Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy against foot processes of aquaporin-4 (AQP4)
water channels. Patients with NMOSD tend to have other coexisting autoimmune/
connective tissue diseases. However, AQP-4-antibody-positive NMOSD coexisting with
ankylosing spondylitis (AS) is rare. AS is an immune-mediated disorder, a subset of axial
spondyloarthropathies, which commonly manifests as chronic inflammatory
back pain in young people, and it has a strong association with
HLA-B27. In this study, a 35-year-old Indian man with an undiagnosed progressive axial
spondyloarthropathy (i.e., AS) is reported presenting with acute-onset longitudinally extensive
transverse myelitis, a clinical subset of NMOSD.
Neuromyelitis optica spectrum disorder (NMOSD), a primary
demyelinating disorder of the central nervous system (CNS), is an autoimmune astrocytopathy against foot processes of aquaporin-4 (AQP4)
water channels, which manifests with
optic neuritis, longitudinally extensive
transverse myelitis (LETM), area-postrema syndrome, brainstem syndrome diencephalic syndrome, and cerebral syndrome.1-4
Ankylosing spondylitis (AS) is an immune-mediated disorder, a subset of axial
spondyloarthropathies, which commonly manifests as chronic inflammatory
back pain in young people, and it has a strong association with HLA-B27.5,6 AS characteristically targets the axial skeleton, peripheral joints, entheses (connective tissues between tendons/ligaments and bones), and gut.5,6 Patients with NMOSD tend to have other coexisting autoimmune/
connective tissue diseases.7 For example, cases with NMOSD and
multiple sclerosis, which are other autoimmune primary
demyelinating disorders of the CNS, have been reported.8,9 However, concurrent existence of AS and NMOSD in the same patient even over years of disease course is rare.10,11 In addition, studies describing
neurological manifestations of AS are limited,12 and they focus on joint
inflammation and long-standing bony pathology (
ankylosis) related to
compressive myelopathy, myelo-
radiculopathy, and
cauda equina syndromes.12,13 The authors present a case of a young Indian man with an undiagnosed progressive AS (misdiagnosed and mismanaged by an indigenous medical practitioner) presenting with acute-onset LETM variant of AQP4-positive NMOSD. A 35-year-old healthy, non-comorbid man from rural India came to the outpatient department with complaints of persistent tingling,
numbness, and weakness of both lower limbs (right more than left) for 10 days. The clinical picture showed acute-onset
urinary retention, which was relieved by urinary catheterization. An indigenous medical practitioner had prescribed drugs to treat a
urinary tract infection. His weakness gradually progressed over the following week, causing him to become bedridden. During the removal of the
catheter, he felt urgency, increased frequency of micturition, and overt
urinary incontinence. He gave no history suggestive of any girdle-like sensations, root/radicular/tract
pain, vertebral
pain,
trauma, recent vaccination, and diarrheal or febrile illness. For the last 8 months, he had a complaint of an insidious-onset, persistent, bilateral, dull aching
pain in the gluteal region accompanied by
low-back pain and morning stiffness up to 1 h, which markedly improved with activity and reoccurred following long periods of inactivity. He sometimes had to rise in the middle of the night because of excruciating
pain, which could be relieved after moving around the room and corridors for half an hour. He was taking over-the-counter
diclofenac tablets for
pain relief prescribed by some indigenous medical practitioners who told him that it was due to overwork in agricultural fields, that is, mechanical
back pain. He also had a normal X-ray of the lumbosacral spine. He had no addiction liabilities, and none of the family members had ever suffered from a similar kind of illness. He had never consulted any trained medical practitioner, as his previous
back-pain-related symptoms responded well to the
tablets prescribed by the indigenous medical practitioner(s). During examination, he was found to have recent-onset, asymmetric
spastic paraparesis (right more than left) with upper motor neuron-type urinary bladder symptoms. Cognitive assessment (assessed by the Montreal cognitive assessment test) was normal, and posterior column sensations were preserved. Sensory system examination revealed no definite sensory level. Except for the paretic lower limbs, cerebellar functions were normal in other regions. Neuro-ophthalmological examinations were also normal, and no signs of meningeal irritation were observed. The history and course of the disease and clinical examinations were analyzed. Selective tractopathy (early and predominant motor and autonomic tract affection) was suggested for an intramedullary demyelinating pathology affecting the anterior central cord. This case was initially classified as acute-onset non-
compressive myelopathy at the lower cervical/upper dorsal region level in a patient with a pre-existing axial
spondyloarthropathy. Complete blood cell count; liver, kidney, and thyroid function tests; and plasma
glucose and
electrolytes were normal, except for an increased erythrocyte sedimentation rate (66 mm in the first hour). Magnetic resonance imaging (MRI) of the spinal cord revealed a demyelinating LETM from C5 to D4 level (Figure 1). Meanwhile, an MRI of the sacroiliac joints revealed bilateral
sacroiliitis. Brain and orbital MRIs were devoid of any lesions. Anti-
aquaporin 4 (AQP-4)
antibodies were tested by cell-based assay in serum and cerebrospinal fluid (CSF), and both were positive. CSF further revealed lymphocytic
pleocytosis and increased intrathecal
protein production. Visually evoked potential recordings were also normal. In addition, anti-
myelin oligodendrocyte glycoprotein antibodies were negative. Anti-nuclear antibody (ANA), ANA-profile, autoimmune
vasculitis profile (
c-ANCA,
p-ANCA), neurovirus panel (i.e., polymerase chain reaction for adenovirus, Epstein-Barr virus, herpes simplex viruses 1 and 2, human herpesviruses 6 and 7, cytomegalovirus, enteroviruses, varicella-zoster virus,
Japanese encephalitis, and dengue virus), CSF-polymerase chain reaction for Mycobacterium tuberculosis,
angiotensin-converting enzyme, anti-
phospholipid, and anti-thyroid
antibodies were negative.
Anti-CCP-antibody and
rheumatoid factor were also negative, including
creatine phosphokinase level and serum
vitamin B12. Moreover, serologies for
hepatitis B, C, human immunodeficiency virus, and
scrub typhus were negative. However,
HLA-B27 assay was positive. The final diagnosis was AQP4-positive NMOSD associated with AS. He was placed on pulse intravenous
methylprednisolone (1 g/day for 5 days). Consequently, his lower limb power improved remarkably. Cyclical
rituximab therapy was initiated to prevent relapses. At 3-month follow-up, he had no residual neurological deficit except for persistence of
paresthesias. Neuroimaging and visually evoked potential studies revealed no active or new lesions. After 6 months of
therapy, a subjective and objective improvement was observed in disease severity based on the
Ankylosing Spondylitis Disease Activity Score. Our patient satisfied the new Assessment of SpondyloArthritis International Society diagnostic/classification criteria for AS and the Wingerchuk criteria for NMOSD,4,14 an association that has been rarely reported.10,11 Amid the extra-articular complications of long-standing AS,
neurological manifestations are considered infrequent.15 However, subclinical neurological complications may be frequent in AS.12 Common
neurological manifestations result from bony (vertebral)
ankylosis, subluxation of joints, ossification of anterior and posterior longitudinal ligaments, secondary spinal canal
stenosis, bony (vertebral) fractures, and subsequent compressions over nerve radicles/roots/cauda equina, and
inflammation-related (entrapment)
peripheral neuropathies.12,16,17
Acute transverse myelitis can occur as a subset of several primary
demyelinating disorders of the CNS (i.e.,
multiple sclerosis, NMOSD,
myelin oligodendrocyte glycoprotein antibody disease, and
acute disseminated encephalomyelitis) and various systemic autoimmune connective tissue disorders (i.e.,
systemic lupus erythematosus,
mixed connective tissue disease, Sjögren syndrome,
inflammatory bowel disease, and
neurosarcoidosis).18
Acute transverse myelitis (short or long segment) is an infrequent extra-articular complication of AS.18 It has been reported to evolve either as a distinct neurological complication of AS, or it may develop secondary to
TNF-alpha-inhibitor
therapy for the treatment of AS.18,19 AS is a heritable inflammatory
spondyloarthropathy that primarily affects the axial skeleton, which is mediated by T-cells; B-cells only play a minor role.5 On the contrary, the key for the pathogenesis of NMOSD is the production of
autoantibodies against AQP-4 channels expressed on astrocytes, leading to
complement-mediated damage, with ensuing
demyelination.
Myelitis usually shows high signal intensity on the tbl2-weighted image and contrast enhancement in the spinal cord.1-4 Despite the difference in molecular mechanisms, the diagnosis of these diseases in the same individual may not be coincidental. Recent evidence has shown T-cell-mediated inflammatory responses in cases of NMOSD.20 In particular, Th17 and Th2-related
cytokines are elevated in the CSF of NMO patients.20 Environmental factors such as Escherichia coli have also been proven to aggravate autoimmunity in AS and NMOSD (however, body fluid cultures for Escherichia coli, performed in our patient, showed similar association, and they were found negative two times).21,22 Although large-scale epidemiological studies investigating the underlying pathogenesis related to these diseases are lacking, studies have demonstrated an increased incidence of
optic neuritis among patients with AS.23
Systemic sclerosis and mixed and
undifferentiated connective tissue diseases were excluded after expert opinions (from two board-certified rheumatologists and two dermatologists) because of the lack of suggestive clinical findings (e.g., absence of skin thickening,
salt-and-pepper appearance, nail changes, Mauskopf
facies, sclerodactyly,
calcinosis cutis, Raynaud's phenomenon, other cutaneous manifestations,
pulmonary arterial hypertension/
interstitial lung disease,
dysphagia, muscular
pain/weakness renal impairments, absence of ANA,
anti-centromere antibodies, anti-Scl-70, PM-Scl
antibodies, anti-
ds DNA,
PCNA, CENP-B, anti-
nucleosomes, anti-Smith, anti-U1-RNP, anti-Jo1, anti-Mi2, anti-Ro52, anti-La
antibodies, and normal C3 and
C4 complement levels) (The European League Against
Rheumatism and the American College of Rheumatology classification criteria 2019).24 Finally, our patient was treated with intravenous
steroids followed by
rituximab infusions, a monoclonal anti-CD20 antibody directed against B-cells. In particular, this patient clinically and radiologically responded to
immunomodulatory drugs, which might support a possible common pathogenic basis of the two processes.
TNF-alpha inhibitors are commonly used as novel
therapeutics in AS; however, they can potentially result in serious complications, that is, secondary
demyelinating disorders.25 However, such inhibitors in this patient were not used. When used in cases of AS, they show satisfactory results.25,26 Therefore, it was decided to treat him with
rituximab only without adding any second immunomodulatory. Other possible therapeutic options include
cyclophosphamide and
mycophenolate mofetil, but they were not used because of their low efficacy-safety balance. Moreover,
plasmapheresis was not available in our specific setting, despite solid evidence that early treatment with therapeutic strategy (5-7 courses) provides good long-term outcomes in patients with NMOSD.27 Therefore, when dealing with a case of acute non-
compressive myelopathy, history and clinical examination are important to determine the potential underlying etiology and identify an undermined systemic disorder with apparently unrelated non-specific features. Connective tissue disorders should always be considered as a differential diagnosis and be ruled out in all cases of either seropositive or seronegative NMOSD. A diagnosis of AS should be considered in relevant circumstances when dealing with a case of isolated seronegative LETM. Moreover, early diagnosis and treatment of AS are quintessential to prevent lifelong distressing disabilities. However, whether patients with AS have any extra predilection to develop NMOSD throughout their life requires further studies.