MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis.

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.

Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis (p < 0.001) and area postrema relapses (P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS (p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January (P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.

The clinical profile of NMOSD in Australia and New Zealand.

Neuromyelitis optica spectrum disorders (NMOSD) are an inflammation of the central nervous system associated with autoantibodies to aquaporin-4. We have undertaken a clinic-based survey of NMOSD in the Australia and New Zealand populations with the aim of characterising the clinical features and establishing the value of recently revised diagnostic criteria. Cases of possible NMOSD and age and sex-matched controls with multiple sclerosis (MS) were referred from centres across Australia and New Zealand. Cases were classified as NMOSD if they met the 2015 IPND criteria and remained as suspected NMOSD if they did not. Clinical and paraclinical data were compared across the three groups. NMOSD was confirmed in 75 cases and 89 had suspected NMOSD. There were 101 controls with MS. Age at onset, relapse rates and EDSS scores were significantly higher in NMOSD than in MS. Lesions and symptoms referable to the optic nerve were more common in NMOSD whereas brainstem, cerebellar and cerebral lesions were more common in MS. Longitudinally extensive spinal cord lesions were seen in 48/71 (68%) of cases with NMOSD. Elevations of CSF, white cell count and protein were more common in NMOSD. We have confirmed a clinical pattern of NMOSD that has been seen in several geographical regions. We have demonstrated the clinical utility of the current diagnostic criteria. Distinct patterns of disease are evident in NMOSD and MS, but there remains a large number of patients with NMOSD-like features who do not meet the current diagnostic criteria for NMOSD and remain a diagnostic challenge.

Anti-MAG neuropathy: Role of IgM antibodies, the paranodal junction and juxtaparanodal potassium channels.

OBJECTIVE: To improve understanding of disease pathophysiology in anti-myelin-associated glycoprotein (anti-MAG) neuropathy to guide further treatment approaches. METHODS: Anti-MAG neuropathy patients underwent clinical assessments, nerve conduction and excitability studies, and ultrasound assessment. RESULTS: Patients demonstrated a distinctive axonal excitability profile characterised by a reduction in superexcitability [MAG: -14.2 ±â€¯1.6% vs healthy controls (HC): -21.8 ±â€¯1.2%; p < 0.01] without alterations in most other excitability parameters. Mathematical modelling of nerve excitability recordings suggested that changes in axonal function could be explained by a 72.5% increase in juxtaparanodal fast potassium channel activation and an accompanying hyperpolarization of resting membrane potential (by 0.3 mV) resulting in a 94.2% reduction in discrepancy between anti-MAG data and the healthy control model. Superexcitability changes correlated strongly with clinical and neurophysiological parameters. Furthermore, structural assessments demonstrated a proximal pattern of nerve enlargement (C6 nerve root cross-sectional area: 15.9 ±â€¯8.1 mm2 vs HC: 9.1 ±â€¯2.3 mm2; p < 0.05). CONCLUSIONS: The imaging and neurophysiological results support the pathogenicity of anti-MAG IgM. Widening between adjacent loops of paranodal myelin due to antibodies would expand the pathway from the node to the juxtaparanode, increasing activation of juxtaparanodal fast potassium channels, thereby impairing saltatory conduction. SIGNIFICANCE: Potassium channel blockers may prove beneficial in restoring conduction closer to its normal state and improving nerve function in anti-MAG neuropathy.

Neurofascin-155 IGG4 Neuropathy: Pathophysiological Insights, Spectrum of Clinical Severity and Response To treatment.

INTRODUCTION: Sensorimotor neuropathy associated with IgG4 antibodies to neurofascin-155 (NF155) was recently described. The clinical phenotype is typically associated with young onset, distal weakness, and in some cases, tremor. METHODS: From a consecutive cohort of 55 patients diagnosed with chronic inflammatory demyelinating polyneuropathy, screening for anti-NF155 antibodies was undertaken. Patients underwent clinical assessment, diagnostic neurophysiology, including peripheral axonal excitability studies and nerve ultrasound. RESULTS: Three of 55 chronic inflammatory demyelinating polyneuropathy patients (5%) tested positive for anti-NF155 IgG4. Patients presenting with more severe disease had higher antibody titers. Ultrasound demonstrated diffuse nerve enlargement. Axonal excitability studies were markedly abnormal, with subsequent mathematical modeling of the results supporting disruption of the paranodal seal. DISCUSSION: A broad spectrum of disease severity and treatment response may be observed in anti-NF155 neuropathy. Excitability studies support the pathogenic role of anti-NF155 IgG4 antibodies targeting the paranodal region. Muscle Nerve 57: 848-851, 2018.

Motor unit remodelling in multifocal motor neuropathy: The importance of axonal loss.

OBJECTIVE: To estimate the degree of axonal loss in patients diagnosed with multifocal motor neuropathy (MMN) using a novel assessment of motor unit numbers and size. METHODS: Automated motor unit number estimation using a compound muscle action potential (CMAP) scan was undertaken in median nerves with conduction block. Results were compared with 30 age-matched healthy controls. RESULTS: Compared with healthy controls, MMN patients had fewer motor units (MMN: 33±11vs HC: 93±36 [mean±SD]; p<0.0001) and larger 'size of the largest unit' (MMN: 1.2±0.5mVvs HC: 0.4±0.1mV; p<0.0001), despite having normal distal CMAP amplitudes (MMN: 7.6±1.8mVvs HC: 8.7±2.5mV; p=0.24). CONCLUSIONS: MMN is associated with marked axonal loss which may be masked by striking re-innervation resulting in preservation of distal CMAP amplitudes. SIGNIFICANCE: Assessment of motor unit properties should be incorporated into assessment of disease progression in MMN, given that nerve conduction studies are insensitive to motor unit remodelling.

Incidence and prevalence of NMOSD in Australia and New Zealand.

OBJECTIVES: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. BACKGROUND: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. METHODS: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. RESULTS: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD. CONCLUSIONS: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.

Differentiating lower motor neuron syndromes.

Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features.

Axonal damage in central and peripheral nervous system inflammatory demyelinating diseases: common and divergent pathways of tissue damage.

PURPOSE OF REVIEW: Axonal injury is the pathological correlate of fixed disability in the inflammatory demyelinating disorders of the central and peripheral nervous system. The mechanisms that initiate and propagate neurodegeneration in these conditions are poorly understood, and a lack of available neuroprotective and proreparative therapies represent a significant unmet clinical need. In this article, we review new data pertaining to the convergent and divergent immunological, cellular, and molecular mechanisms that underpin neurodegeneration in multiple sclerosis and the chronic inflammatory demyelinating neuropathies that will inform the development of targeted therapies. RECENT FINDINGS: New insights have been gained from recognition of the axon as an integral component of the axon-myelin unit, identification of defects in axonal transport, elucidation of mechanisms of Wallerian degeneration and, in the central nervous system, the appreciation of trans-synaptic axonal degeneration, and widespread cortical synaptopathy. Concurrently, specific immune triggers of axonal injury, particularly in the peripheral immune system; and inhibitors of repair and regrowth, have been identified. SUMMARY: Neurodegeneration is a critical determinant of disability in the inflammatory demyelinating diseases of both the central nervous system and peripheral nervous system. Current therapies are restricted to agents that (effectively) treat the inflammatory components of these conditions. Although propagated, and in some instances triggered, by inflammation, axon damage will in future years be treated or prevented with adjuvant, targeted therapies that exploit emerging pathways to neurodegeneration.

A new era in the treatment of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. The importance of early treatment in minimising long-term disability is increasingly recognised. Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects.

Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP.

Antibodies to neurofascin exacerbate adoptive transfer experimental autoimmune neuritis.

Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy are autoimmune disorders of the peripheral nervous system in which autoantibodies are implicated in the disease pathogenesis. Recent work has focused on the nodal regions of the myelinated axon as potential autoantibody targets. Here we screened patient sera for autoantibodies to neurofascin and assessed the pathophysiological relevance of anti-neurofascin antibodies in vivo. Levels of anti-neurofascin antibodies were higher in sera from patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy when compared with those of controls. Anti-neurofascin antibodies exacerbated and prolonged adoptive transfer experimental autoimmune neuritis and caused conduction defects when injected intraneurally.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 1 historical and established therapies. MS Neurology Group of the Australian and New Zealand Association of Neurologists.

Multiple sclerosis (MS) is a potentially life-changing immune mediated disease of the central nervous system. Until recently, treatment has been largely confined to acute treatment of relapses, symptomatic therapies and rehabilitation. Through persistent efforts of dedicated physicians and scientists around the globe for 160 years, a number of therapies that have an impact on the long term outcome of the disease have emerged over the past 20 years. In this three part series we review the practicalities, benefits and potential hazards of each of the currently available and emerging treatment options for MS. We pay particular attention to ways of abrogating the risks of these therapies and provide advice on the most appropriate indications for using individual therapies. In Part 1 we review the history of the development of MS therapies and its connection with the underlying immunobiology of the disease. The established therapies for MS are reviewed in detail and their current availability and indications in Australia and New Zealand are summarised. We examine the evidence to support their use in the treatment of MS.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 3 treatment practicalities and recommendations. MS Neurology Group of the Australian and New Zealand Association of Neurologists.

In this third and final part of our review of multiple sclerosis (MS) treatment we look at the practical day-to-day management issues that are likely to influence individual treatment decisions. Whilst efficacy is clearly of considerable importance, tolerability and the potential for adverse effects often play a significant role in informing individual patient decisions. Here we review the issues surrounding switching between therapies, and the evidence to assist guiding the choice of therapy to change to and when to change. We review the current level of evidence with regards to the management of women in their child-bearing years with regards to recommendations about treatment during pregnancy and whilst breast feeding. We provide a summary of recommended pre- and post-treatment monitoring for the available therapies and review the evidence with regards to the value of testing for antibodies which are known to be neutralising for some therapies. We review the occurrence of adverse events, both the more common and troublesome effects and those that are less common but have potentially much more serious outcomes. Ways of mitigating these risks and managing the more troublesome adverse effects are also reviewed. Finally, we make specific recommendations with regards to the treatment of MS. It is an exciting time in the world of MS neurology and the prospects for further advances in coming years are high.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 2 new and emerging therapies and their efficacy. MS Neurology Group of the Australian and New Zealand Association of Neurologists.

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of ß-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes.

Beneficial effect of a multimerized immunoglobulin Fc in an animal model of inflammatory neuropathy (experimental autoimmune neuritis).

Intravenous immunoglobulin (IVIg) is one of the first-line therapies for inflammatory neuropathies. Clinical use of IVIg for these disorders is limited by expense and availability. Here, we investigated a synthetic product alternative to IVIg. The aim of this study was to test the therapeutic efficacy of a novel recombinant polyvalent murine IgG2a Fc compound (stradomer™) in experimental autoimmune neuritis (EAN). Seventy-four Lewis rats were immunized with myelin, randomized into three groups, and were treated with albumin, IVIg, or stradomer at 1% of IVIg dose. Rats were assessed clinically, electrophysiologically, and histologically. The clinical disease severity was evaluated by clinical grading and weight changes. The electrophysiological studies recorded motor conduction velocity (MCV), amplitudes, and latencies of the evoked compound muscle action potential (CMAP) and spinal somatosensory evoked potential. The treatment efficacy of the IVIg and stradomer groups was compared to the albumin (control) group. We demonstrate that stradomer has a similar therapeutic efficacy to human IVIg in EAN. Rats receiving stradomer or IVIg showed significantly lower clinical scores and less prominent weight loss compared with controls. A statistically significant improvement in both MCV and the amplitudes of distal and proximal evoked CMAP was observed in the stradomer and IVIg groups. Finally, treatment with both IVIg and stradomer resulted in statistically less inflammation and demyelinating changes in the sciatic nerve as evidenced by lower histological grade. These results reveal the potential of using fully recombinant multimerized immunoglobulin Fc instead of IVIg for treating inflammatory neuropathies.

Different mechanisms underlying changes in excitability of peripheral nerve sensory and motor axons in multiple sclerosis.

INTRODUCTION: Subtle involvement of peripheral nerves may occur in multiple sclerosis. Motor excitability studies have suggested upregulation of slow K+ currents, probably secondary to altered motoneuron properties resulting from the central lesion. This study concentrates on sensory axons. METHODS: Excitability of median nerve axons at the wrist was studied in 26 patients. RESULTS: Sensory recordings were possible in 22 patients, and reduced superexcitability was the sole abnormality. There was no evidence for changes in membrane potential or demyelination. The decrease was significant in patients taking immunomodulatory therapy. These findings could be reproduced in a computer model by changing the gating of fast K+ channels. Motor axon findings were consistent with previously reported increased slow K+ current. CONCLUSIONS: The sensory findings differ from motor findings. They can be explained by a humoral factor, possibly cytokines, which can penetrate the paranode and have been documented to alter the gating of K+ channels.

Chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the commonest treatable neuropathy in the western world. Untreated it may result in severe disability but if diagnosed and treated early there is effective treatment for the majority of patients. Typical CIDP is readily recognised but the diagnosis of other subgroups can be more challenging. The pathology of polyradiculoneuropathies such as CIDP characteristically affects the most proximal regions of the peripheral nervous system, nerve roots and major plexuses. It is important to test these regions with electrodiagnostic studies since routine neurophysiology may not encounter regions of pathology. Although accepted as an autoimmune disorder with an underlying immunopathology involving T cell and B cell responses, there is no agreement on major target antigens; however recent studies have highlighted a role for molecules in non compact myelin which play an essential role in the formation and maintenance of the nodal structures and hence in the function of ion channels central to saltatory conduction. Controlled trials have proven the efficacy of corticosteroid, intravenous immunoglobulin and plasma exchange in the short term and intravenous immunoglobulin also in the long term. Immunosuppressive agents are widely used but their efficacy has not been proven in controlled trials. Recent trials have shown the importance of attempting treatment withdrawal in patients apparently in remission to conserve treatments that are very expensive and in short supply, since a significant proportion of patients may enter long lasting remission following short term therapy. For the relatively small group of patients who do not respond to these first line therapies new agents including monoclonal antibodies may have a role.

The multiple sclerosis work difficulties questionnaire.

BACKGROUND: A better understanding of the workplace difficulties experienced by people with multiple sclerosis (PwMS) may be critical to developing appropriate vocational and rehabilitative programs. OBJECTIVE: We aimed to assess the factor structure, internal consistency and validity of the new Multiple Sclerosis Work Difficulties Questionnaire (MSWDQ). METHODS: Work difficulty items were developed and reviewed by a panel of experts. Using the MSWDQ, cross-sectional self-report data of work difficulties were obtained in addition to employment status and MS disease information, in a community-based sample of 189 PwMS. RESULTS: Exploratory Maximum Likelihood Factor Analysis on the draft questionnaire yielded 50 items measuring 12 factors. Subscale internal consistencies ranged from 0.74 to 0.92, indicating adequate to excellent internal consistency reliability. The MSWDQ explained 40% of the variance in reduced work hours since diagnosis, 40% of the variance in expectations about withdrawing from work, 34% of the variance in expectations about reducing work hours, and 39% of the variance in expectations about changing type of work due to MS. CONCLUSION: The MSWDQ is a valid and internally reliable measure of workplace difficulties in PwMS. Physical difficulties, as well as cognitive and psychological difficulties were important predictors of workplace outcomes and expectations about future employment.