NEUROMYELITIS OPTICA

Signs and Symptoms

Neuromyelitis optica (NMO) was first described by Albutt in 1870, but the term was not applied until 1894 by Devic; hence the alternate name Devic’s disease.1,2 It wasn’t until 2004 that a serologic marker was identified, allowing NMO to be differentiated from multiple sclerosis (MS) rather than being considered a subset of the condition.3

Patients will manifest signs and symptoms characteristic of demyelinating disease, including the clinical hallmarks of optic neuritis and transverse myelitis. The painful vision loss seen in NMO is quite severe, with acuity typically worse than 20/200; recovery is less complete than as seen in MS. In contrast to optic neuritis seen in adults with MS, bilaterality is common.4 Other findings associated with NMO include weakness and paresthesia of the limbs, severe radicular back pain, spastic diplegia, bladder paralysis, loss of sphincter control, paroxysmal painful spasms of the limbs and trunk, intractable nausea and intractable hiccups.

Respiratory failure is the main cause of death in patients with NMO.1 Within five years of onset, 50% of NMO patients are bilaterally blind and cannot walk unassisted.5

There are numerous autoimmune conditions associated with NMO, including myasthenia gravis, celiac disease, ulcerative colitis, sclerosing cholangitis, systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid antibody syndrome, Sjögren’s syndrome, autoimmune hypothyroidism, immune thrombocytopenic purpura, pernicious anemia, narcolepsy, pemphigus foliaceus, alopecia areata, psoriasis, scleroderma, dermatitis herpetiformis, polymyositis, chronic inflammatory demyelinating polyneuropathy, paraneoplastic disorders, insulin dependent diabetes mellitus, autoimmune encephalitis and sarcoidoisis.6,7

NMO has a female predilection, with a ratio of women to men of 9:1.5 There is also a higher incidence in people of color.5 While NMO is considered within the spectrum of demyelinating diseases, the median age of onset is 39 years, which is approximately 10 years later than in MS. However, NMO has been known to develop both in children and the elderly.2,6

NMO can follow either a monophasic or relapsing course. In the monophasic course, optic neuritis will concurrently accompany transverse myelitis or the two conditions will develop within a short period of time of each other. This then may be the only manifestation of the disease. Should no other occurrences develop within three years, the patient is considered to have a monophasic course. In the relapsing form, patients will have recurrences of the autoimmune inflammation and subsequent accumulation of disability. Approximately 80% to 90% of patients will manifest the more severe relapsing form of NMO.5 The five-year mortality rate of relapsing NMO is 32% compared to 10% for the monophasic form of the disease.8

Pathophysiology

Neuromyelitis optica is an immune-mediated, chronic inflammatory disorder of the central nervous system (CNS) affecting both white and gray matter, preferentially attacking the myelin of the optic nerve and spinal column. It is thought to be triggered by an environmental factor such as infection in genetically susceptible individuals.8

Once considered a variant of MS, NMO is now recognized as a separate demyelinating disorder with pleiotropic presentations, due to the identification of a specific autoantibody response against the astrocyte water channel aquaporin-4 (AQP4) in the majority of individuals with the disease.3,9-11

Aquaporin is the predominant water channel in the CNS, regulating the flow of water in cells. The aquaporin protein is in high concentration in the optic nerves, spinal cord, hypothalamus and periventricular regions of the brain. AQP4 is expressed in astrocytes and astrocytic processes surrounding small blood vessels. The AQP4 autoantibodies, also commonly known as NMO-IgG antibodies, bind to the astrocytic foot processes, recruiting and activating humoral immune system including the complement system, which leads to the mobilization of polymorphonuclear cells, inflammation and tissue edema.5,6

In contrast to multiple sclerosis episodes, NMO attacks are mediated by B-cells rather than T-cells, further differentiating the two conditions. The cellular infiltration initiated by NMO-IgG antibodies target the astrocytes in the CNS, causing cytopathic destruction of these cells. Additionally, vascular destruction, tissue necrosis, demyelination, and gliosis will accompany the inflammatory process.5,6,8-13 The subsequent inflammatory reaction in the optic nerves gives rise to optic neuritis and the spinal cord damage results in transverse myelitis. The non-ocular physical signs and symptoms will be dictated by which spinal cord segments are involved.

Management

Proper diagnosis of NMO and differentiation from MS is crucial to proper management, especially since the two diseases are treated differently and some MS treatments may worsen the course of NMO. Contrast-enhanced magnetic resonance imaging (MRI) of the brain and entire spinal cord is obligatory in the diagnostic evaluation. During an acute attack, MRI will show an enhancing central cord lesion extending over three or more cord segments. There will also be enhancement of the optic nerves if an optic neuritis is present.

It is currently accepted that a diagnosis of NMO can be made with high specificity if two absolute criteria—optic neuritis and acute myelitis—are present, and additionally two of the following three supporting criteria: (1) normal brain MRI or MRI brain abnormalities not consistent with MS, (2) spinal cord MRI with contiguous T2-weighted signal abnormality extending over three or more vertebral segments, (3) NMO-IgG serpositivity.1,5,6

There exist some patients with recurrent optic neuritis or recurrent longitudinally extensive myelitis alone who are also positive for NMO-IgG antibody. Additionally, they may also have abnormal brain MRI indicative of brainstem encephalopathy but do not meet the classic diagnostic criteria of NMO. Due to the NMO-IgG seropositivity and often eventual progression to classic NMO in many cases, these individuals are considered to be within the NMO-spectrum disorder classification.14,15

Optical coherence tomography (OCT) can be helpful diagnostically, demonstrating thinning of the retinal nerve fiber layer (RNFL). OCT shows more severe retinal damage with thinner average RNFL, particularly of the superior and inferior quadrants after optic neuritis episodes in neuromyelitis optica than in relapsing-remitting multiple sclerosis.16-18

There is no cure for NMO and no FDA-approved therapies, though several immunomodulators have demonstrated effectiveness in managing the disease. The treatment goals for NMO involve rescue therapy for the acute phase of the disease and long-term disease-modifying immunomodulatory therapy to reduce neurologic disability.

During an acute attack of optic neuritis and myelitis, prompt rescue therapy with intravenous corticosteroids may reduce the degree of permanent tissue damage and neurological disability. Typical therapy involves 1gm/day of methylprednisolone for five days. If the patient’s status does not improve, the next immediate step is five to seven cycles of therapeutic plasma exchange (TPE). This is crucial to prevent neurogenic respiratory failure. While corticosteroids exert global anti-inflammatory and immunosuppressive effects, TPE removes autoantibodies, immune complexes and inflammatory mediators from the patient’s plasma.1,6,8,19

Beyond rescue therapy for the acute phase of the disease, there exists an immediate need for immunomodulatory therapy to reduce the accumulation of neurologic disability. Numerous reports indicate the effectiveness of azathioprine (Imuran) in reducing the relapse rate and ameliorating the neurologic disability in patients with NMO. As such, azathioprine is considered the first-line immunomodulatory therapy for NMO. The full effect of azathioprine may be delayed for several months. For this reason, oral steroids are typically used concurrently.

Rituximab (Rituxan) has shown good effect and is generally considered to be the second-line agent for NMO. Additionally, other non-specific immunosuppressant drugs, such as methotrexate, tacrolimus, mycophenolate mofetil and mitoxantrone have demonstrated effectiveness.8-11,13,19-24 Standard MS therapies, including beta-interferons and glatiramer acetate, have been used in patients with NMO, but to little effect. In fact, it appears that interferon beta may worsen the course of NMO, underscoring the importance of differentiating the conditions.1

Clinical Pearls

Bilateral simultaneous optic neuritis should raise suspicion for NMO.

Incomplete recovery of visual function from MS-suspected optic neuritis should raise suspicion for NMO.

NMO should be considered in patients who have repeated attacks of optic neuritis yet fail to show MRI brain lesions consistent with MS.

Optic neuritis arising from MS does not necessarily need corticosteroid therapy, but optic neuritis arising from NMO does.

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6. Trebst C, Jarius S, Berthele A, et al. Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol. 2014;261(1):1-16.

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14. Sato DK, Lana-Peixoto MA, Fujihara K, de Seze J. Clinical spectrum and treatment of neuromyelitis optica spectrum disorders: evolution and current status. Brain Pathol. 2013;23(6):647-60.

15. Jacob A, McKeon A, Nakashima I, et al. Current concept of neuromyelitis optica (NMO) and NMO spectrum disorders. J Neurol Neurosurg Psychiatry. 2013;84(8):922-30.

16. de Seze J, Blanc F, Jeanjean L, et al. Optical coherence tomography in neuromyelitis optica. Arch Neurol. 2008;65(7):920-3.

17. Ratchford JN, Quigg ME, Conger A, et al. Optical coherence tomography helps differentiate neuromyelitis optica and MS optic neuropathies. Neurology. 2009;73(4):302-8.

18. Naismith RT, Tutlam NT, Xu J,et al. Optical coherence tomography differs in neuromyelitis optica compared with multiple sclerosis. Neurology. 2009;72(12):1077-82.

19. Fujihara K. Treatment of neuromyelitis optica. Nihon Rinsho Meneki Gakkai Kaishi. 2012;35(2):129-35.

20. Costanzi C, Matiello M, Lucchinetti CF, et al. Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology. 2011;77(7):659-66.

21. Uzawa A, Mori M, Kuwabara S. Neuromyelitis optica: concept, immunology and treatment. J Clin Neurosci. 2014;21(1):12-21.

22. Nomura K. Treatment of neuromyelitis optica. Nihon Rinsho. 2013;71(5):829-38.

23. Kim SH, Huh SY, Lee SJ, et al. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol. 2013;70(9):1110-7.

24. Ramanathan RS, Malhotra K, Scott T. Treatment of neuromyelitis optica/neuromyelitis optica spectrum disorders with methotrexate. BMC Neurol. 2014;14:51.