Myelin oligodendrocyte glycoprotein (MOG) antibody-associated longitudinally extensive transverse myelitis (LETM) and primary Sjogren syndrome: a rare association

Background

In addition to the well-recognised entities of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), the field of central nervous system (CNS) inflammatory disorders has been widened by the inclusion of a new pathogenic entity characterised by the presence of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in the serum with concomitant demyelination. Neuromyelitis optica (NMO) is associated with autoantibodies directed against aquaporin-4 (AQP4), which can be found in 70% of patients.1 Studies have demonstrated the pathogenic role of MOG antibodies in a subset of patients with AQP4-negative NMOSD.2 MOG antibody disease (MOGAD) represents a new disease entity that accounts for a fraction of the previously diagnosed AQP4 antibody-negative NMOSD. The clinical features, neuroimaging and disease course follow a pattern distinct from MS or AQP4-positive NMOSD. MOGAD encompasses a variety of clinical phenotypes, including optic neuritis (ON)—unilateral and bilateral, longitudinally extensive transverse myelitis (LETM), acute disseminated encephalomyelitis (ADEM), short-segment transverse myelitis (TM) and ON+TM.3

ADEM is an immune-mediated demyelinating disorder mostly affecting children with a postulated post-infectious association. It is clinically characterised by multifocal neurological deficits with imaging evidence of ill-defined white matter lesions in the brain and spinal cord. It is a diagnosis of exclusion. Given the presumed autoimmune aetiology, it is treated with immunosuppression. Based on antibody testing, a patient’s combined presentation of ON and TM suggests the possibility of NMOSD or MOGAD.4

Multiple case reports and review articles have been published regarding the association between NMOSD and various autoimmune diseases.5–8 Among the systemic autoimmune diseases, systemic lupus erythematosus (SLE) and Sjogren syndrome are reported to be the most common; whereas, among organ-specific autoimmune diseases, autoimmune thyroiditis and myasthenia gravis are mostly encountered in a setting of NMOSD.6 Despite the availability of abundant research material linking NMOSD with autoimmune disorders, the same does not hold for a recently recognised entity like MOGAD. In contrast, a recently published study points out that SLE and associated autoantibodies are not as strongly associated with MOGAD as with AQP4-positive NMOSD.9 In addition to this, to the best of our knowledge, only three case reports have highlighted an association between Sjogren syndrome and MOGAD, with two reporting on the ON phenotype of MOGAD and a single case report on the LETM phenotype of MOGAD.10–12 Herein, we report a single case of a woman in her 30s with an LETM phenotype found to be anti-MOG antibody positive who was subsequently diagnosed with primary Sjogren syndrome as per the 2016 American College of Rheumatology-European Alliance of Associations for Rheumatology (ACR-EULAR) criteria.13 This is the second reported instance of MOGAD with an LETM phenotype in a patient with primary Sjogren syndrome and the first of its kind in the adult population. This highlights the importance of testing for primary Sjogren syndrome in patients with MOGAD and, conversely, the need for testing AQP4 and MOG antibodies in patients with primary Sjogren syndrome who develop TM to determine the type and duration of immunotherapy that needs to be instituted in such patients.

Case presentation

A woman in her 30s with no prior comorbidities presented to the emergency department with gradually progressive weakness in all four limbs for the last 7 days. The onset of this weakness was preceded a couple of days before with a vague neck pain that worsened on neck movement and a tingling sensation that radiated down the upper limbs, anterior chest wall, abdomen and bilateral lower limbs. Moreover, the onset of this weakness was also associated with decreased sensation from the neck downwards, along with constipation and urinary retention for the past 3 days. The patient gave neither any history suggestive of cranial nerve involvement nor a history of preceding infectious prodrome/trauma/vaccination/dog bite/snake bite. The patient provided a history of dry eyes and mouth for 1 year. There was no associated history of joint pain, oral ulcers, rash, alopecia or seizures. There was no history of similar illness in the past or any of the family members.

On examination, the patient was found to be tachypnoeic with a normal pulse rate and blood pressure. CNS examination revealed normal higher mental functions and cranial nerve examination. Motor examination revealed normal bulk, hypotonia across all joints in the four limbs, power of 0/5 for all movements in the four limbs with diminished biceps and triceps reflex, exaggerated knee reflex, normal ankle reflex and bilateral extensor plantar without any clonus. Sensory examination revealed impaired lateral spinothalamic, anterior spinothalamic and dorsal column sensations extending below the C2 dermatome. The bladder was palpated as a tender, firm, globular, midline mass, and around 1.5 L of urine was evacuated post-catheterisation. Gait and cerebellar functions could not be tested because of decreased power; however, there was no nystagmus, scanning speech or pendular knee jerk. Examination of the spine did not reveal any deformities or tenderness.

Given the sudden-onset quadriparesis with upper motor neuron (UMN) signs, and sensory and autonomic involvement, a provisional diagnosis of ‘UMN quadriparesis in spinal shock’ was made, and the patient was planned for further investigations. Due to persistent tachypnoea, the patient was shifted to an intensive care unit for better monitoring. Twenty-four hours later, the patient was intubated and tracheostomised because of the worsening single breath count (SBC).

Investigations

Routine blood investigations were within normal limits, including a complete haemogram, liver function test, kidney function test and coagulation profile. Systemic infections were ruled out with negative blood and urine cultures and a normal serum procalcitonin. The patient tested negative for HIV, hepatitis B, hepatitis C and COVID-19.

Non-contrast CT of the brain showed no major vascular territory infarct or haemorrhage. There was also no mass, collection or hydrocephalus. Posterior fossa structures are normal, with no bony fracture. Basal cisterns and foramen magnum were patent.

MRI of the brain and cervical spine with whole spine screening (figures 1 and 2) revealed long-segment TM—T2-weighted signal hyperintensity extending from the cervical-medullary junction to the lower border of the T5 vertebral level involving almost the entire cross-section of the cord. Optic nerves were unremarkable.

High-resolution CT of the chest showed normal bilateral lung parenchyma. There was no evidence of pleural/pericardial effusion/mediastinal lymphadenopathy. Bony thorax and visualised spine were normal.

Funduscopy revealed no evidence of papilloedema, and visual evoked potential (VEP) study was normal in bilateral eyes.

Cerebrospinal fluid (CSF) analysis revealed elevated protein (77 mg/dL), normal CSF, serum glucose (0.7) and moderate pleocytosis (34 cells/mm³: 74% mononuclear, 26% polymorphonuclear) with normal adenosine deaminase levels (2.9 U/L). CSF sample tested positive for IgG anti-MOG antibodies and negative for IgG anti-AQP4 antibodies by a cell-based immunoassay.

In view of LETM and positive anti-MOG antibodies with negative AQP4 antibodies, the patient was diagnosed with MOGAD LETM phenotype (she did not satisfy the criteria for diagnosis of AQP4-negative NMOSD). After the primary diagnosis was made, the patient underwent an autoimmune workup (table 1).

Salivary scintigraphy revealed reduced trapping function of both the parotid and submandibular salivary glands with slow drainage.

Minor salivary gland biopsy demonstrated focal areas of mild lymphocytic inflammation (less than 50 lymphocytes) within the parenchyma. There was no acinar atrophy or fibrosis noted. Focus score was 0.

The Schirmer test revealed 5 mm wetting in both eyes, indicative of severe bilateral dry eyes. The ocular staining score could not be done due to the inability of the patient to sit for the slit-lamp examination.

Differential diagnosis

The common differential diagnoses for a case of UMN quadriparesis included cervical myelopathy, high cervical cord compression, MS, foramen magnum/high cervical cord tumour, basilar artery occlusion and craniovertebral anomalies.

When the MRI of the brain and cervical spine with screening of the whole spine revealed LETM in the cervicothoracic region, the differential diagnoses were narrowed down to NMO, MOGAD and clinically isolated syndrome. Since there was no evidence of dissemination in space and time, the patient did not fit into the McDonald criteria for diagnosis of MS. Possibilities yet to be explored included NMO or MOGAD.

CSF analysis revealed increased protein and moderate pleocytosis, which was not specific for any of the aetiologies mentioned above. The CSF sample tested positive for MOG antibody and negative for AQP4 antibody. AQP4-positive NMOSD was ruled out, but AQP4-negative NMOSD was still possible along with MOGAD.

Funduscopy was done, which revealed no papilloedema or ON. VEPs were normal in bilateral eyes. MRI of the optic nerve did not reveal any optic nerve sheath thickening, hyperintensities or contrast enhancement, which ruled out the possibility of ON in our patient. Since the MRI of the brain did not reveal any area postrema or brainstem lesions, the diagnostic criteria for AQP4-negative NMOSD were not satisfied. The patient was diagnosed with MOGAD LETM phenotype.

Autoimmune workup revealed strong positive antinuclear antibodies (immunofluorescence assay) with strong positive anti-SS-A and borderline positivity for antinucleosome and antihistone antibodies. Given a background history of dry eyes and dry mouth, the possibility of Sjogren syndrome was considered. Anti-dsDNA, anti-Sm and antiphospholipid antibodies were found to be negative, and C3 and C4 levels were found to be normal. SLE and secondary Sjogren syndrome were ruled out. Salivary scintigraphy was performed, which revealed reduced trapping function of both parotid and submandibular salivary glands with slow drainage. The Schirmer test revealed less than 5 mm wetting in the bilateral eyes, indicative of severe bilateral dry eyes. However, a minor salivary gland biopsy revealed a focus score of 0. It is to be noted that despite a focus score of 0, the patient had other supporting clinical and laboratory criteria for diagnosing primary Sjogren syndrome.

According to the ACR-EULAR criteria for diagnosis of Sjogren syndrome, inclusion criteria were met from the history, a score more than/equal to 4 was achieved, exclusion criteria were satisfied, and hence a diagnosis of primary Sjogren syndrome was established.13

Treatment

When the diagnosis of LETM was made, after ruling out any active infections, the patient was given pulse-dose steroids (methylprednisolone 1 g every day) for 5 days and then continued on oral steroids (1 mg/kg/day dosing of prednisolone) and other supportive management. Meanwhile, because of the persistent tachypnoea and decreasing SBC, the patient was intubated and tracheostomised after 7 days of intubation when it was impossible to wean her off ventilatory support. The patient’s relatives were instructed on various range of motion exercises as part of the physiotherapy programme.

Despite the initial pulse dose of steroids, there was no significant improvement in the patient’s clinical status. Because of this, a decision was taken to initiate the patient on plasmapheresis (PLEX), and the patient received six sessions of PLEX over 2 weeks. After the first two sessions of PLEX, there was minimal improvement in the power of bilateral upper and lower limbs to a grade of 1/5. After the first four sessions of PLEX, it was possible to wean the patient off ventilatory support. After completing six sessions of PLEX, she was started on oral azathioprine (AZA) (50 mg two times per day) as part of steroid-sparing immunosuppressive therapy. Despite the severe disease presentation, the decision was taken to give a trial of AZA instead of rituximab (RTX)/intravenous immunoglobulin (IVIg)/mycophenolate mofetil (MMF), given the financial constraints of the patient. Furthermore, the patient was planned to be followed up regularly to assess treatment response and to switch therapy to one of the aforementioned alternatives in case of no clinical improvement/relapse.

Outcome and follow-up

There was no significant improvement in the patient’s clinical status after the pulse-dose steroids, because of which the patient was started on PLEX. After receiving two sessions of PLEX, there were noticeable voluntary flickering movements in bilateral upper and lower limbs (power of 1/5 in all four limbs). It was possible to wean the patient off ventilatory support after four sessions of PLEX. After completing all six sessions of PLEX, the patient showed gradual improvement in her power.

One month after the onset of quadriparesis, there was a significant improvement in the power, with left upper limb, lower limb and right lower limb power being 3/5 for all movements, and right upper limb power being 2/5 for all movements. The patient was on AZA 50 mg two times per day and prednisolone 10 mg once daily.

On the follow-up visit 4 months after the onset of quadriparesis, the patient was noted to have improved significantly, with full power in bilateral upper limbs and power of 4/5 for all movements in bilateral lower limbs. The patient was on AZA 50 mg two times per day and prednisolone 5 mg once daily.

On the follow-up visit 6 months after the onset of quadriparesis, the patient had improved almost completely with normal power in bilateral upper and lower limbs. Still, some weakness persisted in the small muscles of the hand. The patient was on AZA 50 mg two times per day. She had negative CSF anti-MOG antibody reports. The AZA dose was reduced to 50 mg once daily.

On the follow-up visit 1 year after the onset of quadriparesis, the patient had improved completely. The power of the small muscles of the hand had also normalised. Repeat CSF anti-MOG antibody testing was also negative. AZA was discontinued, and the patient was advised to follow up after 3 months.