Neuromyelitis Optica

Marcelo Matiello¹ and Brian G. Weinshenker²

¹ Department of Neurology, Massachusetts General Hospital and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

² Department of Neurology, Mayo Clinic, Rochester, MN, USA

Introduction

Neuromyelitis optica (NMO) is a severe idiopathic autoimmune disease of the central nervous system (CNS). For reasons not completely understood, NMO preferentially affects the optic nerves and spinal cord causing relapses of optic neuritis (ON) and of transverse myelitis associated with a long lesion in the spinal cord, typically extending three or more spinal segments (longitudinally extensive transverse myelitis, LETM).

For a century since its original recognition as a clinical entity by Devic (1894) and Gault (1894), NMO was regarded as a monophasic disease characterized by near-simultaneous bilateral ON and myelitis in quick succession without recurrence, but with increasing understanding of its pathogenesis and improved ability to differentiate it from prototypic multiple sclerosis (MS), it is now believed to be a relapsing disease in the majority of affected individuals. Whether these two forms are the same disease or pathophysiologically different is a matter of debate. The boundaries between the monophasic form and the relapsing form are unclear, which complicates an analysis of this issue.

Most NMO patients are seropositive for the highly specific autoantibody NMO-IgG. NMO-IgG targets aquaporin-4 (AQP4), leading to complement-dependent cytotoxicity, extensive demyelination, and necrosis, although inflammatory cells, including neutrophils and eosinophils, seem to play an important role. In vitro and animal studies have now shown that NMO-IgG is not just a diagnostic biomarker for NMO; it is an essential component of NMO pathophysiology.

In this chapter, we discuss the current status of the diagnosis and treatment of NMO. It is likely that the rapidly increase in understanding of NMO-IgG-driven pathophysiological mechanisms may lead to specific therapies in the near future.

Diagnosis

Demographic features

Although considered a rare disorder, NMO is vastly underrecognized. Many cases now regarded to be NMO spectrum disorders are diagnosed as MS, isolated or recurrent transverse myelitis, idiopathic or recurrent ON, ADEM, or connective tissue disease-associated myelitis (e.g., lupus or Sjögren myelitis). Population-based studies have recently estimated the incidence and prevalence. In the French Indies, NMO has an incidence of 0.20/100,000 (95% CI, 0.05–0.35) and prevalence of 4.2/100,000 (95% CI, 3.7–5.7). In Southern Denmark, the yearly incidence rate of NMO was estimated to be 0.4 per 100,000 person-years (95% CI, 0.30–0.54) and the prevalence was 4.4 per 100,000 (95% CI, 3.1–5.7) in a largely white population. While MS prevalence differs markedly from country to country, likely due to a combination of genetic and environmental factors, NMO prevalence seems to be similar throughout the world.

NMO typically begins in late middle age, but it may also occur in children. The relapsing form of NMO is eight times more frequent in women than in men, while the monophasic form affects women and men equally.

NMO patients infrequently have relatives with this condition, but familial occurrence is more common than expected from its frequency in the general population. Based on clinical symptoms and frequency of NMO-IgG, the familial form of the disease is indistinguishable from sporadic NMO detection. In a series of 14 families with NMO, no more than 2 generations were affected in any family, and all but 1 family with multiple cases of NMO had only 2 affected members.

Clinical characteristics

Acute attacks

The core clinical features of NMO are acute attacks of ON and myelitis, which are usually more disabling than when they occur as manifestations of prototypic MS.

The occurrence of bilateral simultaneous ON or sequential ON in rapid succession is more suggestive of NMO than MS. Also, the persisting visual deficits are more severe in NMO. Other clinical characteristics of the NMO ON attacks, that is, pain, pattern of visual loss, occurrence of positive visual phenomena, and funduscopic findings, do not distinguish MS- and NMO-related ON.

Myelitis attacks are frequently accompanied by longitudinally extensive (longer than three vertebral segments) lesions on MRI scan and more frequently cause complete (symmetrical and with motor, sensory, and sphincter involvement) than partial myelitis-related deficits. Lhermitte’s symptom (paresthesias in the spine or limbs elicited by neck flexion), paroxysmal tonic spasms, and radicular pain often accompany the myelitis. Paroxysmal dystonic spasms that respond to carbamazepine occur much more frequently and severely in patients with NMO than in those with MS. Pain is also much more frequent in NMO than in MS.

Brainstem syndromes are also common, as are hypothalamic lesions, and this likely reflects areas of high expression of AQP4 in the CNS. Attacks of severe and intractable hiccough and of nausea and vomiting lasting weeks to months are particularly characteristic of NMO. These may be the presenting symptoms, and result from inflammation of the area postrema. Respiratory failure due to acute cervical myelitis or brainstem demyelination is the most common cause of NMO-related death. Death in this context has become less frequent due to improved prophylaxis of attacks with long-term immunosuppression and improved management of acute relapses (see section Treatment).

Hypothalamic manifestations of NMO include narcolepsy, associated with hypocretin deficiency, and syndrome of inappropriate antidiuretic hormone (SIADH). SIADH accompanied 16% of NMO attacks in a series of 43 NMO cases; SIADH occurred in 12% of initial NMO attacks.

Symptomatic brain lesions are compatible with a diagnosis of NMO, but are unusual at disease onset. Occasionally, NMO patients may develop encephalopathy due to transient vasogenic brain edema and may be diagnosed as having posterior reversible encephalopathy syndrome.

Long-term course/disability

The clinical course of NMO is characterized by the stepwise deterioration in the visual, motor, sensory, and bowel/bladder functions as the result of collective attack-related neurological disability. Unlike MS, a progressive course of gradually worsening disability rarely supervenes in the later phases of NMO. Therefore, if attacks can be prevented, the prognosis may be good.

Benign cases of NMO do exist but are much less common after lengthy follow-up than in patients with MS. Eleven of 175 (12%) of NMO patients had a score of 3 or lower on the Expanded Disability Status Scale after a 10-year follow-up. Nonetheless, 3 of these 11 patients experienced a disabling attack of NMO after 15 years of follow-up.

Chronic pain is also more common in NMO than MS. In a comparative study of 37 patients with NMO and 51 with MS, the percentage of patients who reported pain was higher in NMO (83.8%) than in MS (47.1%) (p = 0.0004). The Pain Severity Index score was greater in NMO than in MS (NMO 3.8 ± 2.8, MS 1.6 ± 2.1, p < 0.0001) when the analysis was confined to patients with a history of myelitis.

Association with autoimmunity

Patients with NMO have other autoimmune diseases more frequently than do patients with MS. The most common is autoimmune thyroiditis. However, NMO has been associated convincingly with myasthenia gravis and quite convincingly with celiac disease, lupus, and Sjögren syndrome. The clinical features of the neurological syndromes in connective tissue-associated NMO are similar to those seen in uncomplicated NMO. NMO patients with concomitant autoimmune diseases had similar frequency of NMO-IgG seropositivity as did those without such diseases. In contrast, patients with other autoimmune diseases without clinical features of NMO were consistently seronegative for such autoantibodies. The immunological basis of the association of NMO and other diseases is unknown but is likely due to common genetic and/or environmental susceptibility factors.

Diagnostic criteria

NMO

The diagnosis of NMO has been facilitated since diagnostic criteria were defined. The most recent set of criteria incorporates NMO-IgG testing, which has become available worldwide. The diagnostic criteria no longer specify an arbitrary interval between episodes of ON and transverse myelitis. However, because occurrence of ON and myelitis do not differentiate between NMO and opticospinal MS, the criteria included specificity criteria that usually distinguish between NMO and prototypic MS. The most important clinical criterion for such differentiation is the presence of a longitudinally extensive spinal cord lesion (MRI T2 signal lesion extending over three or more vertebral segments, in the context of an acute myelitis attack). The most important nonclinical criterion is the presence of autoantibodies directed to AQP4. Symptomatic brain lesions are compatible with a diagnosis of NMO but are unusual at disease onset.

NMO spectrum disorder

NMO-IgG serology allows the identification of conditions named NMO spectrum disorders. Patients that are NMO-IgG positive and have one of the conditions listed below likely have similar clinical course and response (or lack of response) to therapy as do patients meeting criteria for NMO.

Limited (or inaugural) forms of NMO:
1. Idiopathic single or recurrent events of LETM
2. Isolated, recurrent or simultaneous bilateral ON
ON or LETM associated with systemic autoimmune disease
ON or myelitis associated with brain lesions typical of NMO (hypothalamic, corpus callosum, brainstem)

Opticospinal MS

Uncertainty persists, at least in some circles, as to whether Asian opticospinal MS is distinct from NMO, even after NMO diagnostic criteria and discovery of NMO-IgG have been reported. Some reports suggest that as currently defined (ON, myelitis, no brain lesions, or perhaps only minor brainstem lesions), opticospinal MS is heterogeneous and probably an admixture between NMO and MS. Multiple studies have shown that regardless of whether patients are labeled as having NMO or OSMS, those who have LETM (isolated or recurrent), intractable vomiting, and hiccough and are seropositive for NMO-IgG have a worse prognosis, higher frequency of severe visual loss, and poor response to interferon-beta. Patients with this clinical and serological profile should be treated with immunosuppressive drugs rather than immunomodulatory MS therapies. Interferon-beta has been convincingly shown to be ineffective for attack prevention in NMO. Recent studies suggest that natalizumab is ineffective, and possibly harmful, possibly because it does not prevent the influx of neutrophils that seem to play an important role in the pathogenesis of NMO.

Differences in relapsing versus monophasic NMO

Contemporary studies classify NMO as either monophasic (no further attacks after ON and TM index events) or relapsing. Predicting monophasic versus relapsing disease course is important, since monophasic NMO patients do not require long-term immunosuppression. Prototypic monophasic disease patients develop uni- or bilateral ON and myelitis within a very short interval, typically within a month or two, but the limits of monophasic disease and its distinction from relapsing disease are not entirely resolved. In a large series of NMO patients, demographic factors (female sex, older age of disease onset), less severe motor impairment with the first myelitis attack, and a longer interval between the first and second attacks were associated with relapsing rather than monophasic disease. In prospective studies, the presence of NMO-IgG also predicted recurrences after a single episode of LETM and of recurrent ON.

Tags: Multiple Sclerosis and CNS Inflammatory Disorders

Aug 10, 2016 | Posted by admin in NEUROLOGY | Comments Off