Inflammatory lesions of the spinal cord, whether completely or partially transverse, are referred to as transverse myelitis. Usually, transverse myelitis is an acute illness which develops over several hours and progresses within the next days. Patients typically present with para- or tetra-paresis, depending on the level of spinal cord involvement, and sensory disturbances. Autonomic involvement may present with bowel or bladder dysfunction.
The term longitudinally extensive transverse myelitis (LETM) refers to lesions extending across at least three contiguous vertebral segments. Patients with LETM represent a particular subgroup of transverse myelitis, different from those with shorter lesions; they have a low risk of evolution towards multiple sclerosis, but more severe clinical symptoms.1
Although LETM most frequently occurs in association with neuromyelitis optica (NMO), it may be caused by spinal cord infarction, compressive myelopathy, or infectious myelopathy; it could appear in the course of autoimmune or inflammatory conditions such as SLE, sarcoidosis, or Behçet’s disease; rarely, it may be an isolated or idiopathic condition.
Neuromyelitis optica (Devic’s syndrome) is a rare inflammatory neurologic disease, characterized by severe optic neuritis and LETM; it has a relapsing course and is associated with NMO immunoglobulin G (NMO-IgG). These antibodies bind to the water channel aquaporin 4 and are highly specific, occurring in 70%–90% of patients in former NMO series, yet are not found in patients suffering transverse myelitis or optic neuritis as manifestation of systemic autoimmune or rheumatic disease.2 The presence of AQP4-IgG provides a possible distinction of NMO from other autoimmune neurologic disorders.
More than 90% of NMO-related LETM patients develop a relapsing–remitting course, accumulating disability; relapse rate is related to the extent of the spinal cord lesion and the presence of AQP4-IgG, but not its titer.3 The diverse courses of NMO observed during longitudinal studies led to the broadening of the diagnostic criteria for NMO spectrum disorders (NMOSD). In AQP4-IgG-positive patients, new criteria allow NMOSD diagnosis in patients with clinical or MRI characteristic findings in at least one of six typical CNS regions, including the optic nerve or the spinal cord. An international panel for NMO diagnosis concluded that NMO clinical syndromes in AQP4-IgG-positive patients may coexist with SLE, highlighting that NMOSD is more likely to be co-associated, than a direct complication of active SLE.4
The standard of care in NMOSD is based on expert opinion and includes early aggressive immunosuppression inducing remission in an acute episode, followed by maintenance therapy for prevention of relapse. Pulses of i.v. 1 g methylprednisolone for 3–5 consecutive days, followed by oral prednisolone, are the standard of care. Effectiveness of azathioprine and rituximab (an anti-CD20 antibody) was demonstrated in a meta-analysis performed by the NEMOS group5 and in recent studies showing reduced relapse rates and disability scores,6 leading to the European Federation of Neurological Societies guidelines and the NOMADMUS group of NMO specialists’ recommendations for treatment with azathioprine or rituximab as first-line therapy for relapse prophylaxis, while mycophenolate mofetil, methotrexate, or cyclophosphamide are second-line therapy.7
Involvement of the CNS is among the severe complications of SLE, typically presenting with seizures or psychosis, and only rarely with transverse myelitis. However, the American College of Rheumatology classification for neuropsychiatric SLE included all features of NMO as a possible SLE-related CNS manifestation.
Since SLE-related LETM is very rare, data on the clinical course, outcome, and treatment efficacy are largely absent from the literature. The prevalence of SLE-related LETM is higher in young women (77% of patients are women, mean age 30 years) and may be the first presenting SLE feature. Case series noted an association with active extra-neurologic SLE in only 40%–60% of cases.8 On the other hand, LETM may occur years after SLE diagnosis, during a flare. Half of LETM patients experience unfavorable neurologic outcome despite aggressive immune suppression, and over a quarter have persistent disability.9
The relapse rate of SLE-associated transverse myelitis remains unknown. Iyer et al. observed a monophasic course in 80% of cases, with poor recovery,10 but Saison et al. reported common relapses during corticosteroid tapering in 50%–60% of the patients,8 confirming the need for maintenance therapy following induction, with some evidence supporting the use of cyclophosphamide, azathioprine, and hydroxychloroquine in this aim.9
This therapeutic approach is partly different from the one towards NMO-related LETM; however, it has been suggested by NMO specialists that a more targeted approach may be more effective with fewer adverse effects. Modulation of the complement system in treatment of NMOSD was proposed with eculizumab.11 Bevacizumab, an anti-VEGF antibody, was reported as a safe add-on therapy to corticosteroids.12 High levels of IL-6 in CNS fluid from patients with NMOSD may justify the use of IL-6 blockade, and clinical trials are ongoing. Aquaporumab, a competitive inhibitor of AQP4, is under investigation.13 These innovative treatments have no proven efficacy for treatment of neuropsychiatric lupus, which underscores the importance of correctly diagnosing the etiology of LETM in every patient, particularly in SLE patients.
This case also highlights the long-term efficacy and safety of IVIg as adjuvant therapy for maintenance of remission in MNO-related LETM in our patient. This approach, proposed long ago based on the assumed IVIg mode of action, was recently supported by a retrospective analysis of 20 NMO patients treated with add-on IVIg. In these patients, IVIg treatment was associated with prevention of both relapse and disability progression. Further studies are needed to determine the optimal dose, dosing interval, and efficacy of this treatment.14