Iron Rims in Patients With Multiple Sclerosis as Neurodegenerative Marker? A 7-Tesla Magnetic Resonance Study.

Introduction: Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system, characterized by inflammatory-driven demyelination. Symptoms in MS manifest as both physical and neuropsychological deficits. With time, inflammation is accompanied by neurodegeneration, indicated by brain volume loss on an MRI. Here, we combined clinical, imaging, and serum biomarkers in patients with iron rim lesions (IRLs), which lead to severe tissue destruction and thus contribute to the accumulation of clinical disability. Objectives: Subcortical atrophy and ventricular enlargement using an automatic segmentation pipeline for 7 Tesla (T) MRI, serum neurofilament light chain (sNfL) levels, and neuropsychological performance in patients with MS with IRLs and non-IRLs were assessed. Methods: In total 29 patients with MS [15 women, 24 relapsing-remitting multiple sclerosis (RRMS), and five secondary-progressive multiple sclerosis (SPMS)] aged 38 (22-69) years with an Expanded Disability Status Score of 2 (0-8) and a disease duration of 11 (5-40) years underwent neurological and neuropsychological examinations. Volumes of lesions, subcortical structures, and lateral ventricles on 7-T MRI (SWI, FLAIR, and MP2RAGE, 3D Segmentation Software) and sNfL concentrations using the Simoa SR-X Analyzer in IRL and non-IRL patients were assessed. Results: (1) Iron rim lesions patients had a higher FLAIR lesion count (p = 0.047). Patients with higher MP2Rage lesion volume exhibited more IRLs (p <0.014) and showed poorer performance in the information processing speed tested within 1 year using the Symbol Digit Modalities Test (SDMT) (p <0.047). (2) Within 3 years, patients showed atrophy of the thalamus (p = 0.021) and putamen (p = 0.043) and enlargement of the lateral ventricles (p = 0.012). At baseline and after 3 years, thalamic volumes were lower in IRLs than in non-IRL patients (p = 0.045). (3) At baseline, IRL patients had higher sNfL concentrations (p = 0.028). Higher sNfL concentrations were associated with poorer SDMT (p = 0.004), regardless of IRL presence. (4) IRL and non-IRL patients showed no significant difference in the neuropsychological performance within 1 year. Conclusions: Compared with non-IRL patients, IRL patients had higher FLAIR lesion counts, smaller thalamic volumes, and higher sNfL concentrations. Our pilot study combines IRL and sNfL, two biomarkers considered indicative for neurodegenerative processes. Our preliminary data underscore the reported destructive nature of IRLs.

Health-related quality of life in multiple sclerosis: temperament outweighs EDSS.

BACKGROUND: The influence of personality on health-related quality of life in patients with multiple sclerosis has been the focus of previous studies showing that introversion and neuroticism were related with reduced health related quality of life. However, no data exist on the impact of temperament on quality of life in this patient group. METHODS: Between April 2014 and March 2016 139 multiple sclerosis patients were recruited from a specialized outpatient clinic of the general hospital of Vienna. Health-related quality of life was measured by "The Multiple Sclerosis International Quality of Life Questionnaire (MusiQol)", temperament by "Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Questionnaire - Münster version" (briefTEMPS-M), and disability by the "Expanded disability status scale". All patients underwent a diagnostic psychiatric semi-structured interview (MINI). RESULTS: Known predictors (like disease duration, EDSS, psychiatric co-morbidities, immunomodulatory treatments) explain the proportion of variation in the outcome of MusiQol global index score in 30.9% in multi-variable linear regression analysis. It increased respectively to 40.3, 42.5, and 45.8% if adding the depressive, cyclothymic, or hyperthymic temperament to the list of variables. An increase of depressive and cyclothymic temperament scores significantly reduced global index score of MusiQol (p = 0.005, p = 0.002, respectively), while the hyperthymic temperament significantly raised it (p < 0.001). CONCLUSION: In MS patients, the depressive and cyclothymic temperament predict a lower and hyperthymic temperament an increased health-related quality of life, independent of current disability status, immunomodulatory treatments, and affective co-morbidities.

Real-life clinical use of natalizumab and fingolimod in Austria.

OBJECTIVES: To compare the efficacy of natalizumab or fingolimod in a nationwide observational cohort using prospectively collected data. MATERIALS AND METHODS: We included all patients starting treatment with natalizumab or fingolimod documented in the Austrian MS Treatment Registry (AMSTR) from 2011 and staying on therapy for at least 24 months. We used propensity scores for several matching methods and as a covariate in multivariate models to correct for the bias of this non-randomized registry study. RESULTS: The study cohort includes 588 patients with RRMS. Ten patients did not produce a propensity score in the common support region, thus leaving 578 cases for final analyses, 332 in the fingolimod and 246 in the natalizumab group. Mean annualized relapse rates (ARR) during the 24 months observation period were 0.19 under fingolimod and 0.12 under natalizumab treatment (P = .005). No statistical significant differences were found analysing the log-transformed ARR, probability for experiencing a relapse, EDSS progression and EDSS regression. The hazard ratio for switching treatment from fingolimod comparing with natalizumab was 0.36 (95% CI: 0.247-0.523), P < .001. CONCLUSIONS: The generalized linear model (GLM) for relapse count as Poisson distributed dependent variable and propensity score as covariate showed a statistically significant reduction for the mean relapse count in the natalizumab group compared with fingolimod. This effect was smaller in the analyses of log-transformed ARR with propensity score matching, loosing statistical significance although showing the same direction for the effect. We assume that the GLM was the more sensitive model analysing this question.

Celiac disease with cerebral and peripheral nerve involvement mimicking multiple sclerosis.

OBJECTIVES: Due to the similarity in the clinical presentation, morphology, and course, celiac disease (CD) may be mixed up with other immunological disorders, such as multiple sclerosis (MS). CASE REPORT: In a 43-year-old Caucasian male with a history of diarrhea and colics since young age, progressive sensory disturbances developed since age 18 years. At age 34, he was diagnosed as relapsing-remitting MS upon an inflammatory CSF-syndrome and non-specific white matter lesions and treated with interferon beta-1b during the next 8 years without effect. At age 35, axonal polyneuropathy and ataxia were diagnosed. Despite normal anti-gliadin, endomysial, and transglutaminase antibodies, CD was diagnosed at age 41, based upon the history, polyneuropathy, positivity for HLA-DQ2 and HLA-DQ8, the white matter lesions, and a beneficial response of the gastrointestinal problems and polyneuropathy to gluten-free diet. CONCLUSIONS: CD may mimic MS and may be present despite the absence of anti-gliadin, endomysial or transglutaminase antibodies. CD should be considered if there is a gastrointestinal problem, polyneuropathy, and ataxia, even if CSF and MRI findings are suggestive of MS.

[Contribution of spinal cord biopsy to the differential diagnosis of longitudinal extensive transverse myelitis]. / Biopsie bei tumorverdächtiger spinaler Raumforderung: Fallstrick Neuromyelitis optica.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are characterized by recurrent optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM) as well as the serological detection of antibodies to aquaporin-4 (AQP4-ab). However, longitudinal extensive spinal cord lesions are not pathognomonic for NMOSD as they can also occur in systemic autoimmune diseases or mimic spinal cord tumors. OBJECTIVES/METHODS: We report a female patient who initially presented with a subacute spinal syndrome and a longitudinal spinal cord lesion on magnetic resonance imaging (MRI). As the brain MRI showed only unspecific white matter lesions and the cerebrospinal fluid was normal, a spinal cord biopsy was performed to exclude malignancies and revealed inflammatory demyelinating changes. In addition, after several deep vein thromboses and the detection of antiphospholipid antibodies, an antiphospholipid syndrome (APS) was diagnosed. Many years after the spinal cord biopsy, AQP4-ab were tested and found to be positive. We discuss the important differential diagnoses of LETM, give an overview of previously reported NMOSD cases in which a spinal cord biopsy was performed and highlight the crucial role of AQP4-ab testing for the differential diagnosis of longitudinal spinal cord lesions. RESULTS/CONCLUSIONS: Considering possible serious sequelae of spinal biopsy procedures, testing for AQP4-ab is mandatory in patients with unclear longitudinally extensive spinal cord lesions and should be performed preoperatively in all cases. In light of the heterogeneity of available assays, different detection methods should be used in doubtful cases. The relationship between NMO and APS needs further clarification; however, AQP4 IgG testing is recommended in patients presenting with APS and myelitis, optic neuritis or brainstem encephalitis.

Contemporary treatment options for relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, encompassing both neuroinflammatory as well as prominent neurodegenerative aspects. A significant proportion of MS patients will develop neurological disability over time and up until recently licensed drugs could not satisfactorily halt this process. However, in the last years MS treatment has raised a stage of rapid progress. Several new drugs with significantly improved efficacy have entered the therapeutic field and several others are currently undergoing phase III clinical trials. In this review, we will summarize efficacy data as well as safety and tolerability issues of currently licensed drugs for relapsing-remitting MS and will give a short update on new drugs currently undergoing late-stage clinical trials.

What to expect after natalizumab cessation in a real-life setting.

BACKGROUND: To minimize the risk of progressive multifocal leucoencephalopathy (PML), treatment with natalizumab is often stopped after 2 years, but evidence upon rebound of disease activity is limited and controversial. OBJECTIVE: To evaluate effects of natalizumab discontinuation on clinical disease activity within twelve months after cessation. METHODS: We retrospectively analyzed data of 201 patients with MS who discontinued natalizumab between 2007 and 2012. Mean change scores of annualized relapse rate (ARR) and expanded disability status scale (EDSS) were calculated for detection of rebound disease activity after twelve months. RESULTS: Natalizumab exposure did not exceed 2 years in 50.2% of patients, and the most common reasons for discontinuation were a long treatment period and concern of PML (56%). A total of 11.9% experienced a rebound phenomenon within twelve months. Mean ARR prenatalizumab was lower (P = 0.001, 95% CI -1.0-0.000) and treatment response to natalizumab poorer (P < 0.001, 95% CI 0.4-1.3) in patients with rebound compared to those without, but rebound was not associated with brief exposure to natalizumab (P = 0.159, 95% CI -9.3-1.5). 86.1% of patients switched to another therapy. Patients without rebound were found more often in the group starting an alternative treatment early (P = 0.013). CONCLUSION: Our data suggest that rebound of MS disease activity affects a subgroup of patients (11.9%), especially those with low disease activity before natalizumab therapy and a longer treatment gap after its withdrawal.

A novel mutation in the MFSD8 gene in late infantile neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinoses (NCL) are lysosomal storage disorders and constitute the most common group of progressive neurodegenerative diseases in childhood. Most NCLs are inherited in a recessive manner and are clinically characterised by a variable age at onset, epileptic seizures, psychomotor decline, visual impairment and premature death. To date, eight causative genes have been identified to underlie various clinical forms of NCL. We performed a genome-wide linkage analysis followed by sequencing the recently described NCL gene MFSD8 in three affected and three unaffected members of a consanguineous Egyptian family with an autosomal recessively inherited progressive neurodegenerative disorder. The clinical picture of the patients was compatible with a late infantile NCL (LINCL); however, impairment of the visual system was not a cardinal symptom in the respective family. By linkage analysis, we identified two putative loci on chromosome 1p36.11-p35.1 and 4q28.1-q28.2. The latter locus (4q28.1-q28.2) contained the MFSD8 gene, comprising a novel homozygous missense mutation in exon 5 (c.362a>g /p.Tyr121Cys), which segregated with the disease in the three affected sibs. We describe a novel mutation in the previously identified MFSD8 gene in a family with a common phenotype of LINCL, but no clinical report of vision loss. Our results enlarge the mutational and perhaps the nosological spectrum of one of the recently identified subtypes of NCL, called CLN7.

Disruption of nigrostriatal and cerebellothalamic pathways in dopamine responsive Holmes' tremor.

Holmes' tremor is an unusual combination of rest, postural and kinetic tremor of the extremities. Medical treatment of this condition still remains unsatisfactory. The case of a 20-year-old female patient is reported who developed right-sided Holmes' tremor 9 months after a left-sided, cavernoma induced midbrain/pontine haemorrhage at the age of 16 years. Beta-CIT single photon emission computed tomography revealed abolished dopamine transporter activity in the left basal ganglia and striatum, in accordance with missing ipsilateral tegmento-frontal connectivity (medial forebrain bundle), demonstrated by diffusion tensor MRI. Tractography showed reduced fibre connectivity of the superior and middle cerebellar peduncles on the lesioned side. Administration of pramipexole and L-DOPA led to a clinically significant reduction in tremor severity. In conclusion, our results support the notion that Holmes' tremor was a result of diminished striatal dopaminergic input in our patient.

Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations.

We sequenced 61 patients with various idiopathic generalized epilepsy (IGE) syndromes for mutations in the EFHC1 gene. We detected three novel heterozygous missense mutations (I174V, C259Y, A394S) and one possibly pathogenic variant in the 3' UTR (2014t>c). The mutation I174V was also detected in 1 of 372 screened patients with temporal lobe epilepsy. We conclude that mutations in the EFHC1 gene may underlie different types of epilepsy syndromes.

Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes.

Mutations in the chloride channel gene CLCN2 have been reported in families with generalized and focal epilepsy syndromes. To evaluate the contribution of mutations in the CLCN2 gene to the etiology of epilepsies in our population, we screened 96 patients with different epilepsy syndromes and a putative genetic background. No definite mutations were found in our study population. We conclude that mutations in the CLCN2 gene are only a rare cause of idiopathic generalized epilepsy.

Postictal paresis in focal epilepsies--incidence, duration, and causes: a video-EEG monitoring study.

BACKGROUND: Although familiar to every neurologist, postictal paresis (PP) has only rarely been analyzed systematically. OBJECTIVE: To describe the frequency and duration of PP in patients undergoing video-EEG monitoring, the semiology characteristics of seizures preceding PP, and the pattern of associated symptoms and signs. METHODS: The records of 513 consecutive patients who underwent prolonged video-EEG monitoring during presurgical epilepsy evaluation were reviewed for postictal motor deficit. Three hundred twenty-eight patients fulfilled the inclusion criteria. The videotapes of patients with PP were subsequently analyzed with a careful analysis of ictal motor phenomena at the side of the PP. RESULTS: PP was found in 44 patients (13.4%). PP was always unilateral and always contralateral to the seizure focus and had a median duration of 173.5 seconds (range 11 seconds to 22 minutes). Of all seizures with PP, 77.8% were accompanied by evident and 9.7% by very slight ictal motor phenomena ipsilateral to the side of PP, whereas 9.7% of the seizures showed no motor signs (two seizures [2.8%] could not be evaluated for motor phenomena). The most common ictal lateralizing sign was unilateral clonic activity in 55.6% of all seizures. Concomitant dystonic posturing was found in 47.9% and ictal limb immobility in 24.6% of the seizures. PP was of longer duration if ictal clonic activity was present and after tonic-clonic seizures. CONCLUSIONS: PP is relatively frequent (13.4%), is easy to detect, and has a high lateralizing value. The high incidences of dystonic posturing and of ictal limb immobility in our patients with PP may indicate that an active inhibitory process is involved in its pathogenesis.

Asymmetric ending of secondarily generalized seizures: a lateralizing sign in TLE.

The authors investigated whether asymmetric ending of the clonic phase of secondarily generalized tonic clonic seizures (SGTCS) has lateralizing value concerning the hemisphere of seizure onset. They studied 70 patients with mesial temporal lobe epilepsy who underwent epilepsy surgery. Asymmetric ending of the clonic phase occurred in 43% of patients. The last clonic movement appeared on the upper extremity ipsilateral to the hemisphere of seizure onset in 83%.

Autonomic symptoms during epileptic seizures.

Autonomic symptoms frequently occur during epileptic seizures either as an accompaniment to other seizure symptoms or as the predominant seizure manifestation. They do not represent simple reactions to motor manifestations of seizures, but are mediated by an activation of the central autonomic network. Autonomic symptoms can be divided into cardiovascular changes, respiratory manifestations, gastrointestinal symptoms, cutaneous manifestations, pupillary symptoms, genital and sexual manifestations as well as urinary symptoms. Due to a hemispheric-specific representation of the central autonomic network, certain autonomic symptoms may provide lateralizing and sometimes localizing information on the seizure onset zone, although some of these signs may appear as a result of discharge spreading. Autonomic symptoms indicating a seizure onset in the non-dominant hemisphere include ictal vomiting and retching, spitting automatisms and ictal urinary urge. Autonomic symptoms range from subtle seizure manifestations which become apparent only during meticulous seizure analysis, to severe, sometimes life-threatening events. Cardiovascular and respiratory autonomic symptoms are discussed as the mechanisms underlying sudden unexplained death in epilepsy. When autonomic symptoms represent the sole seizure manifestation, they can pose problems for differential diagnosis of various non-epileptic conditions. Finally, autonomic seizure symptoms open a unique window on the functional organization of the central autonomic network and on brain function in general. (Published with videosequences.)

Ictal urinary urge indicates seizure onset in the nondominant temporal lobe.

The authors describe six patients with medically refractory temporal lobe epilepsy whose seizures were characterized by an aura of ictal urinary urge. All seizures originated in the nondominant temporal lobe as evidenced from interictal spikes, ictal EEG, and MRI. Ictal SPECT, which was obtained in two patients, showed a hyperperfusion of the insular cortex, indicating a critical role of the insula for the generation of this symptom. Ictal urinary urge represents a new lateralizing sign indicating a seizure onset in the nondominant temporal lobe.

Regional cerebral blood flow during temporal lobe seizures associated with ictal vomiting: an ictal SPECT study in two patients.

PURPOSE: Ictal vomiting represents a rare clinical manifestation during seizures originating from the temporal lobes of the nondominant hemisphere. The precise anatomic structures responsible for generation of ictal vomiting remain to be clarified. Ictal single photon emission computed tomography (SPECT), which allows one to visualize the three-dimensional dynamic changes of regional cerebral blood flow (rCBF) associated with the ongoing epileptic activity, should be useful to study the brain areas activated during ictal vomiting. METHODS: We performed ictal Tc-HMPAO SPECT scans in two patients with mesial temporal lobe epilepsy (MTLE) whose seizures were characterized by ictal retching and vomiting. MTLE was documented by typical clinical seizure semiology, interictal and ictal EEG findings, hippocampal atrophy on magnetic resonance imaging (MRI) scan, and a seizure-free outcome after selective amydalohippocampectomy. In both patients, seizures originated in the nondominant temporal lobe. We obtained accurate anatomic reference of rCBF changes visible on SPECT by a special coregistration technique of MRI and SPECT. We used ictal SPECT studies in 10 patients with MTLE who had seizures without ictal vomiting as controls. RESULTS: In the two patients with ictal vomiting, we found a significant hyperperfusion of the nondominant temporal lobe (inferior, medial, and lateral superior) and of the occipital region on ictal SPECT. In patients without ictal vomiting, on the contrary, these brain regions never were hyperperfused simultaneously. CONCLUSIONS: Ictal SPECT provides further evidence that activation of a complex cortical network, including the medial and lateral superior aspects of the temporal lobe, and maybe the occipital lobes, is responsible for the generation of ictal vomiting.

A case of startle epilepsy and SSMA seizures documented with subdural recordings.

PURPOSE: To study the mechanisms of startle-induced supplementary sensorimotor area (SSMA) seizures. METHODS: We present a patient investigated with indwelling subdural grid electrodes covering both the SSMA and the dorsolateral frontal lobe. RESULTS: We found a simultaneous seizure onset in the right dorsolateral premotor cortex and the right SSMA. High-resolution magnetic resonance imaging (MRI) showed a small subcortical lesion adjacent to the right SSMA. The patient became seizure free after resection of the lesion and the ictal-onset zone. CONCLUSIONS: We conclude that an extended region of abnormally excitable tissue within the frontal lobe could facilitate the generation of startle-induced seizures. We speculate that a widespread epileptogenic zone could help to explain why some patients with SSMA or dorsolateral frontal lobe seizures are more likely to have startle-induced seizures.

Clinical symptoms in psychogenic seizures.

PURPOSE: To develop a classification system of psychogenic seizures based on characteristic clinical symptom clusters and sequences in order to facilitate the correct differential diagnosis of epileptic seizures. METHODS: We analysed the symptoms: clonic movements, hypermotor movements, trembling and tonic posturing of the upper/lower extremities, pelvic thrusting, stiffening of the body, version, side-to-side-head movements, non-versive head-turning and falling to the floor. We did this in a series of 16 patients with psychogenic seizures documented with prolonged video EEG monitoring. Nine patients (7 with frontal lobe epilepsy and 2 with primary generalised epilepsy with tonic, clonic seizures) served as a control group. RESULTS: We classified psychogenic seizures into 3 groups, namely (1) atonic psychogenic seizures, (2) psychogenic motor seizures and (3) psychogenic hypermotor seizures characterised by (1) falling to the ground, (2) trembling in the upper/lower extremities and (3) pelvic thrusting in combination with beating and kicking. While version exclusively occurred in epileptic seizures (incidence = 20%) and side-to-side head movements were only observed during psychogenic seizures (incidence = 8%), all other analysed symptoms were observed in both psychogenic and epileptic seizures. CONCLUSION: Our classification scheme should be useful in terms of permitting a more comprehensive clinical assessment of psychogenic seizures and their underlying psychiatric disorders. Furthermore, the differential diagnosis of psychogenic seizures should be considerably improved.

Health-related quality of life (HRQOL), activity of daily living (ADL) and depressive mood disorder in temporal lobe epilepsy patients.

We determined the interrelations of chronological age, age at seizure onset, duration of seizure disorder, cognitive functioning (IQ), scales of activities of daily living, depressive mood disorder and measures of health-related quality of life (HRQOL). Furthermore, we investigated the association of the laterality of seizure onset zone and absence/presence of hippocampal atrophy and/or sclerosis (HA/HS) with measures of HRQOL, activities of daily living (ADL) and depressive mood disorder. In the setting of pre-surgical epilepsy evaluation, a sample of 56 patients with temporal lobe epilepsy (TLE) was studied using the Bonner Skalen für Epilepsie (BPSE) and the depression inventory D-S of von Zerssen. Patients reported high levels of dependency on others and poor coping capabilities. Our data also showed specific ADL-behaviour suggesting social withdrawal and isolation. Our results indicate emotional impairment as a major problem in TLE, because 45% of our patients scored in the depressive range of the D-S depression scale. Depression score was found to be a powerful predictor of self-reported quality of life after adjusting for seizure-related variables, demographic variables and cognitive functioning (IQ). The only scale showing a significant laterality effect was ADL-home. No relationship between the dependent measures of HRQOL, ADL-social, ADL-cultural, depressive mood disorder and laterality of the epileptogenic zone or absence/presence of HA/HS was found. HRQOL and depressive mood disorder are strongly interrelated indicating that patients with depressive symptoms report lower quality of life and specific patterns of ADL. HRQOL, ADL and depressive mood disorder are largely independent of biological markers such as laterality of seizure onset zone and absence/presence of HA/HS in TLE.

Genital automatisms in complex partial seizures.

OBJECTIVE: To determine which brain region is responsible for the generation of sexual automatisms. METHODS: Ninety consecutive patients with medically refractory focal epilepsy (74 with temporal lobe and 16 with frontal lobe epilepsy) referred to an epilepsy monitoring unit were studied. The occurrence of the following sexual automatisms was assessed during prolonged video-EEG monitoring: 1) repeatedly grabbing or fondling the genitals and 2) pelvic or truncal thrusting or similar movements. RESULTS: Five patients repeatedly fondled or grabbed their genitals during or immediately after some of their seizures. All five had temporal lobe epilepsy, as evidenced from prolonged video-EEG monitoring, high-resolution MRI, and good to excellent outcome after epilepsy surgery. Sexual automatisms did not occur with frontal lobe epilepsy. CONCLUSION: Sexual automatisms cannot be related exclusively to frontal lobe seizures. As previously proposed, apparently sexual hypermotoric pelvic or truncal movements are common in frontal lobe seizures, but this study suggests that discrete genital automatisms, like fondling and grabbing the genitals, are more common in seizures evolving from the temporal lobe.