Neuromyelitis optica spectrum disorder in patient with systemic lupus erythematosus – our experience

Introduction. Neuromyelitis optica spectrum disorder (NMOSD) is a rare demyelinating immune-mediated central nervous system disease. It is extremely rare to occur in patients with systemic lupus erythematosus (SLE), and it represents a diagnostic and therapeutic challenge. Case report. A 38-year-old Caucasian woman with medical history of SLE and new onset of flaccid paraparesis, fecal and urinary incontinence, persistent nausea and vomiting was admitted to our hospital. Based on the clinical presentation, magnetic resonance imaging findings and positive aquaporin 4 (AQP4) antibodies, a NMOSD with coexisting SLE were diagnosed. Pulse-doses of cyclophosphamide and glucocorticoids were efficient in patient treatment. Conclusion. In a patient with SLE and symptoms of longitudinal extensive transverse myelitis and/or optic neuritis and area postrema syndrome, assessment of AQP4 antibodies is neccessary for diagnosing NMOSD. Accurate diagnosis, and timely and long-term administration of immunosuppressive therapy are crucial for favorable outcome of these two coexisting diseases.


Introduction
Neuromyelitis optica (NMO) was described at the end of 19th century by Eugene Devic, and until recently it has been commonly called the Devic's syndrome 1 .Traditionally it was defined as a monophasic demyelinating disease of central nervous system (CNS) consisting of optic neuritis (ON) and transverse myelitis (TM).It has changed relatively recently, first with the discovery of a highly specific serum aquaporin-4 (AQP4) immunoglobulin G antibody 2  with an understanding that affection of central nervous system (CNS) in this disease may be more restricted, or more extensive than previously thought.In turn, this led to understanding that all demyelinating diseases with positive AQP4 antibodies and variable affection of CNS should be labeled as NMO spectrum disorders (NMOSD) 3 .Current diagnostic criteria also recognise monophasic and relapsing NMOSD, as well as AQP4 antibody positive and AQP4 antibody negative NMOSD, both having characteristic magnetic resonance imaging (MRI) findings in one of six regions of CNS (optic nerve, spinal cord, area postrema, brainstem, diencephalon and cerebelum) 4 .
It is not so uncommon that a patient with NMOSD develops another autoimune disorder, such as systemic lupus erythematosus (SLE), Sjögren's syndrome, autoimmune thyreoiditis, or myasthenia gravis 5 .On the other side, it is estimated that the probability of a patient with SLE developing NMO is extremely low -approximately 1 : 5.000.000 6.Neurological manifestations similar to NMO and due to CNS demyelinisation can occur as a part of clinical picture of SLE.It is therefore important to distinguish if the neurological manifestations are caused by autoimune disease, or, they are just a part of coexisting NMOSD.

Case report
A 38-year-old Caucasian woman with a medical history of SLE was transferred to our hospital due to longitudinally extensive transverse myelitis (LETM) and for further diagnostics and treatment.
SLE was diagnosed a year prior to this, and was based on nonerosive polyarthritis, leukolymphopenia, positive antinuclear antibodies (ANA) and antibodies to double-stranded DNA (anti-dsDNA).Since then, the patient had been treated with prednisolone 10 mg/day and hydroxychloroquine 400 mg/day.After introduction of the therapy the patient was generally well with the exception of periodical polyarthralgia.
Three weeks before admission to our institution, a fever, persistant nausea, vomiting, hiccups, headache, abdominal pain and dry cough occurred.She was admitted to a local hospital and initially treated for gallbladder calculosis and cholecystitis.During the second week in the hospital, she became somnolent, developed a rapidly progressive paraparesis (within 24 hours) and fecal and urinary incontinence.MRI scanning of the cervical and thoracic spine showed hyperintense signal in T2-weighted sequence in C7-T1, T1-T4 and T8-T11 spinal cord segments (Figure 1).MRI scanning of the brain showed hyperintense signal in T2-weighted sequence in dorsal and lateral medulla on the left (Figure 2).Postcontrast signal enhancement in both optical nerves was observed.The NMO was suspected.The patient was treated with pulse doses of methylprednisolone 1 gram daily for 5 days followed by intravenous immunoglobuline (IVIg) 400 mg/kg day for 4 days, while hydroxychloroquine was discontinued.Patient's state was deteriorating despite the treatment, so she was transferred to our hospital.irment of light touch, pinprick and vibration sensation in the legs, but without a clear sensory level.Expanded disability severity scale (EDSS) at this point was 8.5.
Computed tomography of the chest showed bilateral pleural effusions.
Visual evoked potentials (VEP) showed prolonged P100 latencies of 127 ms on the left and 121 ms on the right eye.The patient did not report any visual loss, nor could any visual disturbance be observed through usual clinical examination.
Based on the presence of longitudinally extensive transverse myelitis (LETM), subclinical ON, area postrema syndrome and positive AQP4 antibodies, NMOSD were diagnosed.SLE erythematosus disease activity index 2,000 (SLEDAI-2K) was at this point 9.
Monthly cyclophosphamide (CF) pulses of 15 mg/kg were introduced, and methylprednisolone 1 mg/kg was continued for 2 weeks, then, gradually reduced.Followed by therapy introduction the neurological symptoms gradually improved and sphincter function completely recovered.
Over the next 6 months the patient received 6 monthly pulse doses of CF and methylprednisolone dose was 10 mg/day.On follow-up after 6 months, she was ambulatory without any assistance on distances greater than 1,000 m.Neurological examination revealed residual spastic paraparesis to a lesser degree, with EDSS of 3.5.SLE activity was low (SLEDAI-2K: 3).

Discussion
In the SLE patient, according to American College of Rheumatology nomenclature, 19 neuropsychiatric syndromes (NPSLE) can be defined 7 .Among the least frequent is myelitis, present in 1-2% of patients 8 .It can present itself as TM consisting of spinal cord lesions of one to two spinal se-gments or as LETM extending 3 or more vertebral segments confirmed by T2-weighted MRI 9 .
The relationship between TM and present antiphospholipid (APL) antibodies in SLE is proven.It is considered that APL-induced vasculitis of spinal blood vessels and direct cytotoxic effect to nervous tissue have a role in occurrence of TM in patients with SLE 10 .
Since LETM represents a very rare manifestation of SLE, other possible causes should be sought for, including multiple sclerosis, infections, tumors, trauma and nutritional deficiencies.LETM is also one of the main clinical characteristics and a part of the modern diagnostic criteria for NMOSD 11 .In our patient, repeated assessment of antiphospholipid antibodies was negative, possible infective causes were excluded and McDonald's revided 2010 criteria for multiple sclerosis were not met 12 .VEP latencies are often delayed in NMOSD (as it was in this case), but this finding, although illustrative of optical nerve demyelination is not specific for NMOSD, and can be seen in a variety of clinical entities, especially in multiple sclerosis 13 .In our case, there were several more unique clinical characteristics of the NMOSD -constant hiccups, nausea and vomiting.These are manifested in 15.7-62% of patients 14 .Area postrema and solitary tract nuclei in dorsomedial medulla are frequently affected areas (as confirmed in the presented case by MRI finding), which can be explained by a rich expression of APQ4 in this area 15 .
So far, the interconnection between autoimmune diseases and NMOSD has not been completely clarified.It is considered that there is a genetic predisposition of certain patients for developing several types of autoimmune diseases.It has been demonstarted that only patients with SLE who have ON and/or myelitis have positive APQ4 antibodies, whereas those with other NPSLE do not have 16 .
In the NMOSD treatment, pulse-dose corticosteroids, plasmapheresis and IVIgs are recommended in acute phase.This is followed by long-term immunopression with rituximab, azathioprine and mycophenolate mofetil as recommended 17 .There are no recommendations for the treatment of patients with coexisting SLE and NMOSD.Current knowledge is based on retrospective cases and short series 18 .

Conclusion
Antiaquaporin-4 antibody should be sought for in patients with SLE and the first attack of LETM, ON and/or area postrema syndrome.Positive anti aquaporin-4 antibodies in these cases can easily lead to diagnosing a coexisting NMOSD in patient with SLE.
Accurate and timely diagnosis followed by a long-term immunosupressive therapy are necessary to reduce neurological sequellae and establish adequate control of both diseases.

Fig. 2 -
Fig. 2 -T2W magnetic resonance imaging (MRI, axial section) of brain showing hyperintense signal in dorsal and lateral medulla oblongata on the left (arrow).On admission, she had a low grade fever (37.8 o C), mild malar rash and low blood pressure (80/60 mmHg).Basal respirations were auscultatory inaudible.Flaccid paraplegia and spastic paresis of both arms as well as urinary retention and fecal incontinence were the dominant neurological findings upon admission.There was also a discrete right peripheral n. facialis weakness, billateral hand action tremor, mild impa-