Longitudinal extensive transverse myelitis: a rare neurological complication of systemic lupus erythematosus

Abstract

We present a 47-year-old woman with recently diagnosed systemic lupus erythematosus who developed progressive numbness and tingling of her upper and lower extremities, followed by weakness and difficulty ambulating. She was diagnosed with longitudinal extensive transverse myelitis involving her entire cervical and thoracic spinal cord. Infectious workup was unrevealing. She failed to respond to pulse–dose intravenous steroids, but slowly improved with the addition of plasmapheresis and cyclophosphamide. Following maintenance treatment with mycophenolate mofetil and slow tapering of oral steroids, she has maintained complete remission with significant recovery of neurological function.

Background

Acute myelitis is a rare medical emergency with an incidence of 1–4 cases per million. Common signs and symptoms of acute myelitis include paresis, sensory deficits and smooth muscle dysfunction.¹ Systemic lupus erythematosus (SLE)-associated myelitis occurs in 1%–2% of SLE patients and may be difficult to diagnose and treat. Longitudinal extensive transverse myelitis (LETM) is a rare variant of myelitis and is defined as the involvement of more than three to four continuous spinal segments.² There are very few case reports of LETM associated with SLE.^3–15 SLE-associated myelitis can present as the first manifestation of underlying SLE and may occur irrespective of the underlying lupus disease activity.^{8 10} Herein, we describe a female patient with SLE who presented with LETM, and responded remarkably well over time to aggressive immunomodulatory therapy.

Case presentation

A 47-year-old Mexican woman with a history of type 2 diabetes, hypertension and recently diagnosed SLE presented with numbness, weakness and pain of her bilateral upper and lower extremities progressing over 2 months. Her symptoms deteriorated such that she was unable to ambulate, and later developed constipation and urinary retention. She had been recently started on hydroxychloroquine 400 mg daily and prednisone 20 mg two times per day at another hospital several weeks prior, but her neurological symptoms continued to progress. Neurological examination on admission to our hospital revealed 4/5 upper extremity and 3/5 lower extremity strength, with reduced sensation to light touch below the umbilicus. Deep tendon reflexes were decreased, and plantar reflexes were down going bilaterally (ie, negative Babinski sign).

Investigations

Laboratory evaluations on admission to our hospital revealed a normal complete blood count, complete metabolic panel and urinalysis. Antinuclear antibody (ANA) was positive by ELISA, but negative by immunofluorescence. Anti-Ro/SSA was elevated (56 AU/mL; normal 0–40 AU/mL), anti-double-stranded DNA was positive at a titer of 1:10 (normal<1:10) and complements C3 and C4 were both decreased (C3=68.4 mg/dL; normal 85–170 mg/dL and C4=13.5 mg/dL; normal 16–40 mg/dL). Anti-La/SSB, anti-Smith, anti-RNP, rheumatoid factor and antineutrophil cytoplasmic antibodies were all negative. Antiphospholipid antibodies (ie, anticardiolipin antibodies, anti-β2 glycoprotein 1 antibodies and lupus anticoagulant) and anti-aquaporin-4 receptor antibody were all negative. Lumbar puncture revealed white cell count 0.061 × 10⁹ /L (normal 0–0.004 × 10⁹/L) with a monolymphocytic pleocytosis, protein 90 mg/dL (normal 14–54 mg/dL) and normal glucose. Oligoclonal bands were absent. Serum and cerebrospinal fluid (CSF) analyses for syphilis, Lyme disease, herpes simplex viruses 1/2 and varicella virus were all negative.

Contrast MRI of the brain demonstrated non-specific white matter changes in the periventricular white matter tracts, and diffuse abnormal signal in the brainstem extending into the cervical cord. MRIs of the spine revealed diffuse spinal cord enhancement and swelling from C1 to T12, felt to be on basis of myelitis (figure 1A,B).

Figure 1.

(A) Cervical spine and (B) thoracic spine MRIs at presentation demonstrating diffuse spinal cord enhancement and swelling.

Differential diagnosis

The differential diagnosis of LETM includes multiple sclerosis (MS), which is the most common cause of central nervous system (CNS) demyelination. MS is a chronic autoimmune disease involving the brain, spinal cord and optic nerves, and myelitis is a common manifestation of MS. MRI shows characteristic white matter lesions, which are typically ovoid in shape and located in a periventricular distribution. CSF usually demonstrates oligoclonal bands with an elevated IgG index, which were absent in our patient.¹⁶

Neuromyelitis optica (NMO), also known as Devic’s disease, is an autoimmune disease affecting predominantly the optic nerves and spinal cord, and may also be associated with LETM. Diagnostic criteria for NMO require the presence of optic neuritis, and at least two of the three supportive criteria: contiguous spinal cord lesion on MRI extending three or more segments, initial brain MRI not meeting usual diagnostic criteria for MS and the presence of anti-aquaporin-4 receptor antibody.^{3 16} Our patient did not have signs or symptoms of optic neuritis, and anti-aquaporin-4 receptor antibody testing was negative.

Acute disseminated encephalomyelitis (ADEM) can also cause LETM. ADEM is an autoimmune demyelinating disease of the CNS that typically occurs after infection, which was excluded by CSF analysis in our case.¹⁶

Intramedullary tumours, particularly ependymomas and astrocytomas can lead to LETM; however, the onset of symptoms is more chronic versus acute.

Radiation therapy is also known as a cause of LETM, which usually occurs months to years following radiation to areas including the CNS.¹⁶ Our patient had no prior history of radiation therapy.

Treatment

Methylprednisolone 1000 mg intravenous daily was administered for 5 days, with limited clinical improvement. Plasmapheresis was subsequently initiated for 7 cycles, and 3 monthly courses of intravenous cyclophosphamide (0.5 mg/m²) were administered. She was subsequently treated with prednisone 60 mg daily, and hydroxychloroquine 400 mg daily was continued throughout. Following cyclophosphamide, she was treated with mycophenolate mofetil 1000 mg two times per day, and prednisone dose was progressively tapered off over 2 years.

Outcome and follow-up

With the above regimen, our patient demonstrated gradual clinical improvement. She was initially quadriparetic and wheelchair-dependent, but was eventually able to feed herself independently and ambulate with a walker. After several months, she was able to ambulate independently and perform all activities of daily living, and return to work full-time at a bookstore. Her neuropathic pain was well controlled with gabapentin, baclofen and oxycodone as needed. Contrast MRIs of her spine 5 months later revealed decreased calibre of the spinal cord diffusely and decreased patchy elevated signal intensity, although increased patchy enhancement at focal areas of the cervicothoracic spine (figure 2A,B). Repeat cervical and thoracic MRIs 10 months later showed interval resolution of these foci of enhancement. She presently remains clinically stable on hydroxychloroquine 400 mg daily, and her mycophenolate mofetil dose was recently decreased to 500 mg two times per day.

Figure 2.

(A) Cervical spine and (B) thoracic spine MRIs after 5 months of treatment. There is decreased calibre of the spinal cord diffusely with decreased patchy elevated signal intensity, but increased patchy enhancement at focal areas.

Discussion

Herein, we describe a case of LETM in a patient with SLE that responded well to aggressive immunomodulatory therapy with pulse–dose steroids, plasmapheresis and cyclophosphamide.

The first case of LETM in an SLE patient was reported by Deodhar et al.⁴ A systematic review of the literature between 1966 and 2008 reported only 22 published cases of LETM associated with SLE. LETM is a rare complication of SLE, but can lead to variable degrees of disability.³ Contrast MRI is the most sensitive test to assess the extent of the disease.⁵ MRI findings in our case revealed diffuse spinal cord enhancement and swelling from C1 to T12. Similar radiographic findings may be seen with other aetiologies of LETM, including infection, MS and other systemic rheumatic diseases, such as Sjögren’s syndrome.^{17 18} Interestingly, our patient had a positive anti-Ro/SSA antibody, but she never had any clinical sicca symptoms or parotid gland enlargement. Therefore, sialometric testing and formal ophthalmological evaluation for xerophthalmia were not performed. However, it remains possible that she had an overlap of SLE and Sjögren’s syndrome contributing to her presentation of LETM, as LETM has been reported in a Sjögren’s syndrome patient without sicca symptoms.¹⁹

Although the pathogenesis of LETM is poorly understood, studies indicate that LETM might be related to either thrombosis or vasculitis of the spinal cord, leading to ischaemia and necrosis. Importantly, the antiphospholipid syndrome may be associated with transverse myelitis in SLE.³ Of note, antiphospholipid antibodies and antineutrophil cytoplasmic antibodies were negative in our patient.

There is no standard treatment for SLE-associated myelitis. A study by Harisdangku et al showed that early diagnosis and initiation of pulse–dose steroids are crucial in improving the prognosis of SLE-associated myelitis.²⁰ The combination of pulse–dose steroids and cyclophosphamide appears to be superior to pulse–dose steroids alone, based on published case series.^{6 21} There is also evidence of a higher remission rates in patients undergoing plasmapheresis, especially in critically ill patients.^{3 22} Our patient failed to improve significantly following pulse–dose steroids, but began to demonstrate clinical improvement following plasmapheresis followed by intravenous cyclophosphamide.

Studies have shown that the presence of anti-aquaporin-4 receptor antibody, anti-Ro/SSA, high titer ANA and vitamin D deficiency are associated with a risk of LETM recurrence.¹⁵ A study by Jiao et al also suggested that the recurrence of LETM is rare among patients with negative anti-aquaporin-4 receptor antibody. This is consistent with the clinical course of our patient, who has maintained clinical remission for years and did not present with anti-aquaporin-4 receptor antibody, although anti-Ro/SSA was positive. Immunosuppressive treatment decreased the rate of LETM recurrence in both anti-aquaporin-4 receptor antibody positive and anti-aquaporin-4 receptor antibody negative patients.²³

More than one-third of patients with acute transverse myelitis have a good prognosis, with full recovery or minimal sequelae. One-third of patients have moderate disability, and one-third have severe residual disability.^{1 15 24} Overall, the prognosis of LETM is less favourable than acute transverse myelitis.^{6 15} Fortunately, our SLE patient with LETM exhibited a remarkable progressive recovery of function, and was eventually able to ambulate, perform all activities of daily living and return to work full-time. Thus, appropriate early diagnosis and aggressive treatment of LETM are essential for a favourable outcome.

Learning points.

• Longitudinal extensive transverse myelitis (LETM) is a rare severe neurological complication of systemic lupus erythematosus.

• The differential diagnosis of LETM is broad and includes infections, demyelinating diseases (such as multiple sclerosis, neuromyelitis optica and acute disseminated encephalomyelitis) and intramedullary tumours.

• LETM must be treated aggressively with high-dose steroids, in addition to other immunomodulatory therapies, such as plasmapheresis and cyclophosphamide.