First case of adult onset neuronal intranuclear inclusion disease with both typical radiological signs and NOTCH2NLC repeat expansions in a Caucasian individual.

BACKGROUND AND PURPOSE: Adult onset neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder with a heterogeneous clinical presentation that can mimic stroke and various forms of dementia. To date, it has been described almost exclusively in Asian individuals. METHODS: This case presentation includes magnetic resonance imaging (MRI) of the neurocranium, histology by skin biopsy, and long-read genome sequencing. RESULTS: A 75-year-old Caucasian female presented with paroxysmal encephalopathy twice within a 14-month period. Brain MRI revealed high-intensity signals at the cerebral corticomedullary junction (diffusion-weighted imaging) and the paravermal area (fluid-attenuated inversion recovery), a typical distribution observed in adult onset NIID. The diagnosis was corroborated by skin biopsy, which demonstrated eosinophilic intranuclear inclusion bodies, and confirmed by long-read genome sequencing, showing an expansion of the GGC repeat in exon 1 of NOTCH2NLC. CONCLUSIONS: Our case proves adult onset NOTCH2NLC-GGC-positive NIID with typical findings on MRI and histology in a Caucasian patient and underscores the need to consider this diagnosis in non-Asian individuals.

Glatiramer Acetate Treatment in Multiple Sclerosis-Associated Fatigue-Beneficial Effects on Self-Assessment Scales But Not on Molecular Markers.

Although fatigue is a common symptom in multiple sclerosis (MS), its pathomechanisms are incompletely understood. Glatiramer acetate (GA), an immunomodulatory agent approved for treatment of relapsing-remitting MS (RRMS), possesses unique mechanisms of action and has been shown to exhibit beneficial effects on MS fatigue. The objective of this study was to correlate clinical, neuropsychological, and immunological parameters in RRMS patients with fatigue before and during treatment with GA. In a prospective, open-label, multicenter trial, 30 patients with RRMS and fatigue were treated with GA for 12 months. Inclusion criterion was the presence of fatigue as one of the most frequent and disabling symptoms. Before and during treatment, fatigue was assessed using the Fatigue Severity Scale (FSS), the MS-FSS, and the Modified Fatigue Impact Scale (MFIS). In addition, fatigue and quality of life were assessed using the Visual Analog Scales (VAS). Laboratory assessments included screening of 188 parameters using real-time PCR microarrays followed by further analysis of several cytokines, chemokines, and neurotrophic factors. Fatigue self-assessments were completed in 25 patients. After 12 months of treatment with GA, 13 of these patients improved in all three scales (with the most prominent effects on the MFIS), whereas 5 patients had deteriorated. The remaining 7 patients exhibited inconsistent effects within the three scales. Fatigue and overall quality of life had improved, as assessed via VAS. Laboratory assessments revealed heterogeneous mRNA levels of cytokines, chemokines, and neurotrophic factors. In conclusion, we were not able to correlate clinical and molecular effects of GA in patients with RRMS and fatigue.

Prominent T-Cell Responses against the Acetylcholine Receptor ε Subunit in Myasthenia Gravis.

The human acetylcholine receptor (AChR) is well characterized as the target antigen in myasthenia gravis (MG). Pathogenic antibody responses against the AChR alpha-chain have been investigated extensively and are of diagnostic and prognostic value. However, less is known on the pathogenetic relevance of T-cell responses against epitopes of the different AChR chains (alpha, epsilon, gamma). Using an enzyme-linked immunospot (ELISPOT) assay we measured T-cell responses against recombinant fragments and synthetic peptides of the α and the ε subunits of the human AChR in MG patients (n=15) and in healthy donors (HD; n=9). In MG, highest T-cell responses were noted against recombinantly expressed Epsilon 1-221. Among the synthetic peptides Epsilon 201-215 showed the most prominent T-cell response and represented the peptide with the most remarkable difference between MG and HD. Taken together, prominent T-cell responses against the ε subunit of the human AChR indicate an important role in the pathogenesis of MG.

[It is more than transportation time only: "Drip and ship" delays endovascular thrombectomy in stroke]. / Es ist nicht nur die Transportzeit ­ Das "Drip and ship"-Verfahren kostet Zeit.

BACKGROUND: Intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) are acute therapies approved for ischemic stroke. In Germany there are approximately 110 supra-regional stroke units with and approximately 200 regional stroke units without 24 / 7 EVT. Regional stroke units must cooperate with supra-regional stroke units in order to offer EVT if indicated. In the current paper, we discuss the time delay due to secondary transportation from regional to supra-regional stroke units. METHODS: Acute stroke therapy of all patients treated at the regional stroke unit of the SRH Clinics in Sigmaringen in 2016 was analysed retrospectively. Sigmaringen cooperates with the supra-regional stroke units of the Oberschwabenklinik Ravensburg and the University Hospital Tübingen. RESULTS: A total of 299 patients with ischemic stroke and 168 patients with transient ischemic attack (TIA) were treated at the Sigmaringen stroke unit. Of these, 52 patients received IVT and 21 patients were transferred for EVT; of these, 15 patients actually underwent EVT after their cases were reviewed. The CT-to-Groin-times were more than double as long as compared to those in patients directly admitted to the supra-regional stroke units (median 180 minutes vs. 88 minutes). DISCUSSION: Primary admission of patients with acute stroke to regional stroke units without EVT prolongs the CT-to-Groin time. Implications of this knowledge on current and future patient care structures are discussed.

Apheresis therapies for NMOSD attacks: A retrospective study of 207 therapeutic interventions.

OBJECTIVE: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR). METHODS: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody-seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome. RESULTS: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04-144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89-0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76-631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03-21.62, p = 0.046). CONCLUSIONS: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.

Downregulation of monocytic differentiation via modulation of CD147 by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

CD147 is an activation induced glycoprotein that promotes the secretion and activation of matrix metalloproteinases (MMPs) and is upregulated during the differentiation of macrophages. Interestingly, some of the molecular functions of CD147 rely on its glycosylation status: the highly glycosylated forms of CD147 induce MMPs whereas the lowly glycosylated forms inhibit MMP activation. Statins are hydroxy-methylglutaryl coenzyme A reductase inhibitors that block the synthesis of mevalonate, thereby inhibiting all mevalonate-dependent pathways, including isoprenylation, N-glycosylation and cholesterol synthesis. In this study, we investigated the role of statins in the inhibition of macrophage differentiation and the associated process of MMP secretion through modulation of CD147. We observed that differentiation of the human monocytic cell line THP-1 to a macrophage phenotype led to upregulation of CD147 and CD14 and that this effect was inhibited by statins. At the molecular level, statins altered CD147 expression, structure and function by inhibiting isoprenylation and N-glycosylation. In addition, statins induced a shift of CD147 from its highly glycosylated form to its lowly glycosylated form. This shift in N-glycosylation status was accompanied by a decrease in the production and functional activity of MMP-2 and MMP-9. In conclusion, these findings describe a novel molecular mechanism of immune regulation by statins, making them interesting candidates for autoimmune disease therapy.

Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response.

OBJECTIVE: To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD). DESIGN: This is a retrospective cohort study conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes. RESULTS: 265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-ß (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-ß, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065). CONCLUSIONS: Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-ß.

Influence of female sex and fertile age on neuromyelitis optica spectrum disorders.

BACKGROUND: Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases. OBJECTIVE: To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)). METHODS: Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset. RESULTS: A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p < 0.001). Interval between onset and diagnosis of NMO/SD was longer in women than in men (mean 54 vs 27 months; p = 0.023). In women, attacks occurring ⩽40 years of age were more likely to show complete remission ( p = 0.003) and better response to high-dose intravenous steroids ( p = 0.005) compared to woman at >40 years. CONCLUSION: Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD.

Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses.

OBJECTIVE: Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks. METHODS: A retrospective review was made of patient records to assess demographic/diagnostic data, attack characteristics, therapies, and the short-term remission status (complete remission [CR], partial remission [PR], no remission [NR]). Inclusion criteria were NMO according to Wingerchuk's 2006 criteria or aquaporin-4 antibody-positive NMO spectrum disorder (NMOSD). Remission status was analyzed with generalized estimating equations (GEEs), a patient-based statistical approach. RESULTS: A total of 871 attacks in 185 patients (142 NMO/43 NMOSD, 82% female) were analyzed. The 1,153 treatment courses comprised high-dose intravenous steroids (HD-S; n = 810), plasma exchange (PE; n = 192), immunoadsorption (IA; n = 38), other (n = 80), and unknown (n = 33) therapies. The first treatment course led to CR in 19.1%, PR in 64.5%, and NR in 16.4% of attacks. Second, third, fourth, and fifth treatment courses were given in 28.2%, 7.1%, 1.4%, and 0.5% of attacks, respectively. This escalation of attack therapy significantly improved outcome (p < 0.001, Bowker test). Remission rates were higher for isolated optic neuritis versus isolated myelitis (p < 0.001), and for unilateral versus bilateral optic neuritis (p = 0.020). Isolated myelitis responded better to PE/IA than to HD-S as first treatment course (p = 0.037). Predictors of CR in multivariate GEE analysis were age (odds ratio [OR] = 0.97, p = 0.011), presence of myelitis (OR = 0.38, p = 0.002), CR from previous attack (OR = 6.85, p < 0.001), and first-line PE/IA versus HD-S (OR = 4.38, p = 0.006). INTERPRETATION: Particularly myelitis and bilateral optic neuritis have poor remission rates. Escalation of attack therapy improves outcome. PE/IA may increase recovery in isolated myelitis.

Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients.

BACKGROUND: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. OBJECTIVE: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. METHODS: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). RESULTS: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. CONCLUSION: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.

Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action.

Glatiramer acetate is a synthetic, random copolymer widely used as a first-line agent for the treatment of relapsing-remitting multiple sclerosis (MS). While earlier studies primarily attributed its clinical effect to a shift in the cytokine secretion of CD4+ T helper (T(h)) cells, growing evidence in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), suggests that glatiramer acetate treatment is associated with a broader immunomodulatory effect on cells of both the innate and adaptive immune system. To date, glatiramer acetate-mediated modulation of antigen-presenting cells (APC) such as monocytes and dendritic cells, CD4+ T(h) cells, CD8+ T cells, Foxp3+ regulatory T cells and antibody production by plasma cells have been reported; in addition, most recent investigations indicate that glatiramer acetate treatment may also promote regulatory B-cell properties. Experimental evidence suggests that, among these diverse effects, a fostering interplay between anti-inflammatory T-cell populations and regulatory type II APC may be the central axis in glatiramer acetate-mediated immune modulation of CNS autoimmune disease. Besides altering inflammatory processes, glatiramer acetate could exert direct neuroprotective and/or neuroregenerative properties, which could be of relevance for the treatment of MS, but even more so for primarily neurodegenerative disorders, such as Alzheimer's or Parkinson's disease. In this review, we provide a comprehensive and critical overview of established and recent findings aiming to elucidate the complex mechanism of action of glatiramer acetate.

Enhancement of chemokine expression by interferon beta therapy in patients with multiple sclerosis.

BACKGROUND: Interferon beta has been approved for the treatment of multiple sclerosis (MS). It is believed that immunomodulatory rather than antiviral activity of interferon beta is responsible for disease amelioration. The impact of interferon beta on the chemoattraction of immune cells has not been fully addressed. OBJECTIVE: To address the influence of interferon beta on the expression of chemokines and their receptors in a standardized setting. DESIGN: The expression of 14 chemokines and 14 chemokine receptor genes was determined by quantitative real-time polymerase chain reaction from fresh blood samples. SETTING: Outpatient units in Germany. Patients Untreated and interferon beta-treated patients with MS who tested positive and negative for neutralizing antibodies (NABs) were recruited from August 24, 2006, through December 15, 2006, for the initial study and from March 12, 2007, through April 2, 2007, for the validation study. MAIN OUTCOME MEASURES: Gene expression and serum chemokine protein levels. RESULTS: CCL1, CCL2, CCL7, CXCL10, CXCL11, and CCR1 gene expression was strongly upregulated in interferon beta-treated, NAB-negative MS patients. In contrast, gene expression in interferon beta-treated, NAB-positive MS patients did not differ from untreated control donor individuals. Antibody titers inversely correlated with chemokine and chemokine receptor gene expression. Accordingly, serum chemokine protein levels of interferon beta-treated, NAB-negative MS patients were significantly higher than in untreated or interferon beta-treated, NAB-positive MS patients. CONCLUSIONS: We demonstrate that interferon beta strongly upregulates a set of chemokines and CCR1 in peripheral immune cells. The peripheral upregulation of these chemokines may reduce the chemoattraction of immune cells to the central nervous system and thus add to the therapeutic effects of interferon beta.

Glatiramer acetate: evidence for a dual mechanism of action.

Glatiramer acetate is a disease-modifying drug approved for the treatment of relapsing-remitting multiple sclerosis. Since its discovery almost four decades ago, and in particular since the observation of its beneficial clinical effects in the late 1980s and early 1990s, numerous data have been generated and contribute pieces of a puzzle to help explain the mechanism of action of glatiramer acetate. Two major themes have emerged, namely (i) the induction of glatiramer acetate-reactive TH2 immunoregulatory cells, and (ii) the stimulation of neurotrophin secretion in the central nervous system that may promote neuronal repair.

Immunosuppressive agents in multiple sclerosis.

Immunosuppressive agents have been used in multiple sclerosis (MS) for decades. The approval of several immunomodulatory agents against MS beginning in the 1990s, whose putative mechanisms of action appeared "more MS-specific," curtailed the importance of immunosuppressants, which made them treatment options of second choice. However, with the recent approval of mitoxantrone for treatment of patients with active forms of relapsing-remitting or secondary progressive MS and with a number of oral immunosuppressive agents being assessed in phase II and III clinical trials, a "renaissance" of this type of agents is currently occurring. This review provides an outline of the most important clinical studies and discusses relevant side effects of the major immunosuppressants (i.e., mitoxantrone, azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil, cladribine, and sirolimus/temsirolimus). The current knowledge of the putative mechanisms of action of these compounds is discussed.

Impact of HMG-CoA reductase inhibition on brain pathology.

Over the past two decades, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (HMGCRIs), originally designed to lower cholesterol blood levels, have been found to affect GTPase signaling during normal intracellular tasks. This finding has prompted use of these drugs in pathological situations, where such signaling processes need to be manipulated. Here, we review recent progress on the outcome of modulating GTPase signaling after inhibition of protein prenylation by HMGCRIs. We also discuss current controversies over the direct implications of these cholesterol-lowering agents on cholesterol-rich membrane lipid rafts and associated signaling. By reviewing these two different cellular events and the evidence from clinical studies, an overall assessment can be made of the concept of interfering with the HMG-CoA reductase pathway in different brain pathologies. We thereby provide a rational link between the benefit of applying HMGCRIs in brain pathologies, such as multiple sclerosis, Alzheimer's disease and stroke, and the impact on signaling in specific cell types crucial to disease pathogenesis.

Limited effects of glatiramer acetate in the high-copy number hSOD1-G93A mouse model of ALS.

In amyotrophic lateral sclerosis (ALS), an involvement of the immune system in the degenerative processes has been shown in both humans and the transgenic SOD1-G93A mice. We previously showed that Glatiramer acetate (also known as copolymer-1; COP-1; Copaxone) improves motor function and extends survival times in an inbred strain of ALS mice probably by interacting with pro-inflammatory T(H) lymphocytes. In the course of this study we tested whether these beneficial effects could be reproduced by repeated vaccination of animals with COP-1 without co-administration of complete Freund's adjuvant. In an outbred strain we could not demonstrate a positive effect of COP-1 on survival times, but found a significant improvement of motor performance during the late stage of disease and a moderate decrease of the production of the inflammatory cytokines interferon-gamma and IL-4 by T lymphocytes isolated from the mice's spleen. In conclusion, the effects of COP-1 in the applied hybrid strain displaying a faster disease progression were less pronounced than in the earlier tested inbred strain of ALS mice.