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-abantibodies (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). Conclusion: s 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

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%;p40years. 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

The astrocytic response towards invasive meningiomas

In der vorliegenden Studie untersuchten wir 35 hirninvasive Meningeome (14 WHO-Grad II, otherwise benign, 11 WHO-Grad II, otherwise atypical, 10 WHO-Grad III) und das angrenzende ZNS-Gewebe mittels immunhistochemischer Färbemethoden. Wir verwendeten Antikörper gegen GFAP, Osteonektin und CD44 zur Darstellung der Astrozyten, sowie Antikörper gegen Kollagen IV zur Darstellung der pial-glialen Basalmembran. Die verschiedenen Antikörper zur Darstellung der Astrozyten färben unterschiedliche Anteile des Astrozyten: GFAP und Osteonektin färben vor allem die Astrozytenkörper, während CD44 lediglich die Astrozytenfortsätze färbt. In unseren Färbungen konnten wir festellen, dass invasive Meningeome die durch Anti-Kollagen IV-Antikörper dargestellte pial-gliale Basalmembran durchbrechen. Die pial-gliale Basalmembran steht in engem Zusammenhang zu den subpialen Astrozytenfortsätzen, welche die der Basalmembran direkt anliegende Membrana glia limitans bilden. Bisher war nicht bekannt, wie diese angrenzenden Astrozyten auf die Invasion der Meningeome reagieren. In 100% (35/35) der von uns untersuchten Meningeome konnten wir eine vermehrte Expression von GFAP, Ostenektin und CD44 mit Bildung eines reaktiven Astrozytensaumes beobachten. Der Saum von reaktiven Astrozyten war jedoch nicht durchgehend, sondern durch eindringende Tumorzapfen und –inseln unterbrochen. Bei der Untersuchung der pial-glialen Basalmembran konnten wir feststellen, dass die Astrozytenreaktion mit der Intaktheit der pial-glialen Basalmembran vergesellschaftet war. Eine pial-gliale Grenzmembran konnten wir in 79% (11/14) der Fälle bei WHO-Grad II, otherwise benign, in 64% (7/11) der Fälle bei WHO-Grad II, otherwise atypical und in 70% (7/10) der Fälle bei WHO-Grad III feststellen. Diese pial-gliale Grenzmembran war zum Teil diskontinuierlich oder ausgedünnt und wurde genau wie der Astrozytensaum durch Tumorzapfen und –inseln unterbrochen. Wir konnten feststellen, dass die Basalmembran an denselben Stellen im Tumor anwesend (bzw. abwesend) war, wie der reaktive Astrozytensaum. Vor allem tiefer in das angrenzende Hirngewebe eindringende Tumoranteile zeigten weder eine angrenzende Basalmembran, noch einen reaktiven Astrozytensaum. Diese Beobachtung legt die Schlussfolgerung nahe, dass die Astrozyten der Hirn-Tumor-Grenze durch die Invasion des Meningeoms zugrunde gehen. Der gleichzeitig beobachtete Verlust der pial-glialen Basalmembran legt nahe, dass das Überleben der subpialen Astrozyten mit der Intaktheit der Basalmembran zusammenhängt.Invasive meningiomas disrupt the pial–glial basement membrane. This membrane is closely attached to the subpial glial endfeet forming the glia limitans. The fate of subpial astrocytes during the course of brain invasion by meningiomas is not known. In the present study we immunolabelled sections of 35 brain-invasive meningiomas (14 meningothelial meningiomas WHO grade I, 11 atypical WHO grade II and 10 anaplastic WHO grade III) using anti-collagen IV to label basement membrane material, and antibodies against astrocytic markers CD44, SPARC (secreted protein, acidic and rich in cysteine) and glial fibrillary acidic protein (GFAP). Astrocytes were present at the tumour–brain interface of 14/14 WHO grade I meningiomas, 9/11 WHO grade II tumours and 9/10 WHO grade III tumours. The presence of astrocyteswas associated with an intact basement membrane in 11/14 WHO grade I meningiomas (P<0.01), 6/9 WHO grade II tumours, and 6/9 WHO grade III tumours. However, tumour embedded in deep brain parenchyma lacked both an astrocytic reaction and basement membrane material. In conclusion, astrocytes eventually disappear from the tumour–brain interface during the course of meningioma infiltration. This observation might indicate that the survival of subpial astrocytes is dependent on an intact pial–glial basement membrane

A Novel, Apparently Silent Variant in MFSD8 Causes Neuronal Ceroid Lipofuscinosis with Marked Intrafamilial Variability

Variants in MFSD8 can cause neuronal ceroid lipofuscinoses (NCLs) as well as nonsyndromic retinopathy. The mutation spectrum includes mainly missense and stop variants, but splice sites and frameshift variants have also been reported. To date, apparently synonymous substitutions have not been shown to cause MFSD8-associated diseases. We report two closely related subjects from a consanguineous Turkish family who presented classical features of NCLs but demonstrated marked intrafamilial variability in age at the onset and severity of symptoms. In fact, the difference in the onset of first neurologic symptoms was 15 years and that of ophthalmologic symptoms was 12 years. One subject presented an intellectual disability and a considerable cerebellar ataxia syndrome, while the other subject showed no intellectual disability and only a mild atactic syndrome. The diagnostic genetic testing of both subjects based on genome sequencing prioritized a novel, apparently synonymous variant in MFSD8, which was found in homozygosity in both subjects. The variant was not located within an integral part of the splice site consensus sequences. However, the bioinformatic analyses suggested that the mutant allele is more likely to cause exon skipping due to an altered ratio of exonic splice enhancer and silencer motifs. Exon skipping was confirmed in vitro by minigene assays and in vivo by RNA analysis from patient lymphocytes. The mutant transcript is predicted to result in a frameshift and, if translated, in a truncated protein. Synonymous variants are often given a low priority in genetic diagnostics because of their expected lack of functional impact. This study highlights the importance of investigating the impact of synonymous variants on splicing

Efficacy of glatiramer acetate in neuromyelitis optica spectrum disorder: a multicenter retrospective study

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 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

Confirmation of TACO1 as a Leigh Syndrome Disease Gene in Two Additional Families.

BACKGROUND: In 2009, we identified TACO1 as a novel mitochondrial disease gene in a single family, however no second family has been described to confirm the role of TACO1 in mitochondrial disease. OBJECTIVE: In this report, we describe two independent consanguineous families carrying pathogenic variants in TACO1, confirming the phenotype. METHODS: Detailed clinical investigations and whole exome sequencing with haplotype analysis have been performed in several members of the two reported families. RESULTS: Clinical phenotype of the patients confirms the originally reported phenotype of a childhood-onset progressive cerebellar and pyramidal syndrome with optic atrophy and learning difficulties. Brain MRI showed periventricular white matter lesions with multiple cystic defects, suggesting leukoencephalopathy in both patients. One patient carried the previously described homozygous TACO1 variant (p.His158ProfsTer8) and haplotype analysis suggested that this variant is a rare founder mutation. The second patient from another family carried a homozygous novel frame shift variant (p.Cys85PhefsTer15). CONCLUSIONS: The identification of two Turkish families with similar characteristic clinical presentation and an additional homozygous nonsense mutation confirms that TACO1 is a human mitochondrial disease gene. Although most patients with this clinical presentation undergo next generation sequencing analysis, screening for selected founder mutations in the Turkish population based on the precise clinical presentation may reduce time and cost of finding the genetic diagnosis even in the era of massively parallel sequencing.Wellcome Trust, MR