Continuing Education Activity

Neuromyelitis optica spectrum disorder, otherwise known simply as neuromyelitis optica, is an uncommon but distinct clinical entity from the typical forms of optic neuritis. Clinicians need to be aware of these conditions and evaluate them carefully, especially in the setting of a patient presenting with atypical optic neuritis, as the evaluation should include additional serologic testing. The treatment paradigm may involve chronic immunosuppressive therapy to prevent potential long-term. This activity reviews the evaluation and treatment of neuromyelitis optica spectrum disorder by interprofessional.

Objectives:

• Describe the clinical features of neuromyelitis optica spectrum disorder.
• Outline the distinguishing characteristics of neuromyelitis optica spectrum disorder from other forms of optic neuritis.
• Identify the ancillary testing, neuroimaging, and serologic testing that can aid in the proper diagnosis of neuromyelitis optica spectrum disorder.
• Summarize how interprofessional collaboration can improve treatment for neuromyelitis optica spectrum disorder.

Introduction

In recent years the definition of neuromyelitis optica (NMO), or Devic disease, has been expanded as a specific antibody was discovered in the serum of affected patients. Because of this, the term neuromyelitis optica spectrum disorder (NMOSD) is now used to include optic neuritis with spinal cord manifestations and include other neurologic disorders associated with the serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG).[1] 

NMO was first described by Dr. Eugene Devic, who in 1894 described a patient with optic neuritis with accompanying neuromuscular manifestations. That same year, Fernand Gault, who was Devic’s student, published his doctoral thesis presenting a literature review of previous medical cases, including the clinicopathological findings of Dr. Devic’s case.[2] 

For years, multiple sclerosis (MS) was the most prevalent identifiable cause of optic neuritis. Recent discoveries have highlighted rarer, more sinister manifestations of optic neuritis such as NMOSD and myelin oligodendrocyte glycoprotein (MOG), which necessitate additional evaluation and treatment.

Etiology

The etiology of NMOSD is still unclear. In the past, NMOSD was characterized as a variant of MS, but recent studies have elucidated the differences in the disease process, manifestations, and management. Whole-genome sequencing has identified some at-risk genotypes for NMOSD, and two major histocompatibility complexes have been identified.[3]

Epidemiology

The prevalence of NMOSD is approximately 0.3–4.4 per 100,000.[4] NMOSD characteristically occurs in females (80%) and younger patients (age 30-40).[5] Pediatric cases of NMOSD are rare but have been reported occasionally, comprising less than 5% of the reported cases.[6]

NMOSD occurs worldwide, and most information on the disorder is limited to the economically advantaged countries, likely due to the relative ease of access to magnetic resonance imaging (MRI) and targeted antibody testing compared to emerging countries.[7] Worldwide, NMOSD has a variable prevalence among demyelinating diseases. Among all demyelinating diseases, NMOSD comprises only 1% to 2% in the United States and Italy but comprises 13.7% in India and over 30% in Thailand.[7] 

Ethnicity appears to play a role in the phenotype of the disease. A study done in Cuba showed that black African heritage patients with NMOSD were older, had more lesions on MRI, and more relapses than comparable patients of other ethnicities.[8] The variations in the epidemiology of this disease should give the clinician additional information to consider the diagnosis of NMOSD, especially if a patient presents with a suspected demyelinating disease but is of Asian heritage or is older and of African descent.

NMOSD can correlate with other auto-immune diseases such as systemic lupus erythematosus, celiac disease, Sjögren syndrome, and sarcoidosis.[9] NMOSD attacks have been shown to occur in 20-30% of cases after an environmental trigger, such as post-vaccination or post-infection.[10][11]

Pathophysiology

NMOSD is an inflammatory disease that primarily affects the optic nerve and spinal cord. In the past, NMO/NMOSD was regarded by some as a variant of MS, but the discovery of IgG antibodies against aquaporin-4 has caused NMOSD to be recognized more broadly as a distinct entity with a unique mechanism and pathogenesis.[1][12] 

Aquaporin 4 (AQP4) is a membrane-bound protein with a high concentration in certain parts of the central nervous system, such as the optic nerve, the spinal cord, and the area postrema.[13] In essence, NMOSD is an autoimmune demyelinating astrocytopathy where the AQP4-IgG mediates perivascular lymphocytic infiltration leading to axonal loss with a preference for the aforementioned at-risk areas.[14]

History and Physical

Classically, optic neuritis occurs in a younger, white patient and will present with an episode of acute onset, painful, monocular vision loss, with a relative afferent pupillary defect in the affected eye. The clinical exam of a patient with acute optic neuritis should always have the visual acuity, pupils, and intraocular pressure tested, followed by a thorough neuro-ophthalmic exam. A fundus exam will typically reveal optic nerve head elevation on the affected side. 

Due to the recent literature highlighting the less common but more sinister causes of optic neuritis such as NMOSD or MOG, patients with acute optic neuritis should be specifically asked additional questions on the review of systems. If the patient suffers from intractable hiccups, unexplained nausea or vomiting, or symptomatic narcolepsy, these could be clues that the optic neuritis may be caused by NMOSD.[1][15]

NMOSD may alternatively present less classically, and the AQP4-IgG can be present in other disorders. These disorders can present as isolated longitudinal extensive transverse myelitis, brainstem clinical manifestations, brainstem encephalitis, monophasic optic neuritis, or recurrent optic neuritis.[9] A patient presenting with neurologic manifestations of brainstem lesions (intractable hiccups, vomiting, narcolepsy) should have a complete neurologic exam.

Evaluation

The discovery of the aquaporin-4 antibody has led to serologic testing for this antibody, taking a key role in diagnosing NMOSD.[12] NMOSD is evaluated by clinical examination and serologic testing for the AQP4-IgG as well as MRI with and without gadolinium. Diagnosis is based on core clinical characteristics and supplemented by additional testing, and several criteria exist. Because of this, the international consensus diagnostic criteria was established in 2015, which separated NMOSD into AQP4-IgG status (with testing, without testing, or unknown) and defined clinical and MRI characteristics of NMOSD.[1]Color vision testing may show a decrease in color vision, and visual field evaluation may show a central scotoma. Ancillary testing with optical coherence tomography can aid in the diagnosis and may reveal a thinner nerve fiber layer than in MS cases.[16]

MRI with and without gadolinium can aid in the evaluation of NMOSD. Characteristic findings in optic neuritis include white matter lesions and optic nerve enhancement (T2-hyperintense lesions or T1-weighted contrast-enhancing images).[1] Other MRI manifestations of NMOSD include acute myelitis, which shows longitudinal intramedullary lesions or focal spinal cord atrophic segments.[1] 

Those patients with area postrema syndrome will demonstrate lesions at the dorsal medulla region or area postrema. Those with acute brainstem syndrome will show lesions at the peri-ependymal brainstem. When MRI lesions show enhancement in the optic nerves and spinal cord, the main differential diagnosis of NMOSD is MS. It is important to distinguish these clinical entities as the prognosis and management differ considerably, and some MS drugs can worsen NMOSD.[17][18][19] 

In contrast with MS, NMOSD has some distinct radiologic features that differentiate it as a clinical entity. NMOSD shows longitudinal spinal cord lesions extending over three or more segments, while MS typically has short, multiple lesions.[20]

Treatment / Management

Due to the relative scarcity of NMOSD cases, consensus guidelines are challenging to establish. Most case series recommend a short course of immunosuppressive therapy (usually a corticosteroid), followed by some form of chronic immunosuppressive therapy.[21] Treatment of the acute phase of NMOSD flare usually involves the use of intravenous steroids such as methylprednisolone, often used in high doses (500-100 mg daily) for 5-10 days. Others studies advocate for plasmapheresis treatment (55 ml/kg) as well as intravenous immunoglobulin.

Chronic immunosuppressive therapy can be accomplished with azathioprine or rituximab as first-line agents. Second-line agents may include mycophenolate or methotrexate.[9] These second-line agents may be advantageous due to their less frequent dosing. Newer biologic agents are directed against specific immune mediators such as anti-IL-6, anti-complement, or anti-AQP4-IgG.[9] A retrospective multicenter analysis showed reductions in relapse rate with rituximab, mycophenolate, and azathioprine (with prednisone) of 88.2%, 87.4%, and 72.1%, respectively.[22]

Differential Diagnosis

The differential diagnosis of a patient with optic neuritis typically includes MS, NMOSD, and MOG. MS is the most common of these entities and should therefore be ruled out first. Still, the clinician should be especially aware of the other two as they typically portend a less favorable prognosis and different treatment.

Because NMOSD can also present without ocular symptoms, the presentation and differential of NMOSD broaden significantly when the patient does not have ocular involvement. Still, the primary clinical entity on the differential is MS, but theoretically, any lesion causing MS-like symptoms could be on the differential of NMOSD.

Prognosis

NMOSD has a variable course and prognosis.[15] It is either relapsing (80% to 90%) or monophasic.[10] Some patients suffer chronic disability as a result of relapsing episodes. Studies demonstrated that up to 22% of patients fully recover, while 7% do not show any recovery.[15]

Complications

Complications of NMOSD include visual field defects and motor impairment, with potential blindness and irreversible motor deficits.[23] In severe cases, myogenic respiratory failure is the cause of increased mortality.[15]

Consultations

• Neurology
• Neuroophthalmology

Deterrence and Patient Education

Patient's diagnosed with NMOSD should be aware of the potential complications of the disorder, the comorbid associated autoimmune conditions, and the importance of medication compliance and follow-up.[10] Currently, there are no known preventive strategies for NMOSD.

Enhancing Healthcare Team Outcomes

The neuro-ophthalmologist is often initially involved in diagnosing patients with NMOSD, but patients may also initially present to a primary care provider or neurologist. It is essential to consult with an interprofessional team that includes the ophthalmologist, neurologist, and primary care provider to provide adequate care for these patients. The nurse's role is vital as these patients often require hospital admission with rapid induction of intravenous steroids. The pharmacist will be critical in adjusting the appropriate steroid dose for the patient, which will need to be done considering the other medical issue of the patient. The radiologist is also key in making the appropriate diagnosis based on the MRI results. To date, there are no large randomized clinical trials on the diagnosis and treatment of NMOSD; therefore, we rely primarily on consensus based on expert opinion. Diagnostic criteria are based on historical and case-control studies for diagnosis.[1] [Level 4]