Nadja Borisow

Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS).

Abstract Neuromyelitis optica (NMO, Devic’s syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity. Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings. Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD). In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments. Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals.

Optical Coherence Tomography Reveals Distinct Patterns of Retinal Damage in Neuromyelitis Optica and Multiple Sclerosis

Background Neuromyelitis optica (NMO) and relapsing-remitting multiple sclerosis (RRMS) are difficult to differentiate solely on clinical grounds. Optical coherence tomography (OCT) studies investigating retinal changes in both diseases focused primarily on the retinal nerve fiber layer (RNFL) while rare data are available on deeper intra-retinal layers. Objective To detect different patterns of intra-retinal layer alterations in patients with NMO spectrum disorders (NMOSD) and RRMS with focus on the influence of a previous optic neuritis (ON). Methods We applied spectral-domain OCT in eyes of NMOSD patients and compared them to matched RRMS patients and healthy controls (HC). Semi-automatic intra-retinal layer segmentation was used to quantify intra-retinal layer thicknesses. In a subgroup low contrast visual acuity (LCVA) was assessed. Results NMOSD-, MS- and HC-groups, each comprising 17 subjects, were included in analysis. RNFL thickness was more severely reduced in NMOSD compared to MS following ON. In MS-ON eyes, RNFL thinning showed a clear temporal preponderance, whereas in NMOSD-ON eyes RNFL was more evenly reduced, resulting in a significantly lower ratio of the nasal versus temporal RNFL thickness. In comparison to HC, ganglion cell layer thickness was stronger reduced in NMOSD-ON than in MS-ON, accompanied by a more severe impairment of LCVA. The inner nuclear layer and the outer retinal layers were thicker in NMOSD-ON patients compared to NMOSD without ON and HC eyes while these differences were primarily driven by microcystic macular edema. Conclusion Our study supports previous findings that ON in NMOSD leads to more pronounced retinal thinning and visual function impairment than in RRMS. The different retinal damage patterns in NMOSD versus RRMS support the current notion of distinct pathomechanisms of both conditions. However, OCT is still insufficient to help with the clinically relevant differentiation of both conditions in an individual patient.

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

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.

Expert recommendations to personalization of medical approaches in treatment of multiple sclerosis: an overview of family planning and pregnancy

Multiple sclerosis is the most common chronic autoimmune disease of the central nervous system which preferentially affects females at childbearing age. For this reason, patients and treating physicians were frequently confronted with questions concerning family planning, pregnancy and birth. Preventive and personalized treatment approaches are considered, because topics as heredity, risk of congenital malformations, influence of pregnancy on MS and aspects of drug therapy during the period of conception, pregnancy, puerperium and lactation have to be discussed. Here, we provide an overview about the current state of knowledge regarding these issues.

Exclusive Breastfeeding and the Effect on Postpartum Multiple Sclerosis Relapses

IMPORTANCE Women with multiple sclerosis (MS) experience an elevated risk of relapse after giving birth. The effect of exclusive breastfeeding on postpartum risk of MS relapse is unclear. OBJECTIVES To determine the effect of exclusive breastfeeding on postpartum risk of MS relapse and to investigate the effect of introducing supplemental feedings on that risk. DESIGN, SETTING, AND PARTICIPANTS Data on 201 pregnant women with relapsing-remitting MS were collected prospectively from January 1, 2008, to June 30, 2012, with 1 year follow-up post partum in the nationwide German MS and pregnancy registry. The effect of the intention to breastfeed exclusively (no regular replacement of breastfeeding meals with supplemental feedings) for at least 2 months compared with nonexclusive breastfeeding (partial or no breastfeeding) on the first postpartum MS relapse, using Cox proportional hazards regression model adjusted for age and disease activity, before and during pregnancy was analyzed. Data analysis was performed from August 30, 2013, to May 25, 2015. EXPOSURE Exclusive breastfeeding defined as at least 2 months of breastfeeding without regular replacement of any meal by supplemental feeding. MAIN OUTCOME AND MEASURE First postpartum MS relapse. RESULTS Of 201 women, 120 (59.7%) intended to breastfeed exclusively for at least 2 months and 81 (40.3%) breastfed and included supplemental feeding (42 [20.9%]) or did not breastfeed (39 [19.4%]). Thirty-one women (38.3%) who did not breastfeed exclusively had a relapse within the first 6 months post partum compared with 29 women (24.2%) who intended to breastfeed exclusively for at least 2 months (unadjusted hazard ratio, 1.80; 95% CI, 1.09-2.99; P = .02; adjusted hazard ratio, 1.70; 95% CI, 1.02-2.85; P = .04). The time to first postpartum relapse after the introduction of supplemental feedings did not differ significantly between women who previously breastfed exclusively and those who did not (P = .60). CONCLUSIONS AND RELEVANCE The findings of this study suggest that exclusive breastfeeding is a modestly effective MS treatment with a natural end date. Our study provides further evidence that women with MS who breastfeed exclusively should be supported to do so since it does not increase the risk of postpartum relapse.

Thalidomide causes sinus bradycardia in ALS

ObjectiveNeuroinflammation contributes to motor neuron degeneration in ALS. Thalidomide (THL) shows potent anti-inflammatory properties and increased the lifespan in ALS transgenic mice. Thalidomide was therefore suggested as atherapeutic intervention for the treatment of ALS.We conducted a pilot, randomized clinical trial of THL in patients with ALS to assess safety, feasibility, and preliminary estimates of treatment efficacy.MethodsPatients were randomized to THL in combination with riluzole (n = 18) or riluzole alone (n = 19). THL was initiated at 100 mg per day for 6 weeks. Thereafter, the dose was increased every week by 50 mg until reaching the dose of 400 mg per day and planned to continue for another 12 weeks.ResultsWithin 12 weeks of THL treatment, nine THL patients (50%) developed bradycardia defined as a heart rate below 60 beats per minute (bpm) and ranged from 46 to 59 bpm. Mean heart rate dropped by 17 bpm with THL treatment. Severe symptomatic bradycardia of 30 bpm occurred in one patient. A further patient died from sudden unexpected death. The study was terminated prematurely for safety concerns. The secondary outcome variables showed similar results for both groups.ConclusionBradycardia was the most common adverse event of THL treatment in ALS. THL-related bradycardia does not appear to be ALS-specific. It is conceivable, however, that the unexpected frequency and severity of THL-induced bradycardia may be related to subclinical involvement of the autonomic nervous system in ALS. The cardiac toxicity discourages further clinical trials and compassionate use of THL in ALS. ClinicalTrials.gov Identifier: NCT00231140.

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-β (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-β, 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-β.

Visual evoked potentials in neuromyelitis optica and its spectrum disorders.

Optic neuritis (ON) is a key feature of neuromyelitis optica (NMO). Recently, NMO patients of predominantly Afro-Brazilian origin were evaluated by visual evoked potentials (VEPs) and showed marked amplitude reductions. Here, we analyzed VEPs in a predominantly Caucasian cohort, consisting of 43 patients with definite NMO, 18 with anti-aquaporin (AQP) 4 antibody-seropositive NMO spectrum disorders and 61 matched healthy controls. We found reduced amplitudes in only 12.3%, prolonged latencies in 41.9% and a lack of response in 14.0% of NMO eyes. Delayed P100 latencies in eyes without prior ON suggested this was a subclinical affection. The data indicate heterogenous patterns in NMO, warranting further investigation.

Normal volumes and microstructural integrity of deep gray matter structures in AQP4+ NMOSD

Objective: To assess volumes and microstructural integrity of deep gray matter structures in a homogeneous cohort of patients with neuromyelitis optica spectrum disorder (NMOSD). Methods: This was a cross-sectional study including 36 aquaporin-4 antibody-positive (AQP4 Ab-positive) Caucasian patients with NMOSD and healthy controls matched for age, sex, and education. Volumetry of deep gray matter structures (DGM; thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens) was performed using 2 independent automated methods. Microstructural integrity was assessed based on diffusion tensor imaging. Results: Both volumetric analysis methods consistently revealed similar volumes of DGM structures in patients and controls without significant group differences. Moreover, no differences in DGM microstructural integrity were observed between groups. Conclusions: Deep gray matter structures are not affected in AQP4 Ab-positive Caucasian patients with NMOSD. NMOSD imaging studies should be interpreted with respect to Ab status, educational background, and ethnicity of included patients.

Elektive Termination der Beatmungstherapie bei der amyotrophen Lateralsklerose

BACKGROUND Due to the growing use of artificial respiration in amyotrophic lateral sclerosis (ALS), physicians are increasingly confronted with patients seeking discontinuation of therapy. Yet there are few systematic investigations of the withdrawal of ventilation therapy. PATIENTS AND METHODS In a retrospective investigation of nine German ALS patients, clinical data were recorded from the discontinuation of noninvasive ventilation (n=4) and mechanical ventilation (n=5). RESULTS In cases of residual spontaneous breathing, intensified symptom control of dyspnea and anxiety was possible with intravenous morphine sulfate at a low dose rate (10 mg/h) but high cumulative dose (185-380 mg). The terminal phase after removing the mask was protracted (22:10 h to 28:00 h). In cases of minimal or absent spontaneous breathing the disconnection was realized in deep sedation, which required a moderate total dose of morphine sulfate (120 mg) but a high dosage rate (up to 300 mg/h). The terminal phase in deep sedation was short (15-80 min). CONCLUSION The elective termination of ventilation requires differentiated pharmacologic palliative care. More controlled studies are required in order to establish evidence-based guidelines for the termination of ventilation.