Clinical Medicine 2019 Vol 19, No 2: 169–76 REVIEW N e u r o m y e l i t i s o p t i c a s p e c t r u m d i s o r d e r s Authors: S a i f H u d a , A D a n W h i t t a m , B M a n e e s h B h o j a k , C J a y n e C h a m b e r l a i n , D C a r m e l N o o n a n , E A n u J a c o b F , G a n d H R a c h e l K n e e n Neuromyelitis optica spectrum disorder (NMOSD) is an oedema from C1-T4 with contrast enhancement. His cerebrospinal uncommon antibody-mediated disease of the central nervous fluid demonstrated a lymphocytic pleocytosis (white cell count system. Long segments of spinal cord infl ammation (myelitis), 40 cells/mm 3 ) with normal protein, glucose ratio, and negative severe optic neuritis, and/or bouts of intractable vomiting and oligoclonal bands. Acute inflammatory transverse myelitis was hiccoughs (area postrema syndrome) are classic presentations diagnosed and he was given 1 gram of IV methylprednisolone for ABSTRACT of the disease and may alert the clinician to the diagnosis. 5 days. His serum was sent for aquaporin-4 (AQP4) and myelin Untreated, approximately 50% of NMOSD patients will be wheel- oligodendrocyte glycoprotein (MOG) antibodies (Abs). The steroid chair users and blind, and a third will have died within 5 years of treatment did not result in significant improvement. There was their fi rst attack. Unlike multiple sclerosis, a progressive clinical concern of ascending myelitis and respiratory compromise. He course is very unusual and the accrual of disability is related to was given 5 cycles of plasma exchange and continued on a relapses. Approximately 75% of patients have antibodies against tapering course of prednisolone. After 4 weeks his arm strength aquaporin-4, a water channel expressed on astrocytes. Relapses had improved but he remained paraplegic and was transferred are treated aggressively to prevent residual disability with high- to a rehabilitation facility. During his admission he complained of dose steroids and often plasma exchange. Relapse prevention is severe itching (to the point of excoriation) over his chest as well as crucial and achieved with long-term immuno suppression. In this painful lower limb spasms, which were successfully treated with article we review the pathogenesis, clinical features, diagnosis gabapentin and carbamazepine respectively. His AQP4-Abs were and management of NMOSD. positive and he was commenced on mycophenolate mofetil with prednisolone to prevent further relapses. At follow-up 3 months K E Y W O R D S : Neuromyelitis optica , aquaporin-4 , antibody later he remained relapse-free but wheelchair-dependent with a spastic paraplegia. He used intermittent self-catheterisation four times per day and required regular bowel irrigation for Case vignette constipation. He was commenced on baclofen for spasticity and sildenafil for erectile dysfunction. Interestingly, following plasma A 24-year-old male developed nausea, vomiting, and pain exchange his nausea and vomiting resolved completely suggesting between his shoulder blades with leg weakness. Over the that the vomiting may have been AQP4-Ab mediated area next 72 hours he developed rapidly progressive leg weakness, postrema syndrome. numbness, and urinary retention, and attended his local emergency department. He was admitted but quickly progressed Introduction to flaccid tetraplegia. There were no preceding infections or inciting events. His medical history was unremarkable except Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon for ‘cyclical vomiting syndrome’. Numerous investigations and antibody-mediated disease of the central nervous system. In the treatments including a cholecystectomy had been unsuccessful. UK patients often present to and are first assessed in emergency He had urgent magnetic resonance imaging (MRI) of the departments or acute medical units (AMU). Early diagnosis and spine, which demonstrated a long segment of high T2 signal and treatment are important to reduce the risk of long-term disability and death. The term neuromyelitis optica (derived from neuro-myélite Authors: A post-CCT neuroimmunology fellow, Walton Centre NHS optique aiguë) was first described by Eugène Devic and his Foundation Trust, Liverpool, UK ; B neuroimmunology clinical fellow, doctoral student Fernand Gault in 1894.1 The disease was Walton Centre NHS Foundation Trust, Liverpool, UK ; C consultant therefore previously referred to as Devic’s disease. Until recently neuroradiologist, Walton Centre NHS Foundation Trust, Liverpool, UK ; it was unclear whether neuromyelitis optica was a separate D Technical Specialist Analytical Development, Ipsen, Wrexham, UK ; disease or merely a more severe form of ‘optico-spinal’ multiple E consultant neuro-ophthalmologist, Walton Centre NHS Foundation sclerosis (MS). It was not until 2004 when the putative antigenic Trust, Liverpool, UK ; F consultant neurologist, Walton Centre NHS target, the aquaporin-4 water channel was identified, and Foundation Trust, Liverpool, UK ; G NMOSD clinical lead, Walton the two diseases could be reliably distinguished through the Centre NHS Foundation Trust, Liverpool, UK ; H consultant paediatric detection of AQP4-Abs. 2 The latest iteration of diagnostic neurologist and neuromyelitis optica spectrum disorder paediatric guidelines unify antibody-negative and positive forms under the 3 clinical lead, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK umbrella of NMOSDs. © Royal College of Physicians 2019. All rights reserved. 169 CCMJv19n2-Huda.inddMJv19n2-Huda.indd 116969 77/18/19/18/19 110:040:04 PPMM Saif Huda, Dan Whittam, Maneesh Bhojak et al Since the discovery of AQP4-Abs there have been over 3,000 (a) publications on NMOSD in the PubMed database alone. More Vascular endothelium recently another antigenic target, myelin oligodendrocyte Blood- 4 AQP4 brain glycoprotein (MOG) has been identified in patients with NMOSD. barrier This review aims to provide a basic overview of the pathogenesis, diagnosis, and management of NMOSD. Astrocyte Oligodendrocyte P a t h o g e n e s i s AQP4 is the most widely expressed water channel in the brain, spinal cord, and optic nerves. Within the brain, AQP4 is located in regions in contact with cerebrospinal fluid, and is specifically Neuron localised to the foot processes of astrocytes at the blood brain Myelin sheath Axon MOG barrier. 2,5 AQP4 is also present in the collecting ducts of the kidney, (b) Complement parietal cells of the stomach, airways, secretory glands, and B-cell skeletal muscle. 6 However, these organs are relatively protected from antibody-mediated damage due to local complement inhibitors which are absent in the brain. 7 AQP4-IgG AQP4-Abs are predominantly of the IgG1-isotype. Experimental Astrocyte damage data suggest that AQP4-Abs induce interleukin-6 (IL-6) production in astrocytes expressing AQP4, and that IL-6 signalling to Neutrophil endothelial cells reduces blood-brain barrier function. 8 O n c e bound to the extracellular domain of the AQP4 receptor, AQP4-Abs result in complement- and cell-mediated astrocytic damage, in 9 addition to internalisation of the glutamate transporter EAAT-2. Eosinophil Relave preservaon The astrocyte is subsequently rendered powerless, ultimately of myelin culminating in withdrawal of support for surrounding cells such as oligodendrocytes and neurons. Granulocyte infiltration ensues, (c) Possible role of complement? B-cell matched by oligodendrocyte damage and demyelination (Fig 1 ). 10 In contrast to MS, the demyelination that is seen in NMOSD is a secondary event and occurs as a consequence of primary damage to astrocytes. Epidemiological and genetic factors MOG-IgG The reported incidence and prevalence of NMOSD are dependent on geographical location and ethnicity. Asians and those of African ancestry are at increased risk, with high mortality rates reported in the latter. 11,12 The incidence and prevalence of NMOSD ranges from 0.05–0.40 and 0.52–4.4 Lymphocyte Myelin loss per 100,000 people respectively.13 In contrast to MS, a latitude gradient for the prevalence of NMOSD has not been Fig 1. (a) This fi gure illustrates the sites of expression of aquaporin-4 substantiated. 14 As with many autoimmune diseases, females (AQP4) and myelin oligodendrocyte glycoprotein (MOG) in the central are more susceptible than males (3:1–9:1). 15 A female hormonal nervous system (CNS). AQP4 is expressed on astrocyte 'foot-like' basis for this association may be a factor but requires further processes at the blood-brain barrier. MOG is expressed on oligodendro- cytes on the outermost lamellae of myelin sheaths. (b) AQP4-Abs (IgG) study. 16 The median age at presentation is 39 years, but 15–20% are produced systemically by mature B-cells, and upon crossing the of patients may present to paediatricians (under 16 years) or blood-brain barrier, activate complement-mediated astrocyte damage. 15 elderly care physicians (greater than 65 years). C l u s t e r i n g o f There is relative preservation of myelin initially. The infl ammatory NMOSD in families is rare but recognised, suggesting complex milieu consists of neutrophils and eosiniphils. (c) MOG-Abs (IgG) are genetic susceptibility.17 A recent whole-genome sequence study also produced outside the CNS, and causes demyelination by mecha- identified genetic variants in the major histocompatibility region nisms that are poorly understood. Reprinted with permission from Whittam that contribute to NMOSD aetiology. 18 Approximately one in D, Wilson M, Hamid S et al . What’s new in neuromyelitis optica? A short review for the clinical neurologist. J Neurol 2017;264:2330–44. four patients with AQP4-Ab positive NMOSD have another coexisting autoimmune disease, eg myasthenia gravis, systemic lupus erythematosus (SLE), Sjogren’s and coeliac disease.19–22 Accordingly, specialties such as rheumatology should have a low threshold for testing AQP4-Abs; eg SLE patients with intractable Clinical presentation vomiting/hiccoughs or optic neuritis without obvious cause.