Slow-stimulated Multifocal ERG in High- and Normal-tension Glaucoma

Purpose: To study the ability and sensitivity of the slow stimulation multifocal ERG (mfERG) to detect glaucomatous damage. Methods: Right eyes of 20 patients with normal-tension glaucoma (NTG), 15 patients with high-tension glaucoma (HTG) and 15 healthy volunteers underwent testing with the mfERG (VERIS 4.1TM). The central 50 degrees of the retina were stimulated by 103 hexagons (m-sequence: 213-1, Lmax: 100cd/m2, Lmin: 1cd/m2, background: 50cd/m2). Each m-sequence step was followed by 3 black frames (Lmax: < 1cd/m2). Five response averages of the first order response component (KI) were analyzed: the central 7.5 degrees and the 4 adjoining quadrants. The amplitudes from the first minimum, N1, to the first maximum, P1, and from P1 to the second minimum, N2, were analyzed as well as the latencies of N1, P1, N2 and the latencies of 3 multifocal oscillatory potentials (mfOPs) with their maxima at about 73, 80 and 85ms. Results: For each parameter the percentage of deviation from the mean of the control group was calculated. These values were then added for each individual to form a deviation index (DI). Seventeen patients (85.0%) with NTG and 3 patients (20.0%) with HTG showed a DI outside the normal range. The major changes were observed in the mfOPs of the NTG patients. MfOPs were then selectively filtered at 100-300Hz and their scalar product was analyzed over an epoch of 68-105ms. This confirmed that mfOPs differed significantly from the control in the central 7.5° and, for NTG, in the nasal field. With a logistic regression analysis the mfOPs had a sensitivity to differentiate 85% of the NTG patients and 73% of the HTG patients from normal. Conclusions: Under these conditions, the slow-stimulated mfERG can detect glaucomatous dysfunction in NTG (85.0%). The differences observed between NTG and HTG are in support of a different underlying pathomechanis

Influence of Dopamine Deficiency in Early Parkinson's Disease on the Slow Stimulation Multifocal-ERG

Purpose: In animal studies intravitreal injection of tetrodotoxin (TTX) results in mfERG waveform changes similar to those observed in glaucoma. As TTX blocks amacrine as well as ganglion cells, there is still a question regarding the underlying cell population responsible for these changes in waveform. In an attempt to assess the contribution of the amacrine cells to these changes, a mfERG was obtained from patients with Parkinson's disease as some amacrine cells are mediated by dopamine, a substance lacking in Parkinson's. Methods: Eight patients with early Parkinson's disease underwent ophthalmologic examination, testing of contrast sensitivity and electrophysiological examination according to ISCEV standard at least 12h following their last medication with Dopamine. A slow stimulation mfERG was obtained with a stimulus base interval of 53.3ms and with a stimulus base interval of 106.6ms. During MF-ERG recordings 103 hexagons stimulated the central 50deg of the retina simultaneously and independently (m-sequence 213, Lmax: 200cd/m2, ~100% contrast). Results: Contrast sensitivity and ISCEV standard electrophysiological testing was unremarkable. When the mfERG was analyzed, only four patients had an adequate signal-to-noise ratio to allow further data analysis - one of whom was diagnosed with a multi system atrophy in retrospect. The first order response component was analyzed at a filter setting of 10-300Hz and at 100-300Hz (OPs) and compared to mfERGs of a control group. On average, in patients, the amplitude of N1P1 was slightly lower in the central and nasal response averages. When the three OPs at a latency of 72-89ms were analyzed in the 53.3ms base interval recording, the most marked difference in amplitude was observed in the superior nasal response average of the first OP. Here a mean amplitude of 1.3nV/deg2 in patients compared to a mean amplitude of 1.9nV/deg2 in the control group (P: 0.08). Discussion: In contrast to our previous findings in NTG, there was a consistent presence of three OPs. Under the stimulus conditions applied, we did not find an influence of dopaminergic amacrine cells on the mfERG in our patients with moderate stages of Parkinsion's. The difficulties in obtaining an adequate signal-to noise ratio due to e.g. muscle artifacts even in Parkinson patients of moderate disease stages render a success of mfERG recording in patients with more advanced stages unlikely. The question of the influence of dopaminergic amacrine cells on the mfERG could possibly be addressed using MPDT in animal researc

Cerebrospinal fluid antibodies to aquaporin-4 in neuromyelitis optica and related disorders: frequency, origin, and diagnostic relevance

In 70-80% of cases, neuromyelitis optica (NMO) is associated with highly specific serum auto-antibodies to aquaporin-4 (termed AQP4-Ab or NMO-IgG). Recent evidence strongly suggests that AQP4-Ab are directly involved in the immunopathogenesis of NMO

Analysis of Lymphocytic DNA Damage in Early Multiple Sclerosis by Automated Gamma-H2AX and 53BP1 Foci Detection: A Case Control Study

Background In response to DNA double-strand breaks, the histone protein H2AX becomes phosphorylated at its C-terminal serine 139 residue, referred to as γ-H2AX. Formation of γ-H2AX foci is associated with recruitment of p53-binding protein 1 (53BP1), a regulator of the cellular response to DNA double-strand breaks. γ-H2AX expression in peripheral blood mononuclear cells (PBMCs) was recently proposed as a diagnostic and disease activity marker for multiple sclerosis (MS). Objective To evaluate the significance of γ-H2AX and 53BP1 foci in PBMCs as diagnostic and disease activity markers in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS) using automated γ-H2AX and 53BP1 foci detection. Methods Immunocytochemistry was performed on freshly isolated PBMCs of patients with CIS/early RRMS (n = 25) and healthy controls (n = 27) with γ-H2AX and 53BP1 specific antibodies. Nuclear γ-H2AX and 53BP1 foci were determined using a fully automated reading system, assessing the numbers of γ-H2AX and 53BP1 foci per total number of cells and the percentage of cells with foci. Patients underwent contrast enhanced 3 Tesla magnetic resonance imaging (MRI) and clinical examination including expanded disability status scale (EDSS) score. γ-H2AX and 53BP1 were also compared in previously frozen PBMCs of each 10 CIS/early RRMS patients with and without contrast enhancing lesions (CEL) and 10 healthy controls. Results The median (range) number of γ-H2AX (0.04 [0–0.5]) and 53BP1 (0.005 [0–0.2]) foci per cell in freshly isolated PBMCs across all study participants was low and similar to previously reported values of healthy individuals. For both, γ-H2AX and 53BP1, the cellular focus number as well as the percentage of positive cells did not differ between patients with CIS/RRMS and healthy controls. γ-H2AX and 53BP1 levels neither correlated with number nor volume of T2-weighted lesions on MRI, nor with the EDSS. Although γ-H2AX, but not 53BP1, levels were higher in previously frozen PBMCs of patients with than without CEL, γ-H2AX values of both groups overlapped and γ-H2AX did not correlate with the number or volume of CEL. Conclusion γ-H2AX and 53BP1 foci do not seem to be promising diagnostic or disease activity biomarkers in patients with early MS. Lymphocytic DNA double-strand breaks are unlikely to play a major role in the pathophysiology of MS

Hypofractionated stereotactic re-irradiation: treatment option in recurrent malignant glioma

BACKGROUND: Hypofractionated stereotactic radiotherapy (HFSRT) is one salvage treatment option in previously irradiated patients with recurrent malignant glioma. We analyzed the results of HFSRT and prognostic factors in a single-institution series. METHODS: Between 1997 and 2003, 19 patients with recurrent malignant glioma (14 glioblastoma on most recent histology, 5 anaplastic astrocytoma) were treated with HFSRT. The median interval from post-operative radiotherapy to HFSRT was 19 (range 3–116) months, the median daily single dose 5 (4–10) Gy, the median total dose 30 (20–30) Gy and the median planning target volume 15 (4–70) ml. RESULTS: The median overall survival (OS) was 9.3 (1.9-77.6+) months from the time of HFSRT, 15.4 months for grade III and 7.9 months for grade IV tumors (p = 0.029, log-rank test). Two patients were alive at 34.6 and 77.6 months. OS was longer after a total dose of 30 Gy (11.1 months) than after total doses of <30 Gy (7.4 months; p = 0.051). Of five (26%) reoperations, none was performed for presumed or histologically predominant radiation necrosis. Median time to tumor progression after HFSRT on imaging was 4.9 months (1.3 to 37.3) months. CONCLUSION: HFSRT with conservative total doses of no more than 30 Gy is safe and leads to similar OS times as more aggressive treatment schemes. In individual patients, HFSRT in combination with other salvage treatment modalities, was associated with long-term survival

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

High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types

OBJECTIVE: To retrospectively determine the frequency of N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) autoantibodies in patients with different forms of dementia. METHODS: Clinical characterization of 660 patients with dementia, neurodegenerative disease without dementia, other neurological disorders and age-matched healthy controls combined with retrospective analysis of serum or cerebrospinal fluid (CSF) for the presence of NMDAR antibodies. Antibody binding to receptor mutants and the effect of immunotherapy were determined in a subgroup of patients. RESULTS: Serum NMDAR antibodies of IgM, IgA, or IgG subtypes were detected in 16.1% of 286 dementia patients (9.5% IgM, 4.9% IgA, and 1.7% IgG) and in 2.8% of 217 cognitively healthy controls (1.9% IgM and 0.9% IgA). Antibodies were rarely found in CSF. The highest prevalence of serum antibodies was detected in patients with “unclassified dementia” followed by progressive supranuclear palsy, corticobasal syndrome, Parkinson’s disease-related dementia, and primary progressive aphasia. Among the unclassified dementia group, 60% of 20 patients had NMDAR antibodies, accompanied by higher frequency of CSF abnormalities, and subacute or fluctuating disease progression. Immunotherapy in selected prospective cases resulted in clinical stabilization, loss of antibodies, and improvement of functional imaging parameters. Epitope mapping showed varied determinants in patients with NMDAR IgA-associated cognitive decline. INTERPRETATION: Serum IgA/IgM NMDAR antibodies occur in a significant number of patients with dementia. Whether these antibodies result from or contribute to the neurodegenerative disorder remains unknown, but our findings reveal a subgroup of patients with high antibody levels who can potentially benefit from immunotherapy

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

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 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