Neuromyelitis optica is a destructive, inflammatory disease of the central nervous system characterized by selective involvement of the spinal cord and optic nerves in most cases. Neuromyelitis optica may also involve the hypothalamus, cerebrum, and the brainstem, especially the medulla (Sato et al 2014).
Historically, the diagnosis of neuromyelitis optica requires both myelitis and optic neuritis. There is usually a time interval between myelitis and optic neuritis, but the deficits may be concomitant. For recurrent attacks, which affect only the optic nerves or spinal cord, but not both, the term “neuromyelitis optica spectrum disorder” has been used. Of course, both myelitis and optic neuritis have other causes, as shown in Table 2, and more specific criteria indicative of neuromyelitis optica are discussed below.
The first manifestation of neuromyelitis optica is optic neuritis in 56% to 76% of patients, transverse myelitis in 13% to 39%, and simultaneous optic nerve and cord involvement in 4% to 11% (Kuroiwa 1985; Whitham and Brey 1985; Ghezzi et al 2004). The interval between visual and cord symptoms can be days (Kuroiwa 1985; Whitham and Brey 1985) or years (Mandler et al 1993; O’Riordan et al 1996). In cases with longer intervals, the diagnosis is understandably less obvious. It is not essential that optic neuritis and myelitis occur concurrently in neuromyelitis optica. One cohort of patients in Brazil had a mean interval of 18 months between optic nerve and cord symptoms. Maximum neurologic deficits occur within 2 to 4 weeks after onset (Adoni et al 2008). Neuromyelitis optica results in visual loss (47% bilateral, 53% monocular), sensory level deficits (24% cervical, 66% thoracic), motor deficits (46% paraparesis, 37% quadriparesis), sphincter disturbances (87%), and respiratory failure (22%) (Whitham and Brey 1985). An expanded disability scale score (EDSS) of 3 occurs at a mean of 6 months, and an EDSS of 6 is reached at a mean of 7 years (Ghezzi et al 2004). This is twice as fast as in multiple sclerosis.
Clinical onset is abrupt. In 68% of cases, a prodrome of headache, low-grade fever, myalgia, fatigue, upper respiratory symptoms, or gastrointestinal symptoms precede neurologic deficits (Kuroiwa 1985; Whitham and Brey 1985; Jeffery and Buncic 1996). Infectious diseases such as mumps, mononucleosis, influenza, varicella, tuberculosis, HIV-1, or syphilis can precede neurologic symptoms (Keefe 1957; Williamson 1975; Khan 1976; Chusid et al 1979; Silber et al 1990; Ahasan et al 1994; Blanche et al 2000; Wilcox et al 2008). Neuropathic pain can be the initial presenting symptom in some patients (Loschner and Snyder 2008; Tsivgoulis et al 2014).
Optic nerve involvement is usually severe, with visual acuity often worse than 20/200 at its nadir. Either central scotomas or peripheral visual field defects can occur, similar to when optic neuritis occurs in multiple sclerosis. The optic disc is edematous when acute inflammation extends past the lamina cribrosa (papillitis) but appears normal in retrobulbar optic neuritis. Ocular pain with eye movement is a prominent symptom of acute optic nerve demyelination.
Spinal cord involvement presents as a rapidly ascending sensory deficit with a sensory level, paraplegia or quadriplegia, and gait disturbance. Myelitis is usually longitudinally extensive, expanding over 3 or more vertebral segments. Variants such as Brown-Sequard syndrome or syringomyelia are rare (Stansbury 1949; Kuroiwa 1985). Autonomic instability results from dysfunction of sympathetic neurons in the spinal cord. Bladder dysfunction usually presents at onset, mainly with urinary retention. Most patients require an indwelling urinary catheter that is maintained for several weeks. Some may require a permanent suprapubic catheter.
Painful tonic spasms can be seen in patients following attacks of transverse myelitis (Sato and Fujihara 2011). An attack of neuromyelitis optica is a medical emergency. Acute respiratory arrest may occur in a high cervical lesion. Complications of paralysis, including dysautonomia, decubitus ulcers, urinary tract infections, and sepsis, are the usual causes of death.
When no further attacks occur after the incipient attacks, the disease is considered monophasic. When a second attack occurs over any period of time, neuromyelitis optica is referred to as relapsing. Neuromyelitis optica is relapsing in 68% and monophasic in 32% of cases (Wingerchuk et al 1999). When neuromyelitis optica is relapsing, the attack rate is 1.3 per year (range 0.1 to 5.5) (Ghezzi et al 2004). Relapses occur within 6 months of the initial attack in 55% of patients, within 18 months in 27%, and after 5 years in 18% (Whitham and Brey 1985). The mean interval until a second attack is 17 months (Ghezzi et al 2004). In contrast to multiple sclerosis, neuromyelitis optica does not have a progressive form (Sato et al 2014).
Risk factors for having future relapses include female sex, short between-attacks interval, systemic autoimmunity, and positive anti-aquaporin-4 antibody (Whitham and Brey 1985; Wingerchuk et al 1999; Weinshenker et al 2006; Levy et al 2014). Young age and male sex are associated with a monophasic course. Respiratory failure occurs more in relapsing patients, especially those with high cervical lesions that compromise the phrenic nerve. The 5-year survival rate is 90% for monophasic and 68% for relapsing patients (Wingerchuk et al 1999). This study has not been repeated, but survival rates are likely better now given earlier recognition of the disease and aggressive treatment. In contrast to adult disease, pediatric neuromyelitis optica has a lower incidence of relapses and has less clinical burden of disease (Jeffery and Buncic 1996; Banwell et al 2008).
Relapsing neuromyelitis optica is often associated with coexisting autoimmunity. About 30% to 50% of patients with neuromyelitis optica have either elevated autoantibodies or autoimmune diseases such as Sjögren disease, systemic lupus erythematosus, Hashimoto thyroiditis, pernicious anemia, connective tissue diseases, ulcerative colitis, or primary sclerosing cholangitis (Wingerchuk et al 1999). For relapsing neuromyelitis optica, the odds ratio for having another autoimmune disease is increased 10-fold (Wingerchuk and Weinshenker 2003). In a review of autoimmunity and neuromyelitis optica, myasthenia gravis was found to coexist with neuromyelitis optica in 2% of cases, often with the diagnosis of myasthenia gravis preceding neuromyelitis optica. In these cases, neuromyelitis optica occurred after thymectomy (Freitas and Guimaraes 2015). Sjögren disease co-occurred with neuromyelitis optica in 16 out of 20 patients in a review, whereas systemic lupus erythematosus and systemic sclerosis co-occurred with neuromyelitis optica in only a few case reports (Freitas and Guimaraes 2015).
Breakthrough disease in otherwise stable patients should prompt an evaluation for urinary tract or gastrointestinal infections. Experiments in mice have shown there is cross-reactivity between aquaporin Z (found in E. coli bacteria) and human aquaporin 4. Thus, a urinary tract infection may cause a relapse due to molecular mimicry (Ren et al 2012). Another lab has shown that the T cell epitope within aquaporin-4 receptors shares homology with a sequence from Clostridium perfringens. Thus, patients presenting with a Clostridium infection may also experience a neuromyelitis optica relapse (Varrin-Doyer et al 2012).
Diagnostic criteria. Since its original description by Devic, there has been considerable debate over whether neuromyelitis optica is a variant of multiple sclerosis. Initially, neuromyelitis optica was recognized as a separate clinical entity (Goulden 1914; Stansbury 1949). Later studies considered it a variant of multiple sclerosis (Ferraro 1937; Putnam and Foster 1942; Lumsden 1957; Kuroiwa 1985). To establish neuromyelitis optica as a distinct entity from multiple sclerosis, several authors have proposed specific diagnostic criteria (Mandler et al 1993; Fazekas et al 1994; O’Riordan et al 1996; Filippi et al 1999; Wingerchuk et al 2006; 2014).
In 2006, the Mayo group proposed diagnostic criteria reflecting the understanding of the serologic and radiographic characteristics of neuromyelitis optica at that time (Wingerchuk et al 2006). In a cohort of patients examined between 1999 and 2005, the criteria were 99% sensitive and 90% specific for neuromyelitis optica, compared to the previous criteria, which were 85% sensitive and 48% specific. Absolute requirements for neuromyelitis optica include having both optic neuritis and myelitis, and 2 of the following 3 criteria:
Due to better understanding of the clinical and radiologic presentations of neuromyelitis optica, new diagnostic criteria were proposed by the International Panel for NMO Diagnosis (Wingerchuk et al 2014). This group met between 2011 and 2014 to revise the previous diagnostic criteria. The group recommended that the term neuromyelitis optica should be replaced with neuromyelitis optica spectrum disorder because the disease manifestations can extend beyond the optic nerves and spinal cord. Secondly, the group recommended dividing NMOSD into 2 groups: an AQ4 antibody-positive group and an AQ4 antibody-negative group. Incorporated into the diagnostic criteria were core clinical features, including the following:
Patients with NMOSD who test positive for AQ4 antibody need 1 core clinical characteristic and no better explanation for symptoms. However, patients with NMOSD who test negative for AQ4 antibody or for whom the antibody test is unavailable require at least 2 of the core clinical characteristics, in addition to all of the following:
As with AQ4 antibody positive patients, there should be no better explanation for the patient’s symptoms.
An abnormal brain MRI, denoting evidence of pathology outside the cord and optic nerves, can occur in neuromyelitis optica. A series of 32 patients with neuromyelitis optica were followed, and after 6 months, MRI was normal in only 16. Fourteen had nonspecific MRI abnormalities, 2 had cervical lesions extending into the brainstem, and 2 actually had an MRI appearance similar to multiple sclerosis (Pittock et al 2006a). Patients with neuromyelitis optica who have an abnormal brain MRI may have other symptoms, including encephalopathy, diplopia, nystagmus, trigeminal neuralgia, or facial numbness, or hearing loss (Sahraian et al 2013). In addition, patients with neuromyelitis optica can initially present with intractable nausea, vomiting, hiccups, fevers, hypothermia, hypersomnia, or narcolepsy due to involvement of the medulla and hypothalamus, respectively (Popescu et al 2011; Sato and Fujihara 2011; Sahraian et al 2013). Patients may present with an encephalopathic syndrome, similar to acute disseminated encephalomyelitis (ADEM) or posterior reversible encephalopathy syndrome (PRES), especially in pediatric cases (Tobin et al 2014).
Classifying patients with neuromyelitis optica who are negative for aquaporin-4 antibody can be a challenge. The term neuromyelitis optica spectrum disorder is applied to the patients who fulfill clinical criteria for neuromyelitis optica but are AQ4 antibody negative. In contrast to patients who are AQ4 antibody positive, patients who are AQ4 antibody negative tend to be mostly Caucasian, do not have a female preponderance, have simultaneous presentation of optic neuritis and transverse myelitis at onset, have monophasic presentations, and typically have less severe long-term visual impairment (Sato et al 2014).