Neuromyelitis optica (NMO) was first identified in the 19th century, as a monophasic, destructive disorder affecting the spinal cord and both optic nerves, but sparing the remainder of the central nervous system (CNS). The position of NMO within the group of CNS demyelinating diseases has been long debated - whether this clinical entity is a severe variant of MS, a form of acute disseminated encephalomyelitis, or a distinct disease [5, 6]. It has gradually become accepted that the spectrum of idiopathic NMO is broader than suggested by the historical definition. The recent discovery of serum autoantibody marker NMO-IgG in 2004 further advances the hypothesis that NMO is actually a distinct disease [3]. NMO-IgG is 73% sensitive and 91% specific for distinguishing NMO from optic-spinal presentations of classical MS. The target antigen of NMO-IgG is aquaporin 4 (AQP4), glial water channel protein, that facilitates water transport, especially in "stress situations" such as brain injury. It is component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier. Data suggest that autoantibodies to aquaporin 4, derived from peripheral B cells, cause the activation of complement, inflammatory demyelination, and necrosis that is seen in neuromyelitis optica [7, 8]. It is also important to emphasize that patients presenting with a first-ever LETM event, who are found to be NMO-IgG seropositive, have a 56% risk of LETM recurrence or optic neuritis (conversion to NMO) during the subsequent 12 months [9]. With the positive NMO-IgG finding we confirmed the diagnosis of NMO in our patient, who satisfied all absolute and supportive diagnostic criteria [1].
According to the data from the literature, most patients with NMO, perhaps more than 90%, have relapsing rather than monophasic disease [9], which was also the case in our patient, but was not recognized as that in the beginning of the disease. Our patient met the features of relapsing NMO, such as female dominance, older age at onset, and probably autoimmune disease - we could assume that steroid therapy unmasked autoimmune diabetes mellitus [10].
For many neurologists, the current standard preventive approach for NMO includes oral azathioprine in a combination with oral prednisone, rituximab (chimeric anti-CD20 monoclonal antibody), mitoxantrone, IVIGs, and cyclophosphamide [11–17]. The best evidence (although all from retrospective series) for long-term immunosuppression in NMO is with azathioprine and rituximab, that are considered first line therapies, while cyclophosphamide is generally considered as a second line agent in NMO. In a recently published retrospective multicenter case series of NMO patients treated with rituximab, that included 25 patients (including 2 children), 23 of whom experienced relapses despite use of other drugs before rituximab, treatment with rituximab appeared to reduce the frequency of attacks, with subsequent stabilization or improvement in disability.[14] Jarius et al reported that treatment with immunosuppressants such as rituximab, azathioprine and cyclophosphamide resulted in a marked reduction in antibody levels as well as in relapse rates, demonstrating a strong relationship between AQP4-Abs and clinical state. Cyclophosphamide resulted in a long-lasting relapse-free interval in one of their patients, with 10 relapses within 1295 days (2.82/year) prior to initiation of therapy but only one within 1610 days (0.23/year) under therapy [15]. Immunoablative cyclophosphamide was also successful in halting relapses in a patient with systemic lupus erythematosus-associated NMO who was unresponsive to high-dose oral and intravenous corticosteroids, intravenous immunoglobulin, mycophenolate mofetil, tacrolimus, low-dose daily oral cyclophosphamide and rituximab [17].
After treating diseases attacks with pulse corticosteroid therapy and IVIGs in our patient, we included oral azathioprine in a combination with oral prednisone in the therapy, but since there was no significant therapeutic response, we decided to use cyclophosphamide therapy. That resulted in good clinical improvement and gradual decrease in cord swelling and T2 signal hyperintensity. We were also considering to use rituximab, but at that time this agent was not approved for treating NMO in Croatia.
It is important to point out that one does not need to wait for a second attack of transverse myelitis or optic neuritis prior to commencing immunosuppression if NMO-IgG is positive, since NMO-IgG itself predicts a relapsing course. Unfortunately, at the time we received positive finding of NMO-IgG antibodies from Mayo Clinic, our patient experienced relapse. If immunosuppresive therapy had been started earlier in the course of the disease (patient's clinical worsening started to happen one year before admission to our institution), maybe the prognosis for this patient could be more favourable.
