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44-years-old female with no significant past medical history presented with 6 months of progressive weakness, that culminated in an inability to walk and well as urinary retention. MRI consistent with transverse myelitis. Infectious work up negative, and only found to have positive lupus anticoagulant and high-titer anti-cardiolipin IgG. Did not respond to high dose steroids and plasmapheresis.
- Can the transverse myelitis be related to her positive antiphospholipid antibodies? She did not have any DVT/PE or pregnancy losses in her history
- If she failed steroids – is there a role in trying other immunosuppression drugs, like IVIG or rituximab?
As described in the following report transverse myelitis can be associated with antiphospholipid antibodies, although the manifestation is relatively rare. The report will describe the case reports in the literature with a focus on progression and treatments.
The evidence regarding the treatment of transverse myelitis and in particular aPL associated myelopathies is very limited. Nevertheless, there are some reports and suggestions of successful treatments with cyclophosphamide and to a lesser extent with IVIG. Considering the quantity and quality of the data the conclusions and descriptions should be related with caution.
Neither the services nor the research report constitute medical advice of any kind and are not intended to be a substitute for professional medical advice.
Medical Meta Findings
- Can the transverse myelitis be related to her positive antiphospholipid antibodies?
Transverse myelitis can be a rare manifestation of APLA syndrome. A direct binding of antiphospholipid antibodies to CNS antigens leading to a distinct neuroimmunological mechanism was described, separate from the well-known pro-thrombotic effect of antiphospholipid antibodies. Nevertheless, the typically acute onset may be suggestive of a more vascular mechanism6. The classification criteria for APS are met if at least one clinical criterion (vascular thrombosis or pregnancy morbidity) and one laboratory criteria (presence of lupus anticoagulant, anticardiolipin antibodies, or anti-β2 glycoprotein I antibodies) are present. “Non-criteria” symptoms, such as headache, epilepsy, and transverse myelitis, are frequently associated with APS but are not considered for the diagnosis. The lack of recognition of these “non-criteria” can result in diagnostic difficulties in cases of isolated “non-criteria” manifestation5. Generally, as indicated by several articles, transverse myelopathy is a rare manifestation of antiphospholipid syndrome and its prevalence ranges between o.4% to 4% 6, 7, 8.
The following review will present several case reports and case series describing transverse myelitis associated with antiphospholipid antibodies or syndrome:
Clinical, radiologic, and therapeutic analysis of 14 patients with transverse myelitis associated with antiphospholipid syndrome: report of 4 cases and review of the literature – An article1 published in 2011 in The Seminars in Arthritis and Rheumatism (Q1, Impact Factor 6.16 ), described all the cases published in PubMed from 1966 till 2010 in which antiphospholipid syndrome and transverse myelitis were mentioned. In addition, four more cases were treated by the Rheumatology Division of the Hospital das Clínicas da Faculdade de Medicina da Universidade in São Paulo, Brazil, and showed an association between antiphospholipid syndrome and transverse myelitis.
Fourteen cases of patients with antiphospholipid syndrome (APS) and transverse myelitis (TM) were reviewed. The age of these patients ranged from 8 to 83, and cases of TM predominantly occurred among patients with primary APS (9/14). The clinical presentation of TM was characterized by effects on the thoracic spinal cord (9/14) that were associated with sphincter disturbances (8/14). The onset of symptoms was sudden in 8/14 cases, and the symptoms of myelitis were recurring in 3 cases. One case resulted in death. In most cases, treatment was based on corticosteroid pulse therapy (12/14), but some patients were treated with pulse cyclophosphamide (5/14), plasmapheresis (3/14), or rituximab (1/14). Generally, the therapeutic response was satisfactory, and complete improvement was seen in 9/14 patients.
The treatments’ characteristics and outcomes are shown in the following table:
Transverse myelitis as a rare presentation of antiphospholipid – antibody-associated disorders – An article2 published in Multiple Sclerosis And Related Disorders journal (Q2, Impact Factor 4.34) in 2020, presented a case report of a 35-year-old man, suffering from a clinical and radiological manifestation of progressive transverse myelitis associated with positive antiphospholipid antibodies. The patient was diagnosed with a rare form of antiphospholipid -antibody-associated transverse myelitis after testing positive for cardiolipin, β2 glycoprotein I, lupus anticoagulant, phosphatidylserine, phosphatidylinositol, and phosphatidic acid antibodies, but negative for ANA, ENA, and anti-ds-DNA antibodies. The patient did not meet the full criteria for antiphospholipid syndrome (APS) according to the Sydney criteria and had no history of thrombosis. The patient was treated with azathioprine (100mg/day) and high-dose methylprednisolone, but no antithrombotic treatment was given. After four months, the patient’s neurological symptoms were stable and the spinal cord lesion on MRI had decreased.
Transverse Myelitis in Patients with Antiphospholipid Antibodies – The Importance of Early Diagnosis and Treatment – An article3 published in The Journal of Clinical Rheumatology (Q2, Impact Factor 1.169) in 2002 reviewed
the medical records of 100 patients treated at the Rheumatology Outpatient Clinic in Sheba Medical Center, Israel, to identify patients with transverse myelitis (TM) and positive aPL results. The report did not evaluate the effectiveness of cyclophosphamide therapy but as suggested by four cases with similar clinical characteristics and limited literature, an early diagnosis of TM and aggressive treatment with intravenous cyclophosphamide, methylprednisolone, and anticoagulants (when aPL is present) could improve the prognosis of these patients. It seems that the earlier the diagnosis is made and the more aggressive the treatment is, the better the outcome for the patient. To confirm this, larger patient groups need to be analyzed in prospective clinical trials
The duration between symptom onset and classification of these patients as having TM with positive aPL and initiation of treatment as well as the treatment prescriptions are shown in the following table:
Patient 1 – Following the first treatment course there was an improvement of paraparesis, and after two courses of pulse therapy she was able to walk. She recovered totally after six treatment courses and had no neurogenic bladder either.
Patient 2 – following her first treatment course she had an improvement of her paraplegia with slight movements of her left leg. After the subsequent courses she had further improvement in leg movement, but her anesthetic level remained unchanged.
Patients 3 (shorter treatment due to refusal) and 4 (refusal to therapy) – no change in their condition and they remained confined to a wheelchair.
2. If she failed steroids – is there a role in trying other immunosuppression drugs, like IVIG or rituximab?
A Note Of Caution About The Diagnosis And Treatment Of Suspected Transverse Myelitis – an article13, published in Neurology Journal (Q1, Impact Factor 9.9) in 2014 concluded that “ Treatments with IVIG or PLEX should be avoided if the diagnosis of inflammatory myelopathy is in question due to lack of pleocytosis and/or enhancement of lesion on spinal cord neuroimaging. In these instances, presence of vascular myelopathies should be explored prior to treatment given that both IVIG and PLEX may worsen vascular myelopathies and produce irreversible ischemic cord damage”. Considering the possibility of vascular mechanisms suggested for aPL-associated transverse myelitis, this note of caution might be relevant.
In general, the evidence base regarding the treatment of acute transverse myelitis lacks. The treatments that are currently in use consist of intravenous steroid treatment and plasma exchange and have the most significant efficacy evidence although it is based on several relatively small studies.
Cyclophosphamide was purposed in the literature for patients who continued to progress despite steroid-based therapy9. Nevertheless, it is important to mention that its efficacy was shown mainly in SLE-associated myelopathies3. As described in an article published in 2015 in the Neurologist Journal (Q3, Impact Factor 1.524), the recommendation for cyclophosphamide therapy is based on clinical experience and the authors suggest that it is worth considering this option until further double-blinded placebo trials will be conducted. The authors also suggest that immunomodulatory treatments like azathioprine, methotrexate, and mycophenolate may also be considered in patients presenting with systemic inflammatory diseases9.
IVIG – The possible efficacy of IVIG treatment for transverse myelitis was discussed in an evidence review published by the NHS (National Health Service -England). The authors conclude that although the evidence is very limited, IVIG may have a potential benefit in aborting transverse myelitis attacks10. This claim may be supported by a case report describing a complete recovery of a 4-year-old boy with steroid-resistant transverse myelitis11. Additionally, another case report describes the recovery of a seven-year-old boy, with recurrent transverse myelitis. The boy recovered with steroid therapy from the first episode but failed to respond to methylprednisolone, he was then treated with oral prednisolone with IVIG, aspirin, and warfarin and showed extremely gradual improvements. His hyperaesthesia took 4 weeks to disappear and at the end of 6 months, the power in the lower limbs improved to grade III/V, so that he could walk unaided12.
Rodrigues CE, de Carvalho JF. Clinical, radiologic, and therapeutic analysis of 14 patients with transverse myelitis associated with antiphospholipid syndrome: report of 4 cases and review of the literature. Semin Arthritis Rheum. 2011 Feb;40(4):349-57. doi:10.1016/j.semarthrit.2010.05.004.
Berek K, Fava E, Zinganell A, Hegen H, Auer M, Wurth S, Rhomberg P, Deisenhammer F, Di Pauli F. Transverse myelitis as a rare presentation of antiphospholipid-antibody-associated disorders. Mult Scler Relat Disord. 2020 Oct;45:102405. doi: 10.1016/j.msard.2020.102405. Epub 2020 Jul 17.
Sherer Y, Hassin S, Shoenfeld Y, Levy Y, Livneh A, Ohry A, Langevitz P. Transverse myelitis in patients with antiphospholipid antibodies–the importance of early diagnosis and treatment. Clin Rheumatol. 2002 Jun;21(3):207-10. doi: 10.1007/s10067-002-8287-2.
Sherer Y, Livneh A, Levy Y, Shoenfeld Y, Langevitz P. Dermatomyositis and polymyositis associated with the antiphospholipid syndrome-a novel overlap syndrome. Lupus. 2000;9(1):42-6. doi: 10.1177/096120330000900108.
Pires da Rosa G, Bettencourt P, Rodríguez-Pintó I, Cervera R, Espinosa G. “Non-criteria” antiphospholipid syndrome: A nomenclature proposal. Autoimmun Rev. 2020;19(12):102689. doi:10.1016/j.autrev.2020.102689
Mustafa R. Neurologic Manifestations of Catastrophic Antiphospholipid Syndrome. Curr Neurol Neurosci Rep. 2022;22(10):589-600. doi:10.1007/s11910-022-01228-0
Leal Rato M, Bandeira M, Romão VC, Aguiar de Sousa D. Neurologic Manifestations of the Antiphospholipid Syndrome – an Update. Curr Neurol Neurosci Rep. 2021;21(8):41. Published 2021 Jun 14. doi:10.1007/s11910-021-01124-z
Cervera R, Boffa MC, Khamashta MA, Hughes GR. The Euro-Phospholipid project: epidemiology of the antiphospholipid syndrome in Europe. Lupus. 2009;18(10):889-893. doi:10.1177/0961203309106832
Kaplin AI, Krishnan C, Deshpande DM, Pardo CA, Kerr DA. Diagnosis and management of acute myelopathies. Neurologist. 2005;11(1):2-18. doi:10.1097/01.nrl.0000149975.39201.0b
(2016, January 1). Evidence Review: Intravenous immunoglobulin for acute disseminated encephalomyelitis. NHS England. https://www.engage.england.nhs.uk/consultation/clinical-commissioning-wave8/user_uploads/f06x05-adem-evidence-rev.pdf
Pavlou E, Gkampeta A, Kouskouras K, Evangeliou A, Athanasiadou-Piperopoulou F. Idiopathic acute transverse myelitis: Complete recovery after intravenous immunoglobulin. Hippokratia. 2012;16(3):283-285.
Shaharao V, Bartakke S, Muranjan MN, Bavdekar MS, Bavdekar SB, Udani VP. Recurrent acute transverse myelopathy: association with antiphospholipid antibody syndrome. Indian J Pediatr. 2004;71(6):559-561. doi:10.1007/BF02724305
A Note Of Caution About The Diagnosis And Treatment Of Suspected Transverse Myelitis [TM] (P5.181), Jorge Jimenez Arango, Maureen Mealy, Phillipe Gailloud, Carlos Pardo-Villamizar Neurology Apr 2014, 82 (10 Supplement) P5.181;
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