Will Transverse Myelitis Flare Up Again

June 2014 ; i (1) Article Open Access

Predictors of recurrence following an initial episode of transverse myelitis

Start published April 24, 2014, DOI: https://doi.org/10.1212/NXI.0000000000000004

Abstract

Objective: This report sought to place factors that increased the hazard of recurrence after an initial transverse myelitis (TM) presentation.

Methods: Retrospective cohort written report of 192 patients initially presenting with TM of unknown etiology. Patients diagnosed with multiple sclerosis during the first myelitis episode were excluded. Demographic and laboratory data were analyzed for associations with recurrence.

Results: Ane hundred ten of 192 patients (57%) eventually developed recurrent symptoms: 69 (63%) neuromyelitis optica (NMO) or NMO spectrum disorder, 34 (31%) non-NMO recurrent TM, and 7 (6%) systemic autoimmune disease. Multiple independent risk factors for recurrence were identified: African American race (risk ratio 1.60, p < 0.001, 95% confidence interval i.26–2.03; similarly noted future), female sex (1.88, p = 0.007, one.xix–2.98), longitudinally all-encompassing myelitis at onset (1.34, p = 0.036, ane.01–i.78), Sjogren syndrome antigen A (1.89, p = 0.003, 1.44–ii.48), vitamin D insufficiency (iv.00, p < 0.001, 1.60–10.0), antinuclear antibody titer ≥1:160 (1.69, p = 0.006, 1.23–ii.32), and the presence of inflammatory markers (due east.g., immunoglobulin G index) in the CSF (two.14, p < 0.001, ane.44–3.17).

Conclusions: Sex, race, and serologic biomarkers warrant consideration when assessing risk of TM recurrence. Male sex and Caucasian American race were independently associated with run a risk of monophasic idiopathic TM. Recurrence risk in female and African American patients appears driven by a greater likelihood of developing NMO or NMO spectrum disorder.

GLOSSARY

ANA=

antinuclear antibody;

Ig=

immunoglobulin;

JHH=

Johns Hopkins Infirmary;

LETM=

longitudinally extensive TM;

MAD=

median accented difference;

MS=

multiple sclerosis;

NMO=

neuromyelitis optica;

NMOSD=

NMO spectrum disorder;

OR=

odds ratio;

SLE=

systemic lupus erythematosus;

TM=

transverse myelitis

Transverse myelitis (TM) tin can occur in multiple illness contexts, including multiple sclerosis (MS), neuromyelitis optica (NMO), diverse infections, and autoimmune rheumatologic disorders. When patients nowadays with an initial effect of TM, diagnosis of a relapsing disease has prognostic implications and guides preventive handling. Failure to use appropriate immunomodulatory or immunosuppressive handling may lead to unchecked relapses and long-term inability. In dissimilarity, a patient with suspected monophasic idiopathic TM might only require acute management, symptomatic treatment, and subsequent rehabilitation rather than long-term immunosuppressive treatment. In many circumstances, notwithstanding, the evaluation of an initial TM consequence does not yield sufficient historical, clinical, radiologic, or laboratory data to meet diagnostic criteria for an underlying status.^ane The patient with a outset-time TM episode accompanied past a normal or nondiagnostic brain MRI, normal or inconclusive laboratory information, and no prior neurologic symptoms or historical proposition of systemic affliction may be diagnosed with monophasic idiopathic TM but left with anticipation most the risk of recurrence.

Previous studies accept identified limited biomarkers associated with recurrence. Patients with recurrent TM tend to have lower vitamin D levels during presentation than those with monophasic illness, suggesting an association between recurrent TM and vitamin D insufficiency.^two Anti-Ro (SS-A) antibodies have been associated with recurrent TM.³ It is well known that a first myelitis episode may just herald the onset of MS when it is associated with typical encephalon lesions on MRI and abnormal CSF studies with oligoclonal banding patterns and an elevated immunoglobulin (Ig) Grand alphabetize.^iv A single longitudinally extensive TM (LETM) in the setting of a seropositive NMO-IgG test is sufficient to diagnose NMO spectrum disorder (NMOSD).⁵

Despite this progress, in that location is even so uncertainty surrounding the prognostic implications of an initial myelitis event, and it is not clear to what extent demographic features and/or biomarker testing influence the risk of recurrence. We performed a retrospective cohort study to identify factors at the initial presentation of TM that are associated with developing recurrent neuroinflammatory disease. Features that portend recurrence may prompt consideration of empiric preventive treatment in high-take chances cases. Alternatively, some patients may be spared unnecessary long-term immunosuppression if features of their case suggest a higher likelihood of monophasic disease.

METHODS

Data sources and study participants.

Records of patients referred to the Johns Hopkins Transverse Myelitis Centre from 2005 to 2012 were reviewed for demographic and laboratory data available at the initial evaluation of TM. Referrals included patients initially treated at Johns Hopkins Infirmary (JHH) and patients from a multifariousness of bookish and private hospitals later referred to JHH for consultation. The patients were categorized into 2 groups: monophasic idiopathic TM (declared monophasic after at least iii years of untreated observation) and recurrent TM of any etiology. The recurrent grouping was farther subdivided into recurrent myelitis of unknown etiology, NMO/NMOSD (divers by Wingerchuk 2006 criteria), and autoimmune rheumatologic diagnoses.^{half-dozen,–,9} Time to recurrence is heavily skewed to the correct in patients with TM, with a median of eight months and a median absolute deviation (MAD) of 5 months. Nosotros chose to define monophasic idiopathic TM cases after at to the lowest degree a iii-year relapse-free period because this duration extends more than 5 times the MAD beyond the median relapse time and is therefore probable to reflect the period during which most relapses occur.

TM diagnoses were based on clinical symptoms of acute motor, sensory, or autonomic deficits with a corresponding MRI lesion. Patients diagnosed with monophasic idiopathic TM did not have a clinical history of optic neuritis or previous neurologic deficits, did non examination positive for the NMO-IgG antibody, and did not have brain MRI that was diagnostic of other weather (e.g., MS). Brain MRI findings were considered "nonspecific" (i.e., nondiagnostic) if whatsoever noted abnormalities were non located in typical regions associated with MS (eastward.g., periventricular, callosal, pericallosal, juxta-cortical, or cerebellar). We defined recurrent TM every bit disease involving repeated inflammatory attacks of the spinal cord without symptomatic involvement of the brain; these patients did not meet diagnostic criteria for NMO or NMOSD.⁹ Myelitis cases without documented MRI evidence of spinal string involvement were not included. Longitudinally extensive lesions were divers as ≥iii vertebral segment spinal cord lesions on MRI. Patients diagnosed with specific disorders such as MS during the first myelitis episode were excluded.

Standard protocol approvals, registrations, and patient consents.

This retrospective study was approved by the Johns Hopkins Institutional Review Board.

Statistical analyses.

Statistical analyses were performed using Stata 12 (StataCorp LP, College Station, TX). Univariate logistic regression was used to decide unadjusted odds ratios (ORs) for associations between predictor variables and the take a chance of developing whatever course of recurrent myelitis (including idiopathic recurrent myelitis, NMOSD, and rheumatologic conditions), and corresponding risk ratios were determined via standard 2 × 2 table calculations. Similar analyses were likewise performed to identify associations with the hazard of developing NMO or an NMOSD and with the hazard of developing a rheumatologic disorder (Sjogren syndrome or systemic lupus erythematosus [SLE]). Variables were chosen a priori and included age, sexual practice, cocky-identified race, the presence or absence of a longitudinally extensive lesion during the initial myelitis episode, CSF pleocytosis (white blood prison cell count >v cells/mm^three), elevated CSF protein (>threescore mg/dL), IgG index >0.seven, positive oligoclonal band testing, vitamin D insufficiency (25-OH vitamin D levels <30 ng/mL) or deficiency (<20 ng/mL), vitamin B₁₂ insufficiency, an antinuclear antibiotic (ANA) titer ≥ane:160 (95% of healthy patients are excluded from SLE diagnosis at this cutoff value^x), and the presence of antibodies to double-stranded DNA, Ro (SS-A) antigen, and La (SS-B) antigen. In addition, adapted risk ratios and ORs were calculated with respect to historic period, sex, race (compared as African American vs Caucasian, every bit these were the 2 largest groups), and the presence or absenteeism of a longitudinally extensive spinal string lesion at onset. Risk ratios and adjusted risk ratios were determined using standard ii × 2 table calculations and log-binomial regression, respectively.¹¹ Reported p values are two-tailed with a significance threshold of p <0.05 and were calculated via χ² or Fisher exact tests equally appropriate.

Because the event of recurrent disease was not rare among individuals in this cohort, there is an expected disparity between ORs and risk ratios, with the latter being more than modest and reflective of hazard compared to respective reference categories.

RESULTS

Case records were reviewed for 192 patients whose initial extensive evaluation of myelitis yielded insufficient evidence to confirm a specific disorder; thus, all were initially diagnosed with monophasic idiopathic TM (table ane). Among those who followed up in our clinic, 82 patients remained diagnosed with monophasic idiopathic TM as they did not develop recurrence within at least 3 years without immunosuppressive treatment. I hundred ten patients would eventually be diagnosed with recurrent neuroinflammatory disease: 69 patients with NMO or NMOSD, 34 patients with recurrent TM, and 7 patients with rheumatologic affliction (4 with Sjogren syndrome, 3 with SLE). Age did non differ betwixt recurrent and monophasic patients. There were higher proportions of female (p = 0.007) and African American patients (p < 0.001) in the recurrent group; the sexual practice and race disparities were particularly apparent among NMO diagnoses. Patients with recurrent myelitis were more likely to have had nonspecific brain MRI findings at onset (risk ratio ane.55, p < 0.001, 95% confidence interval ane.23–ane.95).

Table 1

Characteristics of 192 patients who initially presented with idiopathic transverse myelitis

The risk ratios and ORs for associations of predictor variables with the adventure of developing any form of recurrent disease are listed in tables ii and three. Female person sex and cocky-identified African American beginnings were both independently associated with higher gamble of developing recurrent affliction, primarily every bit NMO. Women were nearly twice as probable to develop recurrent disease equally men, and African Americans were more likely to develop recurrent TM than Caucasian Americans (table two). Patients with LETM at onset were more than likely to develop recurrent myelitis, particularly so with eventual NMO or NMOSD.

Table 2

Adjusted hazard and odds ratios for associations of demographic/clinical variables

Table 3

Unadjusted risk ratios for associations of laboratory variables with risk of recurrent disease

CSF pleocytosis at onset of >5 white blood cells/μL, positive IgG index, positive oligoclonal ring testing, vitamin D insufficiency and deficiency (25-OH vitamin D <30 ng/mL and <20 ng/mL, respectively), ANA titer of ≥1:160, and presence of antibodies to Ro/SS-A antigen were all also independently associated with increased risk of developing recurrent myelitis (table 3). Age, elevated CSF protein, vitamin B₁₂ insufficiency, antibodies to La/SS-B antigen, and positive double-stranded DNA antibiotic testing at TM onset were not associated with recurrent disease in this cohort.

Eventual diagnoses of NMO or NMOSD deemed for 69 of the 110 recurrent myelitis cases (62.7%). More specifically, 24 of these 69 cases (35%) were diagnosed with NMO and somewhen tested positive for NMO IgG at some indicate later on the initial presentation; seven cases (10%) met diagnostic criteria for NMO despite negative NMO IgG tests, and 38 cases (55%) were diagnosed as NMOSD. The risk ratios and ORs for associations of predictor variables with the take chances of developing NMO or an NMOSD are listed in tables 2 and iii. Features associated with eventual diagnosis of NMO/NMOSD included LETM at onset, female sexual practice, African American race, elevated IgG alphabetize, vitamin D insufficiency, an ANA titer of ≥one:160, and antibodies to Ro/SS-A antigen.

Give-and-take

In the cohort under study, female and African American patients had an increased risk of recurrence following a first myelitis event for which initial evaluation yielded insufficient evidence to ostend a specific disorder. The risk of recurrence in these groups appears to be driven by their greater likelihood of developing NMO or NMOSD. Male person and Caucasian American patients were more than probable to exist diagnosed with monophasic idiopathic TM (defined herein every bit at least 3 years without a relapse). Patients with an ANA titer of ≥1:160 had increased chance of recurrence, which typically occurred in the context of NMO, Sjogren syndrome, or SLE. This study too supports previously reported associations betwixt the risk of recurrent TM and vitamin D insufficiency, anti-Ro/SS-A antibodies, and prove of inflammation in the CSF during the initial episode. In add-on, the results back up the notion that while LETM is oft associated with recurrence in the context of NMO/NMOSD, information technology tin occur in monophasic cases and not-NMO recurrent TM cases too.¹² In add-on to NMO, idiopathic monophasic TM, and non-NMO recurrent TM, the differential diagnosis of longitudinally extensive myelitis encompasses diverse conditions, including Sjogren syndrome, SLE, sarcoidosis, neuro-Behçet disease, and parainfectious myelitis.^{13,–,sixteen}

There are varied reports of the sex activity distribution beyond all forms of myelitis. Several studies observe a female preponderance among patients with NMO, including sex ratios of 10:i, six.five:1, and 3:1 in Nippon, the United States, and France, respectively.^17,–,20 Reports of the sex distribution in non-NMO recurrent myelitis, however, are somewhat disparate. For case, while the Transverse Myelitis Consortium Working Grouping noted equal incidence of acute TM in men and women, there was a preponderance of male person patients in a series of South Korean idiopathic recurrent TM cases.^21,22 Likewise, among a cohort of 13 patients with idiopathic myelitis in an Italian study, 4 relapsed, all of whom were men.²³ In contrast, there was a markedly higher incidence of TM in women compared to men among a Northern California population, although it was not articulate what proportion of these patients may have had other features conferring risk of an eventual MS diagnosis.²⁴

Reports of the racial and indigenous distribution of TM are varied as well. No particular ethnic or racial predisposition has been noted regarding idiopathic TM.^25,–,28 Among patients of African or East Asian ancestry with demyelinating illness, NMO is a common diagnosis in a considerable number of case series around the world, including series in Japan, Great U.k., Nigeria, and Martinique.^29,–,32 In our analysis, which included 54 African Americans, 48 patients (88.9%) relapsed, while only 6 (xi.1%) remained monophasic. In contrast, out of 128 Caucasian Americans, but 57 patients (44.v%) relapsed.

Amidst patients whose initial workup discloses no diagnosis more specific than idiopathic TM (e.m., a brain MRI without lesions, no current or historical optic neuritis), it may be possible to better anticipate who volition develop recurrent events. Multiple independent risk factors represent considerations to be weighed in clinical circumstances. The presence of CSF abnormalities, vitamin D insufficiency, and serum autoantibodies—particularly NMO-IgG, anti-Ro/SS-A, and loftier titer ANA—should prompt attention to the run a risk of recurrence. In our study, male sex and Caucasian ancestry are more associated with monophasic TM, although this certainly does not preclude the possibility that any individual patient may take a recurrence. A full evaluation and clinical vigilance are warranted for all patients.

A potentially more than controversial issue concerns whether combinations of hazard factors should encourage early on empiric handling with immunosuppression. Such clinical decision-making is highly individualized, and there are no relevant clinical trials on this matter. Weighing the risk of potentially devastating recurrent TM against the risk of immunosuppression-related side effects is fraught with potential complications. In add-on to because a higher index of suspicion in patients with multiple recurrence chance factors, it may be prudent to revisit the evaluation of patients with newly diagnosed "idiopathic" TM ofttimes inside the first half-dozen–12 months. Serologic tests, particularly anti-aquaporin-4 antibodies, ANA, and antibodies to Ro/SS-A antigen, may yield actionable results when repeated. For case, there is evidence that anti-aquaporin-4 antibody titers fluctuate and tin can become detectable before recurrence; nosotros recommend repeating testing yearly for high-risk patients.³³ There are no randomized trials showing that vitamin D supplementation mitigates the hazard of recurrent TM, just supplementation may exist a reasonable and benign intervention in some patients with insufficient or deficient levels.

Some limitations of this study are inherent due to its retrospective design. During the referral procedure, some patients with balmy or relatively uncomplicated myelitis who otherwise might have been referred to the Johns Hopkins Transverse Myelitis Heart may instead accept been managed locally or referred to other clinics to rule out other systemic conditions based on concerns of the referring physician. There may exist a more general selection bias in this study, every bit the examined population is comprised of patients referred to a tertiary intendance heart and does not necessarily represent the population at large. Also, our cohort includes few patients of Asian or Hispanic ethnicities, which prevents pertinent analysis relative to and/or specific to these patient populations. Furthermore, variables were chosen for evaluation a priori, though data collection relied on retrospective review of medical chart data rather than prospective collection. Similarly, MRI was not systematically arranged prospectively, which would have been of involvement in tracking the evolution or development of any associated lesions.

Inferences nigh results from this study may too be tempered by the possibility that some patients currently considered monophasic may eventually develop recurrent disease, and some patients currently diagnosed with recurrent TM of unknown etiology may afterward receive a definitive diagnosis. Appropriately, there is a connected demand to better sympathize how recurrence gamble can be determined earlier and more precisely for patients with TM.

AUTHOR CONTRIBUTIONS

D.J.M., M.A.M., and M.L. conceptualized and designed the report. D.J.K., Chiliad.A.M., A.S., and G.L. each performed data analysis and contributed to interpretation of the results. D.J.K. drafted the manuscript and all authors substantively revised the document for intellectual content.

Written report FUNDING

No targeted funding reported.

DISCLOSURE

Dr. Kimbrough is supported by the NIH T32 Grooming Program in Neuroimmunology and Neuroinfectious Diseases at Johns Hopkins Academy, has received educational grant support from Teva Pharmaceuticals, and has received consulting fees from Medical Logix, LLC for the evolution of standing medical teaching programs. Maureen A. Mealy has served on an advisory board for Novartis. Alexandra Simpson reports no disclosures. Dr. Levy receives research support from the NIH, Guthy Jackson Charitable Foundation, Acorda, Sanofi, NeuralStem, ApoPharma Inc., Viropharma (Shire), and Genentech; is on the scientific informational board for Asterias; has received travel funding from Asterias and Guthy Jackson Charitable Foundation; receives publishing royalties from Lippincott Williams & Wilkins; and serves every bit a consultant for Chugai Pharmaceuticals, Glaxo-Smith-Kline, and Medimmune. Go to Neurology.org/nn for full disclosures.

Footnotes

• Go to Neurology.org/nn for full disclosures. Funding information and disclosures deemed relevant past the authors, if any, are provided at the finish of the article. The Article Processing Charge was paid by the authors.

• Received March xi, 2014.
• Accepted in final form March 17, 2014.

• © 2022 American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivative three.0 License, which permits downloading and sharing the work provided it is properly cited. The piece of work cannot be inverse in any way or used commercially.

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