Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome

Background A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Objective To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes. Methods Retrospective multicenter study. Results The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80% (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40% (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36%) and markedly impaired ambulation due to paresis or ataxia (25%) as the most common long-term sequelae. Functional blindness in one or both eyes was noted during at least one ON attack in around 70%. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70%). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44%. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70%, oligoclonal bands in only 13%, and blood-CSF-barrier dysfunction in 32%. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9%). Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28%, 32%, 15%, 33%, respectively; MS had been suspected in 36%. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases. Conclusion Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome

Background Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are present in a subset of aquaporin-4 (AQP4)-IgG-negative patients with optic neuritis (ON) and/or myelitis. Little is known so far about brainstem involvement in MOG-IgG-positive patients. Objective To investigate the frequency, clinical and paraclinical features, course, outcome, and prognostic implications of brainstem involvement in MOG-IgG-positive ON and/or myelitis. Methods Retrospective case study. Results Among 50 patients with MOG-IgG-positive ON and/or myelitis, 15 (30 %) with a history of brainstem encephalitis were identified. All were negative for AQP4-IgG. Symptoms included respiratory insufficiency, intractable nausea and vomiting (INV), dysarthria, dysphagia, impaired cough reflex, oculomotor nerve palsy and diplopia, nystagmus, internuclear ophthalmoplegia (INO), facial nerve paresis, trigeminal hypesthesia/dysesthesia, vertigo, hearing loss, balance difficulties, and gait and limb ataxia; brainstem involvement was asymptomatic in three cases. Brainstem inflammation was already present at or very shortly after disease onset in 7/15 (47 %) patients. 16/21 (76.2 %) brainstem attacks were accompanied by acute myelitis and/or ON. Lesions were located in the pons (11/13), medulla oblongata (8/14), mesencephalon (cerebral peduncles; 2/14), and cerebellar peduncles (5/14), were adjacent to the fourth ventricle in 2/12, and periaqueductal in 1/12; some had concomitant diencephalic (2/13) or cerebellar lesions (1/14). MRI or laboratory signs of blood-brain barrier damage were present in 5/12. Cerebrospinal fluid pleocytosis was found in 11/14 cases, with neutrophils in 7/11 (3-34 % of all CSF white blood cells), and oligoclonal bands in 4/14. Attacks were preceded by acute infection or vaccination in 5/15 (33.3 %). A history of teratoma was noted in one case. The disease followed a relapsing course in 13/15 (87 %); the brainstem was involved more than once in 6. Immunosuppression was not always effective in preventing relapses. Interferon-beta was followed by new attacks in two patients. While one patient died from central hypoventilation, partial or complete recovery was achieved in the remainder following treatment with high-dose steroids and/or plasma exchange. Brainstem involvement was associated with a more aggressive general disease course (higher relapse rate, more myelitis attacks, more frequently supratentorial brain lesions, worse EDSS at last follow-up). Conclusions Brainstem involvement is present in around one third of MOG-IgG-positive patients with ON and/or myelitis. Clinical manifestations are diverse and may include symptoms typically seen in AQP4-IgG-positive neuromyelitis optica, such as INV and respiratory insufficiency, or in multiple sclerosis, such as INO. As MOG-IgG-positive brainstem encephalitis may take a serious or even fatal course, particular attention should be paid to signs or symptoms of additional brainstem involvement in patients presenting with MOG-IgG-positive ON and/or myelitis

Clinical and Laboratory Features in Anti-NF155 Autoimmune Nodopathy

BACKGROUND AND OBJECTIVES: To study the clinical and laboratory features of antineurofascin-155 (NF155)-positive autoimmune nodopathy (AN). METHODS: Patients with anti-NF155 antibodies detected on routine immunologic testing were included. Clinical characteristics, treatment response, and functional scales (modified Rankin Scale [mRS] and Inflammatory Rasch-built Overall Disability Scale [I-RODS]) were retrospectively collected at baseline and at the follow-up. Autoantibody and neurofilament light (NfL) chain levels were analyzed at baseline and at the follow-up. RESULTS: Forty NF155+ patients with AN were included. Mean age at onset was 42.4 years. Patients presented with a progressive (75%), sensory motor (87.5%), and symmetric distal-predominant weakness in upper (97.2%) and lower extremities (94.5%), with tremor and ataxia (75%). Patients received a median of 3 (2-4) different treatments in 46 months of median follow-up. Response to IV immunoglobulin (86.8%) or steroids (72.2%) was poor in most patients, whereas 77.3% responded to rituximab. HLA-DRB1*15 was detected in 91.3% of patients. IgG4 anti-NF155 antibodies were predominant in all patients; anti-NF155 titers correlated with mRS within the same patient (r = 0.41, p = 0.004). Serum NfL (sNfL) levels were higher in anti-NF155+ AN than in healthy controls (36.47 vs 7.56 pg/mL, p < 0.001) and correlated with anti-NF155 titers (r = 0.43, p = 0.001), with I-RODS at baseline (r = -0.88, p < 0.001) and with maximum I-RODS achieved (r = -0.58, p = 0.01). Anti-NF155 titers and sNfL levels decreased in all rituximab-treated patients. DISCUSSION: Anti-NF155 AN presents a distinct clinical profile and good response to rituximab. Autoantibody titers and sNfL are useful to monitor disease status in these patients. The use of untagged-NF155 plasmids minimizes the detection of false anti-NF155+ cases. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that anti-NF155 antibodies associate with a specific phenotype and response to rituximab

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin

Background: Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders. Objective: To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers. Methods: 614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells. Results: MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7%) patients with a history of both ON and myelitis, 22/103 (21.4%) with a history of ON but no myelitis and 6/45 (13.3%) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67%) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89%) follow-up samples obtained over a median period of 16.5 months (range 0–123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment. Conclusions: To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome

Background: A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Objective: To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes. Methods: Retrospective multicenter study. Results: The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80% (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40% (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36%) and markedly impaired ambulation due to paresis or ataxia (25%) as the most common long-term sequelae. Functional blindess in one or both eyes was noted during at least one ON attack in around 70%. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70%). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44%. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70%, oligoclonal bands in only 13%, and blood-CSF-barrier dysfunction in 32%. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9%). Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28%, 32%, 15%, 33%, respectively; MS had been suspected in 36%. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases. Conclusion: Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis

TNF-Related Apoptosis Inducing Ligand (TRAIL) expression in natural killer (NK) and their role in Experimental Autoimmune Encephalomyelitis (EAE)

Title: TNF-Related Apoptosis Inducing Ligand (TRAIL) Expression in Natural Killer (NK) cells and their role in Experimental Autoimmune Encephalomyelitis (EAE) Introduction: Multiple Sclerosis (MS) is a CD4+ T cell mediated, demyelinating autoimmune disease of the central nervous system (CNS). TRAIL, a 281amino acid homotrimeric member of the TNF/NGF superfamily is expressed as soluble and membrane-bound form by activated T cells, B cells, macrophages and NK cells both in human and mouse and induces caspase-mediated cell death in transformed and non-transformed cells. 1,2 However, it has been shown that TRAIL acts not only as an apoptotic ligand but exerts also an immunoregulatory function. In the animal model of MS, the EAE, it has been demonstrated that, when applied intracerebrally, TRAIL induces neuronal death and exacerbates the disease.3 However, when applied in the periphery, it reduces severity by inhibiting autoreactive T cells. 4 So far, the cell population which mediates the modulation of EAE through TRAIL is undefined. In MS patients, an increased amount of soluble TRAIL in the peripheral blood has been linked to clinical response (stable EDSS score) to IFN-β treatment at the relapsing remitting (RR-MS) form of the disease during the first year of treatment. 5 Additionally, TRAIL induction on NK cells of MS patients after in vitro culture with IFN-β is less pronounced compared to healthy controls (Infante-Duarte, unpublished data). NK cells are members of the innate immune system, but also capable of regulating cells of the adaptive system as autoreactive T cells and dendritic cells. 7 Furthermore, a reduced functional activity of NK cells has been linked to MS relapses and NK cell depletion has been shown to exacerbate EAE. 7-9 Aims: 1. To investigate which factors, e.g. IFN-β, are able to modulate TRAIL-expression in murine NK cells. 2. To investigate the role of TRAIL-expressing NK cells in modulating the clinical course and histopathology of EAE. Methods: Induction of TRAIL on NK cells of wild-type (wt) C57BL/6 mice by IFN-β was investigated at the gene level by Taq-Man analysis and at the protein level through antibody detection using flow cytometry (FACS). EAE was induced in wt C57BL/6 mice through subcutaneous (s.c.) injection of Myelin Oligodendrocyte Glycoprotein (MOG 35-55) peptide in Complete Freund’s Adjuvant (CFA). Shortly after immunisation, “naive” NK cells or TRAIL-expressing NK cells (which were pre-incubated with IFN-β) were injected to the aforementioned mice. Clinical course, severity of disease and histopathological landmarks of mice receiving either NK cells or TRAIL expressing-NK cells were compared with those of control mice (injected with PBS alone). Results: IFN-β induced an increase of TRAIL mRNA expression on murine NK cells at concentrations of 500U/ml and 1000U/ml. An induction of surface TRAIL expression on NK cells with the same concentrations of IFN-β was also confirmed at the protein level. The optimal concentration and incubation time of 1000U/ml for 18 hours was used for TRAIL induction on ‘naïve’ NK cells. In C57BL/6 mice, which received the TRAIL-expressing NK cells intravenously (i.v.), a reduced incidence of EAE induction was observed compared to mice, which received untouched NK cells or PBS alone. Discussion: NK cells represent a putative target of IFN-β treatment in EAE. IFN-β-induction of TRAIL in NK cells may be an important mechanism of action of this drug. TRAIL-expressing NK cells could play a regulatory role during the induction phase of the disease by influencing the priming of T cells or neuron survival in the CNS. Thus, generation of NK cells with immunoregulatory properties may represent a therapeutic strategy for EAE and MS

Effekte der immunmodulatorischen Substanz Laquinimod im Rattenmodell der Experimentellen Autoimmunen Neuritis

Das Ziel der Dissertation war die immunmodulatorische Substanz Laquinimod als Therapie beim Tiermodell der autoimmunen Neuritiden, der experimentellen Neuritis (EAN), zu überprüfen. 38 Lewis Ratten wurden am Tag 0 mit P2 Peptid subkutan immunisiert und täglich (Tag 0 - 28) mit Laquinimod (6,25, 12,5, 25mg/kg) oral einmal täglich behandelt. Die Beurteilung des Krankheitsverlaufs erfolgte täglich. Am Tag 16 nach Immunisierung wurden die Tieren elektrophysiologisch, histologisch und durchflusszytometrisch untersucht. Es zeigte sich eine signifikante Besserung der EAN unter 12,5mg/kg Laquinimod mit Reduktion der Immunzellen-Infiltration und der Demyelinisierung des N. ischiadicus. Zusätzlich zeigte die durchflusszytometrische Analyse der peripheren Lymphknoten und Milz am Tag 16 eine Induktion der regulatorischen plasmatozytoiden dendritischen Zellen. Zusammenfassend, zeigt sich Laquinimod als eine potenziell wirksame Therapie für autoimmune Neuritiden

Role of the neuromuscular ultrasound in the diagnostic of the multifocal motor neuropathy

Multifocal motor neuropathy (MMN) is the one of the most common acquired immune-mediated inflammatory disorders of the peripheral nervous system. The diagnosis is based on the distribution pattern of the neurological semiology and the pathological changes of nerve conduction studies (NCS) in classical cases. However, in cases with subtle clinical presentation, an extended diagnostic workup may be needed, such as cerebrospinal fluid examination, laboratory tests, and nerve biopsy. NCS remain nowadays fundamental not only for the diagnosis, but also for the follow-up and measurement of response to immune-treatment in MMN. New challenges arose though, on how best to acquire a static and dynamic imaging of the peripheral nerves, aiming to provide a holistic approach to the nerve impairment. According to the literature, neuromuscular ultrasound is able to detect in MMN patients thickened or swollen cervical roots, peripheral nerves or brachial plexus, findings that suggest ongoing inflammation. This review provides a timely update on the nerve ultrasound findings in MMN

Immune cell derived BDNF does not mediate neuroprotection of the murine anti-CD52 antibody in a chronic autoimmune mouse model

The murine anti-CD52 antibody, an equivalent of the humanized antibody alemtuzumab, which is successfully used in the treatment of multiple sclerosis, was used to explore a potential neuroprotective effect driven by immune cell derived brain-derived neurotrophic factor (BDNF). Therefore, lineage specific constitutive knockout mice with a BDNF deficiency in T cells and macrophages were used and compared to treated wildtype mice. Neither therapeutic nor preventive application of the murine anti-CD52 antibody in an animal model of multiple sclerosis, the MOG(35-55) EAE, revealed a beneficial contribution of immune cell derived BDNF to the disease outcome. Furthermore, preventive application of the murine anti-CD52 antibody worsened the clinical EAE disease course and could only be overcome by a prolonged recovery phase after treatment and before disease induction