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.