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Background: Progressive multifocal leukoencephalopathy (PML) is a severe complication of immunosuppressive therapies, especially of natalizumab in relapsing-remitting multiple sclerosis (MS). Metabolic changes within PML lesions have not yet been described in natalizumab-associated PML in MS patients., Objective: To study metabolic profiles in natalizumab-associated PML lesions of MS patients by 1 H magnetic resonance spectroscopy ( 1 H-MRS) at different stages during the PML course. To assess changes associated with the occurrence of the immune reconstitution inflammatory syndrome (IRIS)., Methods: 20 patients received 1 H-MRS and imaging at 3 T either in the pre-IRIS, IRIS, early-post-PML, or late post-PML setting. Five of these patients received individual follow-up examinations, including the pre-IRIS or IRIS phase. Clinical worsening was described by changes in the Karnofsky Performance Scale (KPS) and the expanded disability status scale (EDSS) 1 year before PML and scoring at the time of 1 H-MRS., Results: In PML lesions, increased levels of the Lip/Cr ratio, driven by rising of lipid and reduction of Creatine, were found before the occurrence of IRIS ( p  = 0.014) with a maximum in the PML-IRIS group ( p  = 0.004). By contrast, marked rises of Cho/Cr in PML lesions were detected exclusively during the IRIS phase ( p  = 0.003). The Lip/Cr ratio decreased to above-normal levels in early-post-PML ( p  = 0.007, compared to normal appearing white matter (NAWM)) and to normal levels in the late-post-PML group. NAA/Cho was reduced compared to NAWM in the pre-IRIS, IRIS, and early-post-PML group. In NAA/Cr, the same effect was seen in the pre-IRIS and early-post-PML group. These cross-sectional results were confirmed by the individual follow-up examinations of four patients. NAA/Cho, Cho/Cr, and the lipid rise relative to NAWM in PML lesions were significantly correlated with the residual clinical worsening (KPS change) in post-PML patients (Spearman correlations ρ = 0.481, p  = 0.018; ρ = -0.505, p  = 0.014; and ρ = -0.488, p  = 0.020)., Conclusion: 1 H-MRS detected clinically significant dynamic changes of metabolic patterns in PML lesions during the course of natalizumab-associated PML in MS patients. Lip/Cr and Cho/Cr may provide additional information for detecting the onset of the IRIS phase in the course of the PML disease.

Objectives: Low ultraviolet-B (UVB) radiation causes hypovitaminosis D, which is a known risk factor for multiple sclerosis (MS) and associated with MS disease activity. Our objective is to test whether vitamin D supplementation is most effective in lowering disease activity during the period of the year with low UVB radiation and consequently low serum 25-hydroxyvitamin D 3 (25(OH)D 3 ) concentration., Methods: Retrospective analysis of medical records from our outpatient department identified 40 MS patients with available data of at least 6 months before and during oral vitamin D supplementation. Serum 25(OH)D 3 concentration was analyzed using immunoassay. UVB radiation data were provided by the local government. Annualized and quarterly relapse rates before and during vitamin D supplementation served as outcome parameters., Results: During vitamin D supplementation (18,950 international units/week (mean, SD 3,397)), serum 25(OH)D 3 concentration increased by 51 nmol/L and the UVB-related seasonal variability in 25(OH)D 3 levels ceased (rho = -0.13, p  > .05). Furthermore, the annualized relapse rate decreased by approximately 50%. This was almost solely driven by the prominent reduction in the quarterly relapse rate in late winter/early spring, when 25(OH)D 3 levels of nonsupplemented patients were the lowest., Conclusions: Our study demonstrated the modulation of seasonal MS disease activity through vitamin D supplementation. Given the prominent reduction in the quarterly relapse rate in late winter/early spring, our data indicate a beneficial effect of supplementing MS patients with vitamin D, especially during this period of the year.

Objective: Progressive multifocal leukoencephalopathy (PML) is an emerging complication of immunosuppressive therapies, especially natalizumab in multiple sclerosis (MS). Factors associated with functional outcome of natalizumab-associated PML (natalizumab-PML) have not been sufficiently described., Methods: We retrospectively analyzed medical records of all patients with natalizumab-PML ( n = 32) treated in our hospital since 2009. Disability measured by Expanded Disability Status Scale (EDSS) at two different time points (highest available EDSS during PML and last available EDSS after PML diagnosis) served as functional outcome parameters. Clinical, laboratory, and imaging data were analyzed for association with functional outcome by applying Spearman's rho and multivariate regression analysis., Results: In all, 31/32 patients survived PML. A poor functional outcome was associated with higher age, higher initial John Cunningham virus (JCV) copy number in cerebrospinal fluid (CSF), and more extensive PML lesions on initial magnetic resonance imaging (MRI). No association between functional outcome and the duration of natalizumab therapy or a delayed PML diagnosis was observed., Conclusion: This study will be useful for neurological practice to estimate functional outcome or disease severity of natalizumab-PML in primary care settings.

Purpose: Early diagnosis and treatment of multiple sclerosis-related progressive multifocal leukoencephalopathy (PML) significantly improve clinical outcomes. However, there is a lack of information regarding the restart of immunomodulatory therapy in the post-PML setting, when multiple sclerosis activity reappears. We aimed at the examination of metabolic differences using 1H-magnetic resonance spectroscopy (1H-MRS) in multiple sclerosis patients at various post-PML stages and at the exploration of differences according to their disease and JC virus (JCV) status., Methods: 1H-MRS of PML lesions was carried out on 15 relapsing-remitting multiple sclerosis patients with natalizumab-associated PML. Patients were grouped according to their stage after PML infection as early post-PML, less than 19 months after PML onset (n = 5), or late post-PML group, more than 23 months after PML onset (n = 10). The latter group was further categorized according to persisting JCV load in the cerebrospinal fluid., Results: Early post-PML patients showed significantly higher Lipid/Creatine ratios within PML lesions than late post-PML (p = 0.036). Furthermore, N-Acetyl-Aspartate/Creatine and N-Acetyl-Aspartate/Choline were significantly reduced in early post-PML and late post-PML lesions relative to normal-appearing white matter. In late post-PML, virus-positive patients showed significantly higher ratios of Choline/Creatine (p = 0.019) and consequently a reduced N-Acetyl- Aspartate/Choline ratio (p = 0.010) in contrast to virus-negative patients. In late post-PML patients with persisting viral load, an elevated Choline/Creatine ratio correlated significantly with higher disability., Conclusions: 1H-MRS may provide additional information related to underlying PML disease activity in various post-PML stages. In particular, Choline/Creatine levels, Lipid levels, and N-Acetyl- Aspartate/Choline are relevant markers in the post-PML setting, taking also the JCV status into account.

Glatiramer acetate (GA) is an approved therapy for relapsing-remitting multiple sclerosis, but its efficacy for the prevention of attacks in neuromyelitis optica spectrum disorder (NMOSD) remains unknown. We did a multicenter retrospective analysis of GA-treated patients with NMOSD, identified through a national registry. Annualized relapse rate and expanded disability status scale (EDSS) were the main outcome measures. We identified 23 GA-treated patients (21 female, 16 aquaporin-4 antibody-positive). GA was given for <6 months in seven patients; reasons for stopping were relapses (n = 3), confirmation of NMOSD (n = 2) and side effects (n = 2). Of 16 patients treated ≥ 6 months with GA (15 female, 11 aquaporin-4 antibody-positive), 14 experienced at least one relapse. There was no reduction in the mean annualized relapse rate in the total group (1.9 ± 1.1 before vs. 1.8 ± 1.4 during GA therapy), as well as in those patients who were aquaporin-4 antibody-positive, or had a history of prior immunotherapy or not. The median EDSS increased (2.5 start vs. 3.5 finish of GA, P < 0.05). GA therapy was discontinued in 15/16 patients; reasons were therapeutic inefficacy in 13 and post-injection skin reactions in two patients. We conclude that GA is not beneficial for preventing attacks in most patients with NMOSD, particularly in aquaporin-4 antibody-positive cases.

Background: Fingolimod (FTY) is the first oral medication approved for multiple sclerosis therapy. Until now, little has been known about the effects of FTY withdrawal regarding disease activity and development of tumefactive demyelinating lesions (TDLs), as already described in patients who discontinue natalizumab., Methods: In this study we present the clinical and radiological findings of two patients who had a severe rebound after FTY withdrawal and compare these with patients identified by a PubMed data bank analysis using the search term 'fingolimod rebound'. In total, 10 patients, of whom three developed TDLs, are presented., Results: Patients suffering from TDLs were free of clinical and radiological signs of disease activity under FTY therapy (100% versus 57%, compared with patients without TDLs) and had rebounds after a mean of 14.6 weeks (standard deviation 11.5) [patients without TDLs 11.7 (standard deviation 3.4)]., Conclusion: We propose that a good therapeutic response to FTY might be predisposing for a severe rebound after withdrawal. Consequently, therapy switches should be planned carefully with a short therapy free interval.

Introduction: Activated prothrombin time (aPTT) and thrombin time (TT) can serve as indicators for anticoagulation effect of dabigatran etexilate (Pradaxa), the new oral reversible, competitive inhibitor of thrombin. Further, a significant elevation of these coagulation parameters might demonstrate an increased risk of bleeding probably due to an accumulation of dabigatran., Case Reports: We present 2 cases of patients with atrial fibrillation as well as mild and moderate renal impairment, which were treated with dabigatran. The patient with the mild renal impairment [creatinine clearance in 24-hour urine collection (CrCl) 50.2 mL/min] had a comorbid slightly disturbed liver synthesis and prolongation of aPTT. Increased risk of bleeding could be identified by significant elevated coagulation parameters (TT and aPTT) during dabigatran treatment. Further speculative in this case increased risk of bleeding might be due to an accumulation of dabigatran possibly caused by comorbid kidney and liver impairment and an effective gain of dabigatran caused by reduced hepatic synthesis of coagulation factors., Conclusions: Especially in multimorbid elderly patients with comorbid liver and kidney dysfunction, a measurement of coagulation parameters not only before but also soon after initiation of treatment might provide additional information about the risk of bleeding.

Objective: Progressive multifocal leukoencephalopathy (PML), caused by JC virus (JCV), can occur in patients receiving natalizumab for multiple sclerosis (MS). JCV detection by quantitative polymerase chain reaction (qPCR) in cerebrospinal fluid (CSF), or brain biopsy, is required for probable or definite diagnosis of PML. However, in some patients only low levels of JCV DNA (<100 copies/ml) are present in CSF, making the diagnosis challenging. Our objective was to assess the complementary value of a CSF JCV antibody index (AIJCV ) in the diagnosis of natalizumab-associated PML., Methods: AIJCV was assessed in 37 cases of natalizumab-associated PML and 89 MS-patients treated with natalizumab without PML. Sera and CSF were tested in a capture enzyme-linked immunosorbent assay, using JCV-VP1 fused to glutathione S-transferase as antigen. Albumin levels and total immunoglobulin G concentration were determined by immunonephelometry, and the AIJCV was calculated as published., Results: Twenty-six of 37 (70%) patients with natalizumab-associated PML exhibited an AIJCV > 1.5, whereas this was seen in none of the controls (p < 0.0001). At time of the first positive qPCR for JCV DNA, 11 of 20 (55%) patients with natalizumab-associated PML had an AIJCV > 1.5. JCV DNA levels of <100 copies/ml were seen in 14 (70%) of these 20 patients, of whom 8 (57%) demonstrated an AIJCV > 1.5., Interpretation: Determination of the AIJCV could be an added tool in the diagnostic workup for PML and should be included in the case definition of natalizumab-associated PML., (© 2014 American Neurological Association.)

Background: Risks of natalizumab (NAT) therapy have to be weighed against disease recurrence after stopping NAT., Objectives: The objective of this paper is to identify risk factors for recurrence of relapses after switching from NAT to fingolimod (FTY) in relapsing-remitting multiple sclerosis (RRMS)., Methods: Patients (n = 33) were treated with NAT for ≥1 year, and then switched to FTY within 24 weeks (mean follow-up on FTY 81.1 (SD 26.5) weeks). Annual relapse rates (ARR) and Expanded Disability Status Scale scores (EDSS) were assessed. Descriptive statistics, univariate logistic regression analysis, and receiver operating characteristic curves were conducted., Results: Overall, 20 patients (61%) had relapses after discontinuation of NAT and 16 (48%) during FTY therapy. The maximum incidence of relapses occurred between weeks 13-24 post-NAT. The last EDSS during the switching period predicted relapses during subsequent FTY therapy. EDSS >3 separated most powerfully between the groups (sensitivity 64%, specificity 88%) and significantly predicted relapses (relative risk 3.27, 95% CI: 1.5-7.3). Seventy-five percent of patients with EDSS ≤ 3 remained free of relapses, compared to 18% of patients with EDSS >3., Conclusions: There was an increase of the ARR in the first year after switching from NAT to FTY. Last EDSS during the switching period was a predictor of relapses during FTY., (© The Author(s), 2014.)

Patients with psychogenic nonepileptic seizures (PNESs) often have additional epileptic seizures (ESs). Distinguishing between those with ESs and those without ESs is difficult but mandatory. We hypothesize that these two patient groups differ in clinical data, which might be useful for establishing diagnosis. All patients with PNESs (n=114) from the Bethel Epilepsy Centre treated between 1/11/2010 and 1/11/2011 were included. Thirty-six percent had additional epilepsy. In contrast, 84 of the 114 patients with PNESs took antiepileptic drugs (AEDs) (AED treatment: patients with PNESs=44/73, patients with PNESs+ESs=40/41), most of them (65.5%) as polytherapy. Significant differences between both groups were as follows: patients with PNESs were older at disease onset, had a shorter duration from onset to inpatient visit, were less frequently on AEDs, were less frequently on antiepileptic polytherapy, and had a normal EEG compared with patients with PNESs+ESs. Multivariate stepwise logistic regression revealed age at seizure onset, number of AEDs, and difference between number of AEDs and psychiatric drugs as significant predictors of patients with ESs in PNESs (Nagelkerke's r2=0.59). Therefore, clinical data proved to be useful in the diagnostic process., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Natalizumab (Nat) is a humanized monoclonal antibody used for the treatment of relapsing multiple sclerosis (MS). Nat inhibits lymphocyte migration via the blood brain barrier (BBB) by blockage of an integrin adhesion molecule, very late antigen 4. During the phase III clinical trials, it was shown that Nat reduces disease activity and prevents disability progression. In addition, several smaller studies indicate a positive influence of Nat on cognition, depression, fatigue, and quality of life (Qol). Therapeutic efficacy has to be weighed against the risk of developing potentially fatal progressive multifocal leukoencephalopathy (PML), an opportunistic infection by JC-virus (JCV) with an incidence of 3.4/1000 (95% CI 3.08-3.74) in Nat treated MS patients. In this review article, we will review data on the presumed mechanism of Nat action, clinical and paraclinical efficacy parameters, and adverse drug reactions with a special focus on PML.

Objective: Little is known about seizures in natalizumab-associated progressive multifocal leukoencephalopathy (NAT-PML)., Methods: A review of clinical records of 15 NAT-PML patients with multiple sclerosis (MS) treated at a German university hospital., Results: Some 53% (8/15) of our patients developed seizures with often multiple semiologies (seven grand mal, three simple partial motor and two psychomotor seizures). Series of seizures or status epilepticus occurred in seven of these eight. Seizure onset was on average 61 days after onset of NAT-PML and was associated with immune reconstitution inflammatory syndrome (IRIS) in five of eight patients. After having observed severe seizures during NAT-PML in seven of our first nine patients, we started preventive antiepileptic treatment (PAT) with levetiracetam (1000-1750 mg/day). Patient subgroups analyzed for seizures and PAT did not differ in baseline characteristics. Only one of six patients, who received PAT, had a seizure compared with seven of nine patients without PAT (2-tailed Fisher's exact test, p = 0.04)., Conclusions: Although the small sample size and retrospective nature of the study are limitations, we propose to treat NAT-PML patients with PAT early after diagnosis, as seizures seem to be common and severe in NAT-PML.

Objective: Although the prognosis of natalizumab-associated progressive multifocal leukoencephalopathy (PML) seems to be better than HIV-associated PML, little is known about the long-term functional outcome in multiple sclerosis (MS) patients and the subsequent return of MS disease activity. We evaluated retrospectively 15 patients with natalizumab-associated PML treated at our centre., Patients and Methods: Fifteen MS-PML patients (nine women, six men) were referred to us from adjacent local centres. The patients had a median natalizumab exposure of 34 months at PML diagnosis. They received standardised treatment as described in previous work. Expanded Disability Status Scale (EDSS) and Karnofsky score in the year pre-PML, at PML-diagnosis (pre-immune reconstitution inflammatory syndrome (IRIS)) and post-PML were determined in 3-6 monthly intervals., Results: The median follow-up of these 15 patients was 21.5 months. None of the 15 patients died. Three patients had a Karnofsky score of 80 or higher, nine patients between 50-70 and three patients of 40 or lower at latest examination. Eight of the 15 patients developed seizures during acute PML phase. Fifty percent of those patients were not seizure-free one year post PML, despite continuation of antiepileptic treatment. The median EDSS in the year pre-PML was 2.5, 4.5 at PML diagnosis, 6.5 post-IRIS and 5.5 at latest examination. CSF became virus-free in eight of the 15 patients after a median time of 4.5 months. In nine patients, disease reappeared after a median time of seven months from PML diagnosis., Conclusions: Although the clinical outcome of natalizumab-treated PML patients is much better than in patients with HIV-associated PML, this may be further improved by treatment at reference centres using standardised therapy regimens and transient intensive care if needed. Systematic studies of appropriate MS immunotherapies after PML are critically needed.

Observation of psychogenic nonepileptic seizures (PNESs) during video-EEG represents the diagnostic gold standard for PNESs. Different provocative techniques have been used to increase PNES frequency during EEG. These techniques include placebo administration, suggestion strategies, or both. In order to avoid the appearance of deception, we investigated the following hypothesis: If patients with PNESs were informed about the possible reduction of seizure threshold caused by hyperventilation and photic stimulation prior to EEG without any other suggestive strategies, PNESs would occur more frequently. In total, 34 inpatients with a diagnosis of PNESs, who had been informed prior to EEG about the increased seizure risk during hyperventilation and photic stimulation (study group), and 80 "noninformed" patients (control group) were enrolled. Psychogenic nonepileptic seizures occurred significantly more often in the study group compared to controls (38% vs. 10.0%, p=0.001). Our results imply that simply providing correct and explicit information about provocation techniques substantially increased the PNES rate., (© 2013.)

Importance: A patient with a Caspr2 autoantibodies-associated syndrome had an unusual clinical triad and an excellent response to B-cell-anergizing therapy using the humanized monoclonal antibody tocilizumab directed against the interleukin 6 (IL-6) receptor., Observations: A 55-year-old man had an atypical clinical triad of epilepsy, dysarthria, and paroxysmal kinesigenic dystonia, and a high titer of Caspr2 antibodies was detected in his serum and cerebrospinal fluid. Screening for underlying neoplasias was negative. With initial methylprednisolone sodium succinate and alternate treatment using plasma exchange and immunoabsorption as well as subsequent IL-6 receptor blockade through tocilizumab, a complete and stable remission of symptoms has been achieved throughout the follow-up period of 7 months., Conclusions and Relevance: In our patient, the implementation of a B-cell-anergizing therapy using tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, has shown an excellent response. Larger case series or even controlled studies are needed to confirm the efficacy of tocilizumab in autoimmune synaptic or presynaptic diseases.

Autoscopic phenomena in general may-among other conditions-occur during epileptic seizures and near death experiences. We set the hypothesis that ictal autoscopic phenomena and near death experiences have a similar semiology as measured by the Near Death Experience Questionnaire. We also investigated whether patients with aura before temporal lobe seizures with or without autoscopic phenomena could be distinguished by this questionnaire. For these purposes, we examined five patients with ictal autoscopy and 12 patients with aura before temporal lobe seizures without ictal autoscopy as controls. We used a cut-off of 7 points or higher on the Near Death Experience Questionnaire for indicating the semiology of a near death experience and for distinguishing patients with ictal autoscopy from controls. This cut-off separated patients with ictal autoscopic phenomena from aura before temporal lobe seizures without autoscopy (p = 0.0002, two-sided, exact Fisher's Test; specificity: 100 % [CI95 % 77.9 and 100 %], sensitivity: 100 % [CI95 % 54.9 and 100 %]). Furthermore, all autoscopic patients (range 7-10) and none of the controls (range 0-5) had scores of 7 points or higher. Thus, the individual experiences during simple partial autoscopic seizures and near death experiences are similar, at least in some prominent aspects. These findings might be of particular interest for the pathophysiology of near death experiences, as all patients with ictal autoscopic phenomena had an epileptic dysfunction at the temporo-parietal junction or its neighboring regions. Therefore, a malfunction of this brain region might also be involved in near death experiences of other origins especially during states which could cause a near death experience and a cerebral excitability.

We report on a 31-year-old, female patient who presented with somnolence due to an intoxication by the antiepileptic drug, mesuximide (MSM). The serum concentration of its metabolite n-desmethyl-mesuximide (85.7 mg/L) was above the so-called therapeutic range (10-40 mg/L) but below the concentration range that led to an impairment of consciousness in previous cases according to the German SPC (>150 mg/L). The symptoms remitted quickly under hemodialysis. In somnolent patients treated with MSM, the treating physicians should be aware of drug intoxication as a possible etiology. Therefore, the serum concentration should be measured early. Due to the, often, long latency until the results are available, treatment initiation may be necessary based on suspicion., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Positive autoscopic phenomena - autoscopy, heautoscopy and out-of-body experience - may occur in a variety of diseases and also in physiological conditions. They are a rare but probably underreported phenomenon in focal epilepsies. Here, we investigate whether ictal lateralized autoscopic phenomena give lateralizing information about the underlying epileptic focus. We present the cases of seven patients from our center who experienced ictal lateralized autoscopic phenomena and analyzed their focus lateralization and localization of the underlying brain lesion. In addition, we reviewed seven cases published in German and English language literature. In the total group of 14 patients with ictal lateralized autoscopic phenomena, 12 (85.7%) of them had a well-defined epileptic focus contralateral to the side of the autoscopic appearance. Therefore, the data point to an association between ictal lateralized autoscopy and contralateral epileptic focus., (Copyright © 2012 Elsevier Inc. All rights reserved.)