whole field of sleep medicine.
doi:10.3389/fneur.2014.00042
PMCID: PMC3980089  PMID: 24765085
periodic idiopathic hypersomnia; nystagmus; sleep; functional magnetic resonance imaging; brain stem; pons; thalamus; cerebellum
11.  Evidence of Conjoint Activation of the Anterior Insular and Cingulate Cortices during Effortful Tasks 
The ability to perform effortful tasks is a topic that has received considerable interest in the research of higher functions of the human brain. Neuroimaging studies show that the anterior insular and the anterior cingulate cortices are involved in a multitude of cognitive tasks that require mental effort. In this study, we investigated brain responses to effort using cognitive tasks with task-difficulty modulations and functional magnetic resonance imaging (fMRI). We hypothesized that effortful performance involves modulation of activation in the anterior insular and the anterior cingulate cortices, and that the modulation correlates with individual performance levels. Healthy participants performed tasks probing verbal working memory capacity using the reading span task, and visual perception speed using the inspection time task. In the fMRI analysis, we focused on identifying effort-related brain activation. The results showed that working memory and inspection time performances were directly related. The bilateral anterior insular and anterior cingulate cortices showed significantly increased activation during each task with common portions that were active across both tasks. We observed increased brain activation in the right anterior insula and the anterior cingulate cortex in participants with low working memory performance. In line with the reported results, we suggest that activation in the anterior insular and cingulate cortices is consistent with the neural efficiency hypothesis (Neubauer).
doi:10.3389/fnhum.2014.01071
PMCID: PMC4306292
functional magnetic resonance imaging; working memory; visual perception; forebrain asymmetry
12.  Thalamo-striato-cortical determinants to fatigue in multiple sclerosis 
Brain and Behavior  2013;3(6):715-728.
Background
The aim was to explore the thalamo-striato-cortical theory of central fatigue in multiple sclerosis (MS) patients with self-reported fatigue. If the theory correctly predicted fatigue based on disruptions of the thalamo-striato-cortical network, we expected altered brain activation in this network in MS participants while performing a complex cognitive task that challenged fatigue.
Methods
MS participants with self-reported fatigue were examined by functional magnetic resonance imaging (fMRI) during the performance of a complex working memory task. In this task, cognitive effort was challenged by a parametric design, which modeled the cerebral responses at increasing cognitive demands. In order to explore the theory of central fatigue in MS we also analyzed the cerebral responses by adding perceived fatigue scores as covariates in the analysis and by calculating the functional connectivity between regions in the thalamo-striatocortical network. The main findings were that MS participants elicited altered brain responses in the thalamo-striato-cortical network, and that brain activation in the left posterior parietal cortex and the right substantia nigra was positively correlated to perceived fatigue ratings. MS participants had stronger cortical-to-cortical and subcortical-to-subcortical connections, whereas they had weaker cortical-to-subcortical connections.
Conclusions
The findings of the present study indicate that the thalamo-striato-cortical network is involved in the pathophysiology of fatigue in MS, and provide support for the theory of central fatigue. However, due to the limited number of participants and the somewhat heterogeneous sample of MS participants, these results have to be regarded as tentative, though they might serve as a basis for future studies.
doi:10.1002/brb3.181
PMCID: PMC3868176  PMID: 24363974
Basal ganglia; functional magnetic resonance imaging; parietal cortex; substantia nigra; working memory
13.  Time to secondary progression in patients with multiple sclerosis who were treated with first generation immunomodulating drugs 
Background:
It is currently unknown whether early immunomodulatory treatment in relapsing–remitting MS (RRMS) can delay the transition to secondary progression (SP).
Objective:
To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort.
Methods:
We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995–2004, n = 730) and a historical population-based incidence cohort (onset 1950–64, n = 186). We retrospectively analyzed the difference in time to SP, termed the “period effect” within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis.
Results:
We found that the “period” affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53).
Conclusion:
Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given.
doi:10.1177/1352458512463764
PMCID: PMC3652599  PMID: 23124789
Disease-modifying drugs; disease progression; disease severity; epidemiology; multiple sclerosis; relapsing–remitting multiple sclerosis; secondary progressive multiple sclerosis; Sweden; time to progression
14.  Increased Concentrations of Glutamate and Glutamine in Normal-Appearing White Matter of Patients with Multiple Sclerosis and Normal MR Imaging Brain Scans 
PLoS ONE  2013;8(4):e61817.
In Multiple Sclerosis (MS) the relationship between disease process in normal-appearing white matter (NAWM) and the development of white matter lesions is not well understood. In this study we used single voxel proton ‘Quantitative Magnetic Resonance Spectroscopy’ (qMRS) to characterize the NAWM and thalamus both in atypical ‘Clinically Definite MS’ (CDMS) patients, MRIneg (N = 15) with very few lesions (two or fewer lesions), and in typical CDMS patients, MRIpos (N = 20) with lesions, in comparison with healthy control subjects (N = 20). In addition, the metabolite concentrations were also correlated with extent of brain atrophy measured using Brain Parenchymal Fraction (BPF) and severity of the disease measured using ‘Multiple Sclerosis Severity Score’ (MSSS). Elevated concentrations of glutamate and glutamine (Glx) were observed in both MS groups (MRIneg 8.12 mM, p<0.001 and MRIpos 7.96 mM p<0.001) compared to controls, 6.76 mM. Linear regressions of Glx and total creatine (tCr) with MSSS were 0.16±0.06 mM/MSSS (p = 0.02) for Glx and 0.06±0.03 mM/MSSS (p = 0.04) for tCr, respectively. Moreover, linear regressions of tCr and myo-Inositol (mIns) with BPF were −6.22±1.63 mM/BPF (p<0.001) for tCr and −7.71±2.43 mM/BPF (p = 0.003) for mIns. Furthermore, the MRIpos patients had lower N-acetylaspartate and N-acetylaspartate-glutamate (tNA) and elevated mIns concentrations in NAWM compared to both controls (tNA: p = 0.04 mIns p<0.001) and MRIneg (tNA: p = 0.03 , mIns: p = 0.002). The results suggest that Glx may be an important marker for pathology in non-lesional white matter in MS. Moreover, Glx is related to the severity of MS independent of number of lesions in the patient. In contrast, increased glial density indicated by increased mIns and decreased neuronal density indicated by the decreased tNA, were only observed in NAWM of typical CDMS patients with white matter lesions.
doi:10.1371/journal.pone.0061817
PMCID: PMC3629257  PMID: 23613944
15.  Work capacity and health-related quality of life among individuals with multiple sclerosis reduced by fatigue: a cross-sectional study 
BMC Public Health  2013;13:224.
Background
Among individuals diagnosed with the chronic neurologic disease, multiple sclerosis (MS), a majority suffers from fatigue, which strongly influences their every-day-life. The aim of this study was to investigate work capacity and health-related quality of life (HRQoL) in a group of MS patients and also to investigate if work capacity and HRQoL could be predicted by background factors, fatigue, heat sensitivity, cognitive dysfunction, emotional distress or degree of disability.
Methods
A descriptive, cross-sectional, designed survey was undertaken A questionnaire was sent to 323 individuals diagnosed with MS, aged between 20 and 65 years, with physical disability on the expanded disability status score (EDSS) in the interval 0 ≥ EDSS ≤ 6.5, living in Östergötland county in eastern Sweden. Questions on background factors, occupation and work, together with the health-related quality of life short form instrument (SF-36), the fatigue severity scale (FSS), the perceived deficit questionnaire (PDQ) and the hospital anxiety depression scale (HAD) were posed. Associations between variables were analyzed using Pearson’s and Spearman’s correlations. Differences between groups were tested using the Chi-square test, the Mann Whitney U-test, and the Student’s t-test. Predictive factors were analyzed using multiple linear and multiple logistic regression analysis.
Results
Of those who completed the questionnaire (n = 257, 79.6%), 59.8% were working. Work capacity was found significantly more among men (p < 0.005), those with a higher level of education (p < 0.001), those reporting less fatigue (p < 0.001), and those having no heat sensitivity (p = 0.004). For work capacity, significant predictors were low physical disability (EDSS), low fatigue, higher level of education, male sex and lower age. Those with work capacity showed significantly higher HRQoL than those who had no work capacity (p < 0.001). Levels of fatigue, cognition and emotional distress were found to be major contributing factors for HRQoL.
Conclusions
Work capacity and HRQoL among individuals diagnosed with MS are highly influenced by fatigue which can be considered as a key symptom. Work capacity was influenced by heat-sensitivity, cognitive difficulties and emotional distress and significant predictive factors besides fatigue, were physical disability (EDSS), age, sex, and level of education. Remaining at work also gives a better HRQoL.
doi:10.1186/1471-2458-13-224
PMCID: PMC3606119  PMID: 23497281
Cognition; Education; Emotional distress; Heat sensitivity; Regression analysis
16.  Low Thalamic NAA-Concentration Corresponds to Strong Neural Activation in Working Memory in Kleine-Levin Syndrome 
PLoS ONE  2013;8(2):e56279.
Background
Kleine Levin Syndrome (KLS) is a rare disorder of periodic hypersomnia and behavioural disturbances in young individuals. It has previously been shown to be associated with disturbances of working memory (WM), which, in turn, was associated with higher activation of the thalamus with increasing WM load, demonstrated with functional magnetic resonance imaging (fMRI). In this study we aimed to further elucidate how these findings are related to the metabolism of the thalamus.
Methods
fMRI and magnetic resonance spectroscopy were applied while performing a WM task. Standard metabolites were examined: n-acetylaspartate (NAA), myo-inositol, choline, creatine and glutamate-glutamine. Fourteen KLS-patients and 15 healthy controls participated in the study. The patients with active disease were examined in asymptomatic periods.
Results
There was a statistically significant negative correlation between thalamic fMRI-activation and thalamic NAA, i.e., high fMRI-activation corresponded to low NAA-levels. This correlation was not seen in healthy controls. Thalamic levels of NAA in patients and controls showed no significant differences between the groups. None of the other metabolites showed any co-variation with fMRI-activiation.
Conclusion
This study shows negative correlation between NAA-levels and fMRI-activity in the left thalamus of KLS-patients while performing a WM task. This correlation could not be found in healthy control subjects, primarily interpreted as an effect of increased effort in the patient group upon performing the task. It might indicate a disturbance in the neuronal networks responsible for WM in KLS patients, resulting in higher effort at lower WM load, compared with healthy subjects. The general relationship between NAA and BOLD-signal is also discussed in the article.
doi:10.1371/journal.pone.0056279
PMCID: PMC3581507  PMID: 23451038
17.  Brain and effort: brain activation and effort-related working memory in healthy participants and patients with working memory deficits 
Despite the interest in the neuroimaging of working memory, little is still known about the neurobiology of complex working memory in tasks that require simultaneous manipulation and storage of information. In addition to the central executive network, we assumed that the recently described salience network [involving the anterior insular cortex (AIC) and the anterior cingulate cortex (ACC)] might be of particular importance to working memory tasks that require complex, effortful processing.
Method: Healthy participants (n = 26) and participants suffering from working memory problems related to the Kleine–Levin syndrome (KLS) (a specific form of periodic idiopathic hypersomnia; n = 18) participated in the study. Participants were further divided into a high- and low-capacity group, according to performance on a working memory task (listening span). In a functional magnetic resonance imaging (fMRI) study, participants were administered the reading span complex working memory task tapping cognitive effort.
Principal findings: The fMRI-derived blood oxygen level dependent (BOLD) signal was modulated by (1) effort in both the central executive and the salience network and (2) capacity in the salience network in that high performers evidenced a weaker BOLD signal than low performers. In the salience network there was a dichotomy between the left and the right hemisphere; the right hemisphere elicited a steeper increase of the BOLD signal as a function of increasing effort. There was also a stronger functional connectivity within the central executive network because of increased task difficulty.
Conclusion: The ability to allocate cognitive effort in complex working memory is contingent upon focused resources in the executive and in particular the salience network. Individual capacity during the complex working memory task is related to activity in the salience (but not the executive) network so that high-capacity participants evidence a lower signal and possibly hence a larger dynamic response.
doi:10.3389/fnhum.2013.00140
PMCID: PMC3628360  PMID: 23616756
functional magnetic resonance imaging (fMRI); executive network; salience network; complex working memory; working memory deficits; periodic idiopathic hypersomnia; Kleine–Levin syndrome (KLS)
18.  Association between Change in Normal Appearing White Matter Metabolites and Intrathecal Inflammation in Natalizumab-Treated Multiple Sclerosis 
PLoS ONE  2012;7(9):e44739.
Background
Multiple sclerosis (MS) is associated not only with focal inflammatory lesions but also diffuse pathology in the central nervous system (CNS). Since there is no firm association between the amount of focal inflammatory lesions and disease severity, diffuse pathology in normal appearing white matter (NAWM) may be crucial for disease progression. Immunomodulating treatments for MS reduce the number of focal lesions, but possible effects on diffuse white matter pathology are less studied. Furthermore, it is not known whether intrathecal levels of inflammatory or neurodegenerative markers are associated with development of pathology in NAWM.
Methods
Quantitative proton magnetic resonance spectroscopy (1H-MRS) was used to investigate NAWM in 27 patients with relapsing MS before and after one year of treatment with natalizumab as well as NAWM in 20 healthy controls at baseline. Changes in 1H-MRS metabolite concentrations during treatment were also correlated with a panel of intrathecal markers of inflammation and neurodegeneration in 24 of these 27 patients.
Results
The group levels of 1H-MRS metabolite concentrations were unchanged pre-to posttreatment, but a pattern of high magnitude correlation coefficients (r = 0.43–0.67, p<0.0005–0.03) were found between changes in individual metabolite concentrations (total creatine and total choline) and levels of pro-inflammatory markers (IL-1β and CXCL8).
Conclusions
Despite a clinical improvement and a global decrease in levels of inflammatory markers in cerebrospinal fluid during treatment, high levels of pro-inflammatory CXCL8 and IL-1β were associated with an increase in 1H-MRS metabolites indicative of continued gliosis development and membrane turnover in NAWM.
doi:10.1371/journal.pone.0044739
PMCID: PMC3444490  PMID: 23028598
19.  Sensory ataxic neuropathy with dysarthria/dysphagia and ophthalmoplegia (SANDO). Two case reports 
Acta Myologica  2011;30(3):188-190.
Case histories of two unrelated patients suffering from sensory ataxic neuropathy, dysarthria/ dysphagia and external ophthalmoplegia (SANDO) are reported. Both patients showed compound heterozygosity for POLG1 gene mutations, and presented with symptom of the clinical characteristics of SANDO. A patient with a p.A467T and p.W748S, well-known mutations showed a progressive course with early onset and multisystem involvement, including symptoms characteristics for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The second patient showed a less well-known p.T251I and p.G848S mutations with late onset and dysphagia/dysarthria dominated, moderate symptoms. This later is the second published case history, when these POLG1 gene mutations are the possible background of late onset SANDO, dominantly presenting with bulbar symptoms.
PMCID: PMC3298093  PMID: 22616202
SANDO; heterozygote POLG1 mutations
20.  Sensitivity to heat in MS patients: a factor strongly influencing symptomology - an explorative survey 
BMC Neurology  2011;11:27.
Background
Many individuals diagnosed with Multiple Sclerosis (MS) are sensitive to increased body temperature, which has been recognized as correlating with the symptom of fatigue. The need to explore this association has been highlighted. The aim of this study was to investigate the occurrence of heat sensitivity and its relations to disease course, disability, common MS-related symptoms and ongoing immunosuppressive treatments among individuals 65 years of age or younger diagnosed with MS.
Methods
A cross-sectional designed survey was undertaken. A questionnaire was sent to MS-patients with an Expanded Disability Status Score (EDSS) in the interval of 0-6.5 and who were between 20 and 65 years of age, living in an eastern region of Sweden (n = 334). Besides occurrence of heat sensitivity (Yes/No) and corresponding questions, the Fatigue Severity Scale (FSS), the MS-related symptom checklist and the Perceived Deficit Questionnaire (PDQ) were included. Data were analysed in relation to data level using Chi-square, Mann Whitney U-test, and Student's t-test. Pearson's and Spearman's correlations were calculated. In the logistic regression analyses (enter) dichotomized MS-symptoms were used as dependent variables, and EDSS, disease-course, time since onset, heat-sensitivity, age and sex (female/male) were independent variables. In the linear regression analyses, enter, mean FSS and summarized PDQ were entered as dependent variables and EDSS, disease-course, time since onset, heat sensitivity, age and sex (female/male) were independent variables.
Results
Of the responding patients (n = 256), 58% reported heat sensitivity. The regression analyses revealed heat sensitivity as a significant factor relating not only to fatigue (p < 0.001), but also to several other common MS symptoms such as pain (p < 0.001), concentration difficulties (p < 0.001), and urination urgency (p = 0.009).
Conclusions
Heat sensitivity in MS patients is a key symptom that is highly correlated with disabling symptoms such as fatigue, pain, concentration difficulty and urination urgency.
doi:10.1186/1471-2377-11-27
PMCID: PMC3056752  PMID: 21352533
21.  The risk for multiple sclerosis in female nurse anaesthetists: a register based study 
Background
Previous studies have suggested that exposure to organic solvents, including volatile anaesthetic agents, may be a risk factor for multiple sclerosis (MS), possibly in combination with genetic and other environmental factors.
Aims
To further investigate the role of volatile anaesthetic agents having similar acute toxic effects to other organic solvents.
Methods
Female nurse anaesthetists, other female nurses, and female teachers from middle and upper compulsory school levels were identified and retrieved from the 1985 census, Statistics Sweden. By means of the unique personal identity number in Sweden, these individuals were linked with the disability pension registers at The National Social Insurance Board and also with data on hospital care 1985–2000 at The National Board of Health and Welfare.
Results
The cumulative incidence rate ratio of MS was found to be increased in female nurse anaesthetists in relation to other nurses (statistically not significant) and teachers (statistically significant), respectively.
Conclusions
These findings give some support to previous findings of an increased risk for MS in nurse anaesthetists. This is interesting in the context of previous observations of organic solvents in general as a potential risk factor in MS.
doi:10.1136/oem.2005.024604
PMCID: PMC2078114  PMID: 16709703
exposure; volatile anaesthetic gases; organic solvents; risk
22.  The study circle as a tool in multiple sclerosis patient education in Sweden 
Objective
Patient education plays an important role in the management of chronic diseases that can cause disability and predictable psychosocial problems. Quality of life assessment in multiple sclerosis (MS) has confirmed that psychosocial complications related to working life, marriage/partnership, and the family often occur. Furthermore, symptoms such as fatigue, pain, and sexual dysfunction have a great impact. We wanted to develop and implement study circles to promote the patients’ abilities to meet such common problems and to provide a network where they can be autonomous and develop appropriate strategies in self-care and existential problems.
Methods
Together with the MS patient organization and a study association, we have arranged study circles for patients with MS, thus providing structured information according to a pedagogic model. The patients are encouraged to work together in groups to learn about the disease and its key symptoms, to develop strategies to master these symptoms in everyday life, and to make necessary changes, ie, self-care management. The programme also contains handicap policies.
Results
Fifteen study circles with a total of 105 patients started during the first year. Fifteen circle leaders were approved. A focus interview showed that the patients are highly satisfied but also revealed some problems in interactions with health care professionals. The study circles were included in a wider project from a newly started multidisciplinary centre for health education for a variety of chronic diseases causing disability, which aims at becoming a regional interface between the health care system, patient organizations, and educational services.
Conclusion
The study circles have an important role to play in the management of MS. Good organization is required to make such a project work since health care services do not normally work so closely with patient organizations and educational services.
Practice implications
Study circles that are permanently established and function well are of great help for the patients and the work at the MS clinic is substantially facilitated. Health care professionals also gain from the arrangement by learning more about the self-perceived impact of the disease.
PMCID: PMC2770404  PMID: 19920967
multiple sclerosis; patient education; pedagogy; health care; self-care; qualitative research
23.  Multiple sclerosis in nurse anaesthetists 
Background: Volatile anaesthetics are chemically related to organic solvents used in industry. Exposure to industrial solvents may increase the incidence of multiple sclerosis (MS).
Aim: To examine the risk among nurse anaesthetists of contracting MS.
Methods: Nurses with MS were identified by an appeal in the monthly magazine of the Swedish Nurse Union and a magazine of the Neurological Patients Association in Sweden. Ninety nurses with MS responded and contacted our clinic. They were given a questionnaire, which was filled in by 85 subjects; 13 of these were nurse anaesthetists. The questionnaire requested information about work tasks, exposure, diagnosis, symptoms, and year. The number of active nurse anaesthetists was estimated based on information from the National Board of Health and Welfare and The Nurse Union. Incidence data for women in the region of Gothenburg and Denmark were used as the reference to estimate the risk by calculation of the standardised incidence ratio (SIR).
Results: Eleven of the 13 nurse anaesthetists were exposed to anaesthetic gases before onset of MS. Mean duration of exposure before diagnosis was 14.4 years (range 4–27 years). Ten cases were diagnosed in the study period 1980–99, resulting in significantly increased SIRs of 2.9 and 2.8 with the Gothenburg and the Danish reference data, respectively.
Conclusion: Although based on crude data and a somewhat approximate analysis, this study provides preliminary evidence for an excess risk of MS in nurse anaesthetists. The risk may be even greater than observed, as the case ascertainment might have been incomplete because of the crude method applied. Further studies in this respect are clearly required to more definitely assess the risk.
doi:10.1136/oem.60.1.66
PMCID: PMC1740375  PMID: 12499460
24.  New data identify an increasing sex ratio of multiple sclerosis in Sweden 
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.
doi:10.1177/1352458514530021
PMCID: PMC4230455  PMID: 24842964
Multiple sclerosis; sex ratio; epidemiology; prevalence proportion; register study

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