Optic neuritis  Visual loss is generally more severe in NMO than in MS (class IV) [42]. The occurrence of bilateral simultaneous ON or sequential ON in rapid succession is more suggestive of NMO (class IV) [40]. Other clinical features of ON including pain, pattern of visual loss, occurrence of positive visual phenomena such as movement-induced phosphenes and findings on examination do not differ from MS-related ON attacks (class IV) [8]. Blindness in at least one eye developed in 60% of recurrent (mean follow-up time 16.9 years) and 22% of patients with monophasic NMO (mean follow-up time 7.7 years) (class IV) [8]. Ophthalmoscopic examination may be normal or exhibit signs of ON, and optic atrophy with disc pallor is typically more pronounced than in MS. In addition, demyelination and necrosis are predominantly seen at the centre of the nerve and may form cavitation (class IV) [43,44].

Visual field testing typically reveals central scotoma, although other visual field changes such as colour blindness, bitemporal hemianopsia, paracentral scotoma and altitudinal deficits are possible. Optic coherence tomography studies in NMO reported a thinner retinal fibre layer than in MS, indicating a more widespread axonal injury (class IV) [45,46].

Myelitis  Spinal cord involvement usually presents in the form of complete transverse myelitis with para- or tetraparesis, an almost symmetrical sensory level and sphincter dysfunction (class IV) [2,8,34,47]. In contrast, spinal cord symptoms in MS are milder and asymmetric and caused by acute partial transverse myelitis (class IV) [48,49]. Radicular pain, paroxysmal tonic spasms and Lhermitte′s signs develop in 1/3 of the recurrent cases, but are rare or absent in patients with monophasic NMO (class IV) [8]. Nausea and intractable hiccups were found in 8/47 (17%) of patients with recurrent NMO due to expansion of the lesion to the medulla (class IV) [50]. Other brainstem symptoms include vomiting, vertigo, hearing loss, facial weakness, trigeminal neuralgia, diplopia, ptosis and nystagmus (class IV) [8,51,52]. Due to involvement of medullary centres of neuromuscular respiration control, neurogenic respiratory failure and subsequent death can occur (class IV) [8].

Other manifestations  Central nervous system involvement beyond optic nerve and spinal cord/brainstem is observed in about 15% of the patients with NMO and include encephalopathy, hypothalamic dysfunction and cognitive impairment (class IV) [8,53,54]. The latter is present in NMO with a similar frequency as reported in MS (class IV) [55]. Magana et al. reported five NMO-IgG seropositive women (N = 3 NMO, N = 2 recurrent LETM), who developed confusion and depressed consciousness consistent with posterior reversible encephalopathy syndrome (PRES) (class IV) [53]. The immune-mediated disruption of AQP4 water channel function may play a central role in the pathogenesis of PRES in these patients. Endocrinopathies associated with NMO include amenorrhea, galactorrhea, diabetes insipidus, hypothyroidism or hyperphagia (class IV) [56].

Outcome  The index events (visual acuity, motor, sensory and sphincter dysfunction) are more severe in monophasic than recurrent NMO (class IV) [40]. Repeated NMO attacks are the main cause of accumulation of neurological impairment, whereas permanent disability in MS is primarily a feature of secondary progression. In a Brazilian cohort, incomplete recovery from the index event predicted future disability (class IV) [4].

A history of other autoimmune diseases, higher attack frequency during the first 2 years of disease and better motor recovery following the index myelitis event were associated with increased risk of fatality in recurrent NMO (class IV) [40]. In this study published in 2003, which may have been biased towards more severe and complicated cases, 32% of patients with recurrent NMO died (median follow-up time 60.2 months) whilst no death occurred in patients with monophasic NMO [40]. There were 24/96 (25%) deaths in the French West Indies cohort, and predictors for mortality were higher attack frequency during the first year of disease, blindness and sphincter signs at onset (class IV) [57]. Mortality in a cohort of recurrent NMO from Brazil (published in 2002) was even higher (50%) (class IV) [12], but recent progress in understanding the disease and its management are likely to have decreased mortality rates.

Optic nerve  There are no studies evaluating differences in magnetic resonance imaging (MRI) presentation of ON in the setting of NMO and MS. Short-tau inversion recovery (STIR) sequences provide fat suppression, which is advantageous for evaluation of the optic nerve. Using STIR sequences, increased signal intensity on T2-weighted scans of the optic nerve is reported in acute ON in 84% and during remission in 20% (class IV) [58]. Disruption of the blood-nerve barrier leads to gadolinium-enhancement on T1-weighted spin echo sequences. Gadolinium-enhancement is a sensitive finding in acute ON (94%) (class IV) [59], is of variable extent and can occasionally extend into the optic chiasm. In a Cuban study in patients with long-duration NMO, gadolinium-enhancement of the optic nerve was found in 32.5% (class III) [60].

Spinal cord  Spinal cord lesions extending over three or more vertebral segments are the most reliable finding for the diagnosis of NMO (class IV) [52]. However, normal appearances or shorter lesions can be found very early during relapse or in residual atrophic stage [52]. Lesions are predominantly located in the cervical and thoracic cord with a central grey matter pattern, reflected by hyperintensities on T2-weighted axial scans and corresponding T1-hypointensities (class IV) [47,61]. Cervical lesions may extend to the lower medulla. Cavity-like longitudinally extensive lesions are seen in cases of severe disease. Acute spinal cord lesions tend to occupy most of the cross-sectional area of an affected segment and are associated with swelling and gadolinium-enhancement (detectable days to months following relapse) (class IV) [2,62,63]. In a study on LETM relapses in NMO (N = 11), gadolinium-enhancement vanished in all patients following treatment with high-dose methylprednisolone, and lesions may almost entirely disappear during remission (class IV) [61].

Conversely, spinal cord lesions expanding over two or more vertebral segments are rarely found in MS [48]. Lesions in MS usually appear as short-segment, asymmetric and often posterior cord lesions (class IV) [49,64]. ‘Snake-eye’ or ‘owl-eye’ sign is a common feature of spinal artery ischaemia and may be a transient finding at an early stage of NMO (class IV) [61].

Brain  Normal brain MRI is initially present in 55–84% of patients with NMO although a development of cerebral white matter lesions can be expected over the course of the disease (class IV) [2,8,34]. Indeed, brain MRI lesions can be detected with serial scans in up to 84.8% of patients with NMO (class IV) [4,51,65–67]. Distribution of NMO-typical brain lesions (8/120 patients) corresponded to structures with high AQP4 expression such as ependymal cells, hypothalamus and brainstem (class IV) [51,65]. Presence of brain lesions may be more common in childhood NMO. A cross-sectional study reported that brain lesions were found in 68% and were predominantly involving the periventricular region (class IV) [68].

Most lesions are non-specific and asymptomatic; Pittock et al. reported brain MRI lesions in 60% of patients, of which 10% were rated MS-like and fulfilled the Barkhof criteria for dissemination in space (class III) [51]. Two or more brain MRI lesions were found in 66% of a Cuban NMO cohort, but presence of lesions did not correlate with disease severity (class IV) [60]. In a Chinese study, most supratentorial lesions were rated as non-specific punctate or small round dot, and located in juxtacortical, subcortical and deep white matter regions (class IV) [67]. Callosal lesions were described in 18.2% (4/22) of AQP4 antibody-positive Japanese patients with NMO spectrum disorders (class III) [69]. These callosal lesions were classified as acute, large and oedematous in three (of four patients) and appeared with a heterogeneous lesion intensity (‘marbled pattern’), whereas callosal lesions in MS (36/56, 64.3%) were reported to be small, isolated and not oedematous. Another study described a cloud-like enhancement of brain lesions in terms of multiple patchy enhancement with blurred margin as typical of NMO (class IV) [70].

Symptomatic brain lesions are not an exclusion criterion for NMO [54,56]. Brain MRI of NMO spectrum disorder patients experiencing a PRES episode revealed bilateral T2-hyperintensities primarily in frontal, parieto-occipital and cerebellar regions (class IV) [53].

Expression of AQP4 within the CNS  Aquaporin 4 is an osmosis-driven, bidirectional water channel that belongs to the subfamily of mammalian aquaporins. In the CNS, AQP4 is expressed at the astrocytic foot processes in close vicinity to the basement membranes, in the optic nerve, in a subpopulation of ependymal cells, in hypothalamic nuclei and in the subfornical organ [79,80]. In NMO, the third extracellular loop of AQP4 is considered as the major epitope for AQP4 antibodies [81]. Astrocytes were shown to undergo necrosis in a complement-dependent manner when exposed to AQP4 antibody containing sera, and disease was induced by passive transfer of antibodies to rats, suggesting a primary pathogenic role of AQP4 antibodies in NMO [82,83]. A recent study evaluated the plasma cell population taken from an early patient with NMO at the molecular level and reported that AQP4-specific IgG is synthesized intrathecally at disease onset and contributes directly to CNS pathology [84].

NMO-IgG/AQP4 antibody assay  The diagnosis of NMO and its distinction from MS has been facilitated by the discovery of NMO-IgG/AQP4 antibodies. The initial assay was based on an indirect immunofluorescence (IIF) method using mouse cerebellum (class II) [17]. With this assay, testing for NMO-IgG had a reported sensitivity of 58–76% and a specificity of 85–99% for NMO. In addition, there are four other assay techniques allowing detection of AQP4 antibodies including cell-based assays (CBA), radioimmunoprecipitation assays, fluoroimmunoprecipitation assays (FIPA) and enzyme-linked immunosorbent assays (ELISA) [85,86]. Sensitivities and specificities of the assays differ and the gold standard remains to be elucidated [85–91]. Cell-based techniques such as CBA may show the best results (class IV) [86].

NMO-IgG/AQP4 antibody and disease characteristics  Neuromyelitis optica-IgG/AQP4 antibodies can be detected years before the onset of NMO [92]. A French study using IIF did not report differences with regard to age and onset of disease, annualized relapse rate, brain MRI findings and CSF abnormalities when comparing NMO-IgG positive and negative patients (class II) [87]. A Cuban study evaluating 48 recurrent patients with NMO (diagnostic criteria of 1999) reported a relatively low prevalence of NMO-IgG (33.3%, method: IIF); however, presence of NMO-IgG was associated with a worse course defined by more frequent relapses, occurrence of myelitis and greater attack-related disability (class II) [87]. Detection of NMO-IgG was also associated with a higher probability for >3 periventricular lesions and localization within the deep white matter, and a more extensive lesion on spinal cord images during remission. A European study reported that AQP4 antibody serum levels correlated with disease activity and were reduced by treatments with rituximab, azathioprine, cyclophosphamide (method: FIPA) (class IV) [93]. Antibody titres were attenuated by methylprednisolone and remained low during remission whilst high titres were associated with complete blindness and more extensive brain lesions (methods: CBA) (class II) [88]. The study also revealed that AQP4 antibody titres positively correlated with the length of spinal cord lesions at the nadir of exacerbations. In another study, measures of complement-mediated cell injury, but not AQP4 antibody titres, were indicative of disease severity [94]. A recent Japanese study evaluated the frequency of AQP4 antibodies in idiopathic demyelinating diseases [10] and found that the HLA-DPB1*0501 allele was associated with seropositive opticospinal MS, but not with classical MS or seronegative opticospinal MS (class II). A French NMO study reported that the presence of NMO-IgG was linked to HLA-DRB1*01*03 (majority DR3) [1]. In a cohort of 130 patients with relapsing–remitting MS, none was tested positive for NMO-IgG [95].

AQP4 antibodies in spatially limited syndromes  Neuromyelitis optica-IgG is also found in patients with LETM (37.9–50%) or RION (14.3–20%) and importantly appear to predict outcome in terms of conversion to NMO (class II) [18,19]. Detection of NMO-IgG in serum of patients with RION (5/25) was associated with a more severe initial ON episode, poor visual outcome and development of NMO (class II) [18]. Of nine NMO-IgG positive LETM patients, five (65%) experienced either another episode of myelitis (N = 4) or ON (N = 1) within 1 year (class II) [19]. The probability of detecting NMO-IgG in the serum of patients with acute partial transverse myelitis (lesion <3 vertebral segments) is low; NMO-IgG was found in 1 of 22 patients (4.5%) (class III) [96]; this patient subsequently developed recurrent LETM. Recently, four cases of AQP4 antibody negative recurrent LETM, which did not seem to be related to NMO, were reported (class IV) [97]. Of note, some NMO or spectrum disorder cases can be NMO-IgG positive and AQP4 antibody negative, or viceversa (class IV) [85]. In a series of three rapidly recurring LETM patients, AQP4 antibodies could not be detected in serum, but in CSF (class IV), confirming the diagnosis of a spatially limited NMO spectrum disorder and mandating initiation of immunosuppressive treatment [98].

Revised diagnostic criteria by Wingerchuk et al. (2006) (class IV) [52]  Two absolute criteria:

• (i) optic neuritis,

• (ii) myelitis.

At least two of three supportive criteria:

• (i) presence of a contiguous spinal cord MRI lesion extending over three or more vertebral segments,

• (ii) MRI criteria not satisfying the revised McDonald diagnostic criteria for MS, and

• (iii) NMO-IgG in serum.

These revised diagnostic criteria of 2006 and previous criteria of 1999 (excluding patients with brain lesions and without considering NMO-IgG) were applied in a series of Spanish and Italian patients with suspected NMO (n = 28) and NMO spectrum disorders (LETM and RION, n = 18), 115 patients with MS served as controls (class IV) [91]. IIF was used for determination of NMO-IgG. Compared with the criteria of 1999, the revised criteria were found to be associated with a higher specificity (83.3% vs. 25%), but slightly lower sensitivity (87.5% vs. 93.7%).

NMSS task force on differential diagnosis of MS, Miller et al. (2008) (class IV) [99]  Major criteria:

• (i) ON in one or two eyes,

• (ii) transverse myelitis, clinically complete or incomplete, but associated with radiological evidence of spinal cord lesion extending over three or more spinal segments on T2-weighted MRI images and hypointensities on T1-weighted images when obtained during acute episode of myelitis, and

• (iii) no evidence for sarcoidosis, vasculitis, clinically manifest systemic lupus erythematosus (SLE) or Sjögren’s syndrome (SS), or other explanation for the syndrome.

All major criteria are required, but may be separated by an unspecified interval.

Minor criteria, from which at least one must be fulfilled consist of (i. and/or ii):

• 1. Most recent brain MRI scan of the head must be normal or may show abnormalities not fulfilling the Barkhof criteria used for McDonald diagnostic criteria including:

  • (i) Non-specific brain T2-signal abnormalities not satisfying the Barkhof criteria for dissemination in space used in the revised McDonald criteria,

  • (ii) lesions in the dorsal medulla, either in contiguity or not in contiguity with a spinal cord lesion,

• (iii) hypothalamic and/or brainstem lesions,

  • (iv) ‘linear’ periventricular/corpus callosum signal abnormality, but not ovoid, not extending into the parenchyma of the cerebral hemispheres in Dawson finger configuration.

• 2. Positive test in serum or CSF for NMO-IgG/AQP4 antibodies.

Spatially limited NMO spectrum disorders: NMO-IgG/AQP4 positive LETM and RION/BON  NMO-IgG/AQP4 positive LETM and RION/BON are limited or inaugural syndromes of NMO. For details on the risk of such patients for converting to NMO refer to the preceding paragraph. The National Multiple Sclerosis Society (NMSS) task force concluded that these limited syndromes should not qualify as NMO, even in the presence of NMO-IgG/AQP4 antibody (class IV) [99]. Currently, there are no diagnostic criteria for spatially limited NMO syndromes and hence the panel decided to propose potential guidelines for work-up and diagnosis (Fig. 1).

Despite the availability of diagnostic criteria, there is an overlap between NMO and other disorders, and MS remains the most important differential diagnosis. In a cohort of 320 patients with clinically isolated syndrome suggestive of MS, 23 patients (7.2%) fulfilled the revised absolute NMO criteria of 2006 at some time (class III) [115]. In paediatric NMO particularly, ADEM has to be considered (class IV) [68]. Other differential diagnoses include spinal cord and/or optic nerve manifestations of viral, bacterial and fungal infections. Toxic exposures, nutritional and metabolic disorders, ischaemia, neoplasia and neurodegenerative diseases may mimic inflammation within the spinal cord and optic nerve. Also, hereditary optic neuropathies and retinal disorders have to be considered. Furthermore, spinal cord compression, arteriovenous malformations and non-cord mimics such as Guillain-Barré syndrome and MG have to be taken into account.

Steroids: Initial or recurrent episodes are usually treated with high-dose intravenous methylprednisolone (1 g daily for three to five consecutive days). This recommendation is taken from studies of MS and idiopathic ON because there are no controlled therapeutic trials which investigated the effectiveness of steroids specifically in NMO. Acute NMO symptoms respond to short courses of high-dose intravenous corticosteroids in up to 80% of patients within 1–5 days, and treatment is generally well tolerated (class IV) [8]. In many countries of the EU, the intravenous therapy with methylprednisolone for MS-related relapses is followed by an oral taper, which lacks controlled trials and needs to be performed slowly.

Plasma exchange: Therapeutic plasmapheresis was effective in patients with severe symptoms that fail to improve or progress despite treatment with corticosteroids. Plasma exchange (1–1.5 plasma volume per exchange) for the treatment of steroid-unresponsive severe mostly MS-related attacks was compared in a double-blinded, sham-controlled protocol (total of seven treatments every other day) in a North American study (class II only for MS, rating not possible for NMO because only two patients with NMO included) [116]. Patients who did not achieve moderate or greater improvement after the first treatment phase crossed over to the opposite treatment. Improvement was found in 8 of 19 (42.1%) patients receiving plasma exchange and only in 1 of 17 (5.9%) receiving sham exchange. In an extension of this study, moderate or marked improvement was detected in 6 of 10 patients after switching to plasma exchange (class III) [117]. However, in three patients, no improvement could be accomplished. Predictive factors for better prognosis were male gender, preserved reflexes and early initiation of plasma exchange. Llufriu et al. performed plasma exchange in four NMO patients with severe episodes of CNS demyelination unresponsive to steroids; one patient had improved at discharge (25%) and the remainder when reassessed after 6 months (75%) (class IV) [118]. Watanabe et al. reported the therapeutic efficacy of plasma exchange (median four exchanges over a period of 1–2 weeks) in 6 NMO-IgG seropositive patients who were unresponsive to high-dose intravenous methylprednisolone treatment (class IV) [119]. Following plasma exchange, three patients experienced a significant functional improvement, whilst one had mild and two no improvement. Clinical response commenced quickly, after one or two exchanges. Benefits were also seen in patients with severe isolated optic neuritis who were unresponsive to high-dose corticosteroids (class IV) [120]. Efficacy of plasma exchange for severe spinal cord attacks in patients with NMO spectrum disorders was shown to be independent of NMO-IgG seropositivity (class IV) [121]. Miyamoto et al. reported four AQP4 antibody positive NMO patients with steroid-refractory relapses in which plasmapheresis was effective (class IV) [122]. Lymphocyte apheresis, a procedure that removes only lymphocytes but not plasma from the blood, was effectively applied in a single NMO-IgG negative NMO patient who did not respond to methylprednisolone or IVIG (class IV) [123].

Intravenous Immunoglobulins (IVIG): IVIG has not been specifically evaluated for ON/LETM relapses of NMO/NMO spectrum disorders and is rarely used for corticosteroid-refractory attacks [124].

Azathioprine & steroids: Azathioprine is a purine synthesis inhibitor and interferes with the proliferation of cells, especially leucocytes. Azathioprine (75–100 mg daily) in combination with oral prednisolone (1 mg/kg/daily) was evaluated in a prospective open-label case series of seven patients with newly diagnosed NMO (class IV) [133]. The combination was effective over a treatment period of 19 months by means of sustained improvement in the EDSS scores and absence of relapses. Treatment with azathioprine may be carried out in analogy to the recommendations for myasthenia gravis. Haematological evaluations are required every 2–4 weeks, the dosage may be reduced in the course and treatment duration of up to 5 years may be considered. The evaluation of long-term side effects of azathioprine treatment in MS revealed that gastrointestinal complaints and leucopenia were very common adverse events (>10%), whilst infections, allergy and haematological disturbances were common (1–10%) [134]. Corticosteroids are used for rapid immunosuppression until azathioprine exerts its full effect. Some patients experience clinical worsening when prednisone is reduced below 5–15 mg/day (class IV) [135]. Long-term treatment with corticosteroids requires osteoporosis prophylaxis.

Cyclophosphamide: Cyclophosphamide, an alkylating chemotherapeutic drug related to nitrogen mustards, is a non-specific immunosuppressant that affects both T-cell and B-cell functions. Immunosuppression is transient when cyclophosphamide is given in standard pulse doses, and the immune system returns to baseline within a few months to a year after cessation [136]. Published treatment regimens for i.v. cyclophosphamide vary and range from 7 to 25 mg/kg every month over a period of 6 months. Uromitexan administration with every dose needs to be included for prevention of haemorrhagic cystitis.

A few case reports suggest that cyclophosphamide is partially effective in NMO syndromes associated with other autoimmune disorders including SLE and SS (class IV) [137–140]. In neuropsychiatric SLE, low-dose i.v. cyclophosphamide (200–400 mg per month, N = 37) and oral prednisone were superior to oral prednisone alone (N = 23, average daily dose of prednisone 20.5 mg in both groups) [141]. In MS, cyclophosphamide is considered a treatment option in aggressive courses refractory to immunomodulatory treatment. However, a recent Cochrane systematic review found only four randomized-controlled MS trials with sufficient data and concluded that cyclophosphamide does not prevent worsening of the EDSS [142]. Occurrence of amenorrhea and sepsis has to be taken into account.

Methotrexate: Methotrexate exerts its immunosuppressive activity via inhibition of dihydrofolate reductase and has anti-inflammatory and immunomodulatory effects. Among eight patients with NMO, four treated with a combination of methotrexate (i.v. 50 mg weekly) and prednisolone (1 mg/kg/daily) were stabilized (class IV) [143]. Among the four patients who were treated with cyclophosphamide only, one stabilized and the remaining three responded positively after switching to the combination of methotrexate and prednisolone.

Mitoxantrone: Mitoxantrone is an anthracenedione antineoplastic agent that intercalates with DNA and inhibits both DNA and RNA synthesis, suppressing T-cell and B-cell immunity. A prospective 2-year case series (12 mg/m² monthly for 6 months, followed by three more treatments, each 3 months apart) reported that four of five patients with recurrent NMO experienced disease stabilization and improvement of MRI measures (class IV) [144]. Mitoxantrone is a toxic agent that must be administered with care to reduce the likelihood of bone marrow suppression, opportunistic infection and cardiomyopathy. Amenorrhoea is a major concern in the treatment of young women. Therapy-related acute leukaemia (TRAL) was studied in 5472 patients with MS treated with a mean dose of 74.2 mg/m² (range: 12–120 mg/m²) [145]. TRAL occurred in 0.3%, median onset was at 18.5 months (range 40–60 months) after start of mitoxantrone treatment and among the 25 patients for which outcome was reported six died (24%). A relationship with total dose is suggested since over 80% of the patients in which acute leukaemia occurred had received >60 mg/m².

Mycophenolate mofetil: Mycophenolate (p.o. 1–3 g/day) is suggested in several other conditions requiring immunosuppression and is mostly used when a rapid onset of treatment effects is not required and azathioprine is not tolerated. The occurrence of treatment effect is more rapid for mycophenolate than for azathioprine. Jacob et al. reported a retrospective study of 24 patients suffering from NMO (N = 15) and NMO spectrum disorders (relapsing LETM N = 7, RION and LETM N = 1 each) with a median treatment duration of 27 months (class IV) [146]. At a median follow-up of 28 months (range 18–89 months), 19 patients (79%) were continuing treatment and one had died. The median annualized post-treatment relapse rate was lower than the pre-treatment rate (P < 0.001). A 9-year-old girl treated with mycophenolate achieved sustained improvement over a 2-year follow-up (class IV) [147]. Some panel members have very good experience with mycophenolate as long-term treatment of NMO and would also consider this therapy as first-line treatment (expert opinion).

Prednisolone: Low-dose oral prednisolone (5–20 mg daily) was shown to reduce relapse frequency in a retrospective study of nine Japanese patients with NMO (class IV) [148]. However, relapses occurred significantly more frequently when steroids were tapered to 10 mg/day or less (odds ratio 8.75).

Rituximab: Rituximab, a chimeric anti-CD20 monoclonal antibody capable of depleting mature and precursor B cells, was shown to reduce disease activity and prevent disability in two studies. The first study, a retrospective analysis of 25 patients with NMO treated with rituximab as escalation therapy was performed in patients from the US and UK (class IV) [149]. Two rituximab regimens were used: (i) 375 mg/m² infused once per week for 4 weeks (N = 18) and (ii) 1000 mg infused twice, with a 2-week interval between the infusions (N = 4). The median annualized pre-treatment relapse rate was 1.7 (range 0–3.2) and dropped to 0 relapses (range 0–3.2) at a median follow-up of 19 months. The EDSS improved in 11 patients, did not change in nine, and worsened in five patients, of whom two died. The second study is an open-label study, which evaluated eight patients with NMO who had failed other therapeutic regimens and were treated with rituximab (four infusions 375 mg/m², once per week) (class IV) [150]. Mean follow-up time was 12 months, and 6 of 8 patients remained relapse-free. B-cell counts were evaluated bi-monthly, and patients were given the option to be retreated with rituximab when B-cell counts became detectable (re-treatment two infusions of 1000 mg, 2 weeks apart).

A 2005 report on the safety of rituximab in patients with cancer and rheumatoid arthritis concluded that overall usage is safe [151]. Infusion-related reactions were reported in 84% and included nausea, headache, fatigue, rash, flu-like symptoms. The incidence of these symptoms is highest after the first infusion and decreases in the course. Thus, the use of acetaminophen, antihistamines and corticosteroids is recommended as pre-treatment. Infections are reported in 30% of rituximab-treated patients but only 1–2% acquire severe infections. Of note, concomitant immunosuppressive therapies enhance the susceptibility to infection.

Other treatment options: There are no studies of fingolimod (FTY-720) or natalizumab in NMO.

Supportive and symptomatic treatment is an essential component of the overall management of NMO and aimed at control or reduction in symptoms impairing functional abilities and quality of life. Such symptoms include spasticity, tonic spasms, NMO-related pain syndromes, bladder symptoms, neurogenic bowel dysfunction, sexual dysfunction and cognitive impairment. Some patients with high cervical cord lesions will require long-term mechanical ventilation.

No trials specifically for symptomatic treatment of NMO have been performed, most evidence is derived from studies in MS, and the readers are referred to recommendations for symptomatic treatment of MS, for instance, from the Multiple Sclerosis Therapy Consensus Group (MSTCG) of the German Multiple Sclerosis Society [155].