Characteristics of Spontaneous Spinal Cord Infarctionand Proposed Diagnostic CriteriaNicholas L. Zalewski, MD; Alejandro A. Rabinstein, MD; Karl N. Krecke, MD; Robert D. Brown Jr, MD;Eelco F. M. Wijdicks, MD; Brian G. Weinshenker, MD; Timothy J. Kaufmann, MD; Jonathan M. Morris, MD;Allen J. Aksamit, MD; J. D. Bartleson, MD; Giuseppe Lanzino, MD; Melissa M. Blessing, DO;Eoin P. Flanagan, MBBCh

IMPORTANCE Spinal cord infarction (SCI) is often disabling, and the diagnosis can bechallenging without an inciting event (eg, aortic surgery). Patients with a spontaneous SCIare often misdiagnosed as having transverse myelitis. Diagnostic criteria for SCI are lacking,hindering clinical care and research.

OBJECTIVE To describe the characteristics of spontaneous SCI and propose diagnosticcriteria.

DESIGN, SETTING, AND PARTICIPANTS An institution-based search tool was used to identifypatients evaluated at Mayo Clinic, Rochester, Minnesota, from January 1997 to December2017 with a spontaneous SCI. Patients provided written consent to use their records forresearch. Participants were 18 years and older with a diagnosis of spontaneous SCI (n = 133),and controls were selected from a database of alternative myelopathy etiologies forvalidation of the proposed diagnostic criteria (n = 280).

MAIN OUTCOMES AND MEASURES A descriptive analysis of SCI was performed and used topropose diagnostic criteria, and the criteria were validated.

RESULTS Of 133 included patients with a spontaneous SCI, the median (interquartile range)age at presentation was 60 (52-69) years, and 101 (76%) had vascular risk factors. Rapidonset of severe deficits reaching nadir within 12 hours was typical (102 [77%]); some had astuttering decline (31 [23%]). Sensory loss occurred in 126 patients (95%), selectivelyaffecting pain/temperature in 49 (39%). Initial magnetic resonance imaging (MRI) spineresults were normal in 30 patients (24%). Characteristic MRI T2-hyperintense patternsincluded owl eyes (82 [65%]) and pencil-like hyperintensity (50 [40%]); gadoliniumenhancement (37 of 96 [39%]) was often linear and located in the anterior gray matter.Confirmatory MRI findings included diffusion-weighted imaging/apparent diffusioncoefficient restriction (19 of 29 [67%]), adjacent dissection/occlusion (16 of 82 [20%]), andvertebral body infarction (11 [9%]). Cerebrospinal fluid showed mild inflammation in 7 of 89patients (8%). Diagnostic criteria was proposed for definite, probable, and possible SCI ofperiprocedural and spontaneous onset. In the validation cohort (n = 280), 9 patients (3%)met criteria for possible SCI, and none met criteria for probable SCI.

CONCLUSIONS AND RELEVANCE This large series of spontaneous SCIs provides clinical,laboratory, and MRI clues to SCI diagnosis. The diagnostic criteria proposed here will aidclinicians in making the correct diagnosis and ideally improve future care for patients withSCI. The validation of these criteria supports their utility in the evaluation of acutemyelopathy.

JAMA Neurol. 2019;76(1):56-63. doi:10.1001/jamaneurol.2018.2734Published online September 24, 2018.

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Author Affiliations: Department ofNeurology, Mayo Clinic, Rochester,Minnesota (Zalewski, Rabinstein,Brown, Wijdicks, Weinshenker,Aksamit, Bartleson, Flanagan);Department of Radiology, MayoClinic, Rochester, Minnesota (Krecke,Kaufmann, Morris); Department ofNeurosurgery, Mayo Clinic,Rochester, Minnesota (Lanzino);Department of Pathology, MayoClinic, Rochester, Minnesota(Blessing).

Corresponding Author: Nicholas L.Zalewski, MD, Mayo Clinic,200 1st St SW, Rochester, MN 55905(zalewski.nicholas@mayo.edu).

Research

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S pinal cord infarctions (SCI) cause acute myelopathy withhigh morbidity.1 A confident diagnosis is challengingwithout an inciting event such as a surgical procedure.2

Onset is more protracted and radiologic distinction from com-peting diagnoses is more difficult than with cerebral infarc-tion. Thus, patients with a spontaneous (ie, nonprocedural,nontraumatic) SCI often receive misdiagnoses. Although gen-erally considered rare,3 recent literature suggests underdiag-nosis of spontaneous SCI, with 2 large studies showing 14% to16% of patients referred for the evaluation of transverse my-elitis ultimately are diagnosed as having SCI.4,5 Misdiagnosismay expose patients to unnecessary and possibly deleterioustreatments, as well as missed treatment opportunities and sec-ondary stroke prevention. Moreover, the lack of diagnostic cri-teria hinders progress in the field of SCI. Based on an analysisof 75 cases of periprocedural SCIs,2 we applied insights fromthese definite cases to spontaneous SCI to better characterizeits clinical, laboratory, and radiologic features and ultimatelypropose criteria for diagnosis of SCI.

MethodsStandard Protocol Approvals, Registrations,and Patient ConsentsThe study was approved by the institutional review board ofMayo Clinic, Rochester, Minnesota. All patients provided writ-ten consent to the use of their medical records for research.

Patients and Inclusion CriteriaWe used an institution research tool to identify patients witha spontaneous SCI evaluated at Mayo Clinic, Rochester, Min-nesota, from January 1, 1997, to December 1, 2017. We searchedclinical notes in the Impression and Diagnosis sections for theterms spinal cord infarction, spinal cord stroke, anterior spinalartery, posterior spinal artery, and vascular myelopathy. We sub-sequently reviewed the data of all patients to verify the diag-nosis. None of the included cases had spinal cord trauma, com-pression, or a recent procedure within 1 month. Inclusioncriteria were final diagnosis of spontaneous SCI and ad-equate clinical (clear timeline and specificity of deficits,appropriate alternative etiologies excluded) and radiologic data(neuroimaging consistent with SCI and/or rule out alterna-tive etiologies). Patients with periprocedural SCI were excludedbut are reported elsewhere.2 Furthermore, we excluded 46 pa-tients in whom SCI was suspected but had incomplete data perour inclusion criteria.

Myelopathy Diagnostic EvaluationThe Mayo Clinic electronic medical record was reviewed forclinical details, laboratory values, neuroimaging findings, elec-trophysiological tests, and cerebrospinal fluid (CSF) results. Alltesting was performed as deemed appropriate by the manag-ing physicians (including N.L.Z., A.A.R., R.D.B., E.F.M.W.,B.G.W., A.J.A., J.D.B., and E.P.F.). Representative neuroimag-ing was reviewed on Quick Query Radiographs and Photo-graphs Electronic Analysis and Display Station NeuroimagingProgram.

Laboratory EvaluationLaboratory evaluation varied as deemed appropriate by eachphysician and included vitamin B12, copper, zinc, syphilis se-rology, Lyme disease serology, varicella-zoster virus serol-ogy, HIV serology, human T-lymphotropic virus 1 serology, an-tinuclear antibody, antibodies to extractable nuclear antigens,anti–cyclic citrullinated peptide, anti–neutrophil cytoplasmicantibody, angiotensin-converting enzyme, hypercoagulableprofile including antiphospholipid antibody evaluation,aquaporin-4–IgG, myelin oligodendrocyte glycoprotein–IgG,and paraneoplastic autoantibody evaluation.

Cerebrospinal Fluid EvaluationCerebrospinal fluid evaluations included white blood cell countand differential, red blood cell count, protein, and glucose. Ad-ditional CSF testing included IgG index, oligoclonal bands, cy-tology, flow cytometry, Gram stain, bacterial culture, vene-real disease research laboratory, Lyme disease serology andpolymerase chain reaction (PCR), cryptococcal antigen,angiotensin-converting enzyme, paraneoplastic autoanti-body evaluation, varicella-zoster virus PCR, Epstein-Barrvirus PCR, cytomegalovirus PCR, enterovirus PCR, mycobac-terium tuberculosis PCR, and culture.

NeuroimagingMayo Clinic neuroimaging was performed with 1.5- and 3-Tmagnetic resonance imaging (MRI) Siemens and General Elec-tric machines. Neuroimaging prior to Mayo Clinic evaluationvaried. Images from other diagnostic centers were reviewedand compared with Mayo Clinic MRIs. Typical Mayo Clinic MRIsequences included sagittal T1, T2, short-τ inversion recov-ery, and axial T2 sequences. Gadolinium was administered atthe discretion of ordering and performing services. Diffusion-weighted imaging (DWI) of the spine was not routinely per-formed. Imaging findings were documented according to ini-tial appearance, with day 0 considered the initial day of deficitonset. The conus medullaris was defined as the very distal endof the spinal cord below the level of the lumbosacral enlarge-ment.

Other Diagnostic EvaluationOther variable diagnostic evaluation included brain MRI,cervical arterial imaging (magnetic resonance angiography,

Key PointsQuestions What are the clinical and neuroimaging findings ofpatients with a spontaneous spinal cord infarction (SCI), and candiagnostic criteria be established to facilitate an accuratediagnosis?

Findings Of 133 patients with a spontaneous SCI, 102 (77%)reached nadir within 12 hours, while others had a stutteringdecline. Magnetic resonance imaging shows confirmatory(eg, vertebral body infarct) and supportive findings whileexcluding other etiologies; cerebrospinal fluid was usuallynoninflammatory (92%).

Meaning The validation of spinal cord infarction diagnosticcriteria supports their utility.

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computed tomography angiography), thoracoabdominal com-puted tomography angiography, full spinal magnetic reso-nance angiography, digital subtraction angiography, and elec-tromyography/nerve conduction studies.

Clinical EvaluationRecords were reviewed to verify clinical details, neuroimagingfindings, and confirm the diagnosis. All patients were seen byMayo Clinic consulting physicians. Forty-five patients from thisseries were included in previous studies,1,5 and a subset of 15 pa-tients with posterior spinal artery infarctions were included ina brief report elsewhere.34 Time of onset was delineated by theinitial neurological deficit (eg, weakness), not the onset of pain.Disability was measured by the American Spinal Injury Associa-tion Impairment Scale6 and ambulatory outcomes. Descriptiveanalyses were performed using JMP Pro 13 (SAS Institute Inc).

Validation CohortFor validation of the proposed SCI diagnostic criteria, we retro-spectively analyzed a cohort of 280 adult patients from our in-stitutionwithalternativeintrinsicmyelopathyetiologiesselectedfrom a myelopathy database. Our cohort included patients withthe following diagnoses: spinal dural arteriovenous fistula, 83

(29.6%); multiple sclerosis, 81 (28.9%); spinal cord sarcoidosis,34 (12.1%)7; aquaporin-4 –IgG seropositive myelitis, 33 (11.8%)8;spinal cord metastasis, 29 (10.4%); myelin oligodendrocyteglycoprotein–IgG seropositive myelitis, 10 (3.6%); infectious my-elitis, 8 (2.9%) (varicella-zoster virus, 4; herpes simplex virus-2, 1; cytomegalovirus, 1; West Nile virus, 1; syphilis, 1); collapsinresponse-mediator protein-5 (CRMP5/anti-CV2), 1 (0.4%); andnitrous oxide toxicity, 1 (0.4%). Clinical and diagnostic informa-tion was reviewed to see if patients met the proposed SCI diag-nostic criteria at the time of clinical presentation.

ResultsPatient DemographicsWe identified 133 patients 18 years and older with a spontane-ous SCI; 71 (53%) were women, and 124 (93%) were white. Me-dian (interquartile range [IQR]) age at presentation was 60(52-69) years and 52 (39-61) years for patients with suspectedfibrocartilaginous embolism. Median (IQR) time from symp-tom onset to evaluation at our facility was 18 (3-217) days; 77patients (58%) were evaluated at our facility within the first31 days. Median (IQR) follow-up was 1 (1-19) month.

Clinical FeaturesSpontaneous SCI presented with rapid severe deficits (eg, paraly-sis) (102patients[77%]nadirwithin12hours)(Table1);31patients(23%) had a more prolonged time to nadir; however, all but 1 pa-tienthadacomponentofrapiddeclinewithseveredeficitswithin12hours.Selectivepainandtemperaturesensorylosswaspresentin 49 of 126 patients (39%). Severe back/limb pain was reportedat onset in 96 patients (72%). A specific physical maneuver(eg, lifting, Valsalva) was described at or proceeding onset in 33patients (25%). Clinical features are shown in Table 1.

Vascular Risk FactorsA history of 1 or more vascular risk factors was present in 101patients (76%): hypertension, 61 (46%); smoking, 61 (46%); hy-perlipidemia, 57 (43%); and diabetes mellitus, 21 (16%). Co-occurring vascular disorders included coronary artery dis-ease, 14 (11%); peripheral vascular disease, 10 (8%); atrialfibrillation, 8 (6%); and previous cerebral ischemia, 3 (2%).

Cerebrospinal Fluid AnalysisA lumbar puncture from the acute evaluation was available in89 patients (66.9%) with the following abnormalities: elevatednucleated cell count (>5 cells/mcL), 7 (8%) (median, 14; range,6-21; neutrophilic predominance, 3; monocytic, 1; lymphocytic,1; unknown, 2); elevated protein (>35 mg/dL), 66 (74%) (median,57; range, 36-655); supernumerary oligoclonal bands (≥3 super-numerary bands), 2 (2%); and elevated IgG index, 1 (1%). Nonehad findings consistent with a specific infection, autoantibody-mediated myelopathy, or other etiology.

NeuroimagingMagnetic resonance imaging spine findings were available in126 patients (94.7%) (1.5-T, 112 [89%]; 3-T, 14 [11%]), (median[IQR] time to initial MRI was 1 [0-2] day); 7 patients (5.2%) did

Table 1. Clinical Features in Spontaneous Spinal Cord Infarction

Clinical FeaturesPatients, No./Total No. (%) (N = 133)

Time to nadir deficit

≤4 h 74 (56)

Stuttering/stepwise decline 2/74 (5)

4-8 h 21 (16)

Stuttering/stepwise decline 1/21 (5)

8-12 h 7 (5)

Stuttering/stepwise decline 3/7 (43)

12-24 h 18 (14)

Stuttering/stepwise decline 12/18 (67)

>24 h 13 (10)

Stuttering/stepwise decline 13/13 (100)

Associated pain 96 (72)

≥ 1 h Before deficit 42 (32)

At deficit onset 81 (61)

Activity/movement before onset 33 (25)

Paraplegia at nadir 54 (41)

Quadriplegia at nadir 11 (8)

Bowel/bladder dysfunction 110 (83)

Examination findingsa

Weakness 118 (89)

Bilateral 97/118 (82)

Sensory loss 126 (95)

Bilateral 104/126 (78)

Selective pain/temperature loss 49/126 (39)

Sensory level 93/126 (74)

Reflexes

Absent reflexes/flaccid tone 33 (25)

Extensor plantar response 60 (45)

a Median (interquartile range), 18 (0-3720) days after onset.

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not have an MRI owing to a contraindication (eg, pacemaker,unstable condition). An intrinsic spinal cord lesion was dem-onstrated on MRI in all but 1 patient who had a normal MRIfinding day 1 (flaccid paraplegia associated with aortic dissec-tion). Thirty patients (24%) initially had a normal MRI resultdespite severe deficits (median day, 0; range day, 0-1). Subse-quent imaging revealed T2-hyperintense cord lesions (me-dian day, 4); 3 of these patients had acute DWI/apparent dif-fusion coefficient imaging, and 1 demonstrated restriction. Thelesion axial localization and imaging pattern varied over thelength of the lesion; a single infarct could have multiple pat-terns. The neuroimaging findings are shown in Table 2. Theposterior one-third of the spinal cord was involved on 1 or moreimaging slices in 57 patients (45%). Five patients with gado-linium enhancement and follow-up imaging available 1 to 3months after SCI had resolution of enhancement (median, 2.5;

range, 1.5-2.5 months). Focal cystic myelomalacia with brightT2-hyperintense signal accompanied by T1 hypointensity wasseen in 31 of 82 cases (38%) on follow-up imaging (Figure 1).Vascular imaging (computed tomography angiography/magnetic resonance angiography/digital subtraction angiog-raphy) was performed in 82 patients and revealed a specific

Figure 1. Magnetic Resonance Imaging T2-Hyperintensity Patternsin Spinal Cord Infarctions

Owl eyesA Cystic myelomalaciaCAnteromedialspot

B

Anteromedialspot

D HologreyF HolocordGAnterior U/VE

Typical patterns of T2-hyperintense signal seen in spinal cord infarction (SCI)include owl eyes associated with noncontiguous anterior pencil-likehyperintensity (A); anteromedial spot confirmed with short anterior pencil-likehyperintensity on sagittal view (B); residual cystic myelomalacia with verybright T2-hyperintensity and associated T1-hypointensity seen longer than 1month after SCI (C); anterior pencil-like hyperintensity with associatedanteromedial T2-hyperintensity (D); anterior U/V with associated anteriorpencil-like hyperintensity on sagittal view (E); hologrey pattern with associatededematous T2-hyperintensity on sagittal view (F); and holocord pattern withassociated edematous T2-hypertensity extending through the conus on sagittalview (G).

Table 2. Neuroimaging Findings in Spontaneous Spinal Cord Infarction

MRI Findings

Patients,No./Total No.(%) (n = 126)

Median (IQR) DaysAfter Deficit Onset

Confirmatory findings

DWI/ADC restriction 19/29 (67) 1 (0-5)

Vertebral body infarction 11 (9) 9 (1-16)

Adjacent arterialdissection/occlusion

16/82 (20) 0 (0-23)

T2-hyperintensity patterns

Owl eyes 82 (65) 3 (1-7)

Anterior pencil-like hyperintensity 50 (40) 8 (1-40)

Anterior U/V (letter shape) 31 (25) 20 (4-136)

Anteromedial spot 30 (24) 9 (4-148)

Hologrey 24 (19) 1 (1-10)

Holocord 20 (16) 5 (1-6)

Gadolinium enhancement 37/96 (39) 10 (4-18)

Linear strip (gray matter/arterial territory)

34/37 (92) NA

Nerve root enhancement 8 (6) 17 (6-31)

Other findings

Initial normal MRI resultswhile symptomatic

30 (24) 0 (0-1)

Longitudinally extensive(≥3 vertebral segments)

75 (60) 5 (1-15)

Noncontiguous/patchy 75 (60) 9 (3-105)

Chronic spinal cord atrophy 39/82 (48) 158 (102-403)

Cystic myelomalacia 31/82 (38) 157 (92-221)

Edema/swelling 27 (21) 5 (2-6)

Concurrent acute cerebral infarct 7/85 (8) 2 (2-31)

Chronic cerebral infarct 4/85 (5) NA

Spinal level

Cervical 37/125 (30) NA

Thoracic 34/125 (27) NA

Thoracic through conus 33/125 (26) NA

Cervical through thoracic 19/125 (15) NA

Cervical through conus 1/125 (1) NA

Isolated conus 1/125 (1) NA

Abbreviations: ADC, apparent diffusion coefficient; DWI, diffusion-weightedimaging; IQR, interquartile range; MRI, magnetic resonance imaging;NA, not applicable.

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abnormality in 16 (20%): Stanford type A aortic dissection, 4;type B aortic dissection, 3; vertebral artery dissection, 4; an-terior spinal artery occlusion, 3; aortoiliac occlusion, 1; and ar-tery of Adamkiewicz occlusion, 1. Of patients with a sus-pected fibrocartilaginous embolism, 10 of 19 (53%) showednearby/adjacent intervertebral disc extrusions.

Additional Diagnostic EvaluationsAmbulatory 24-hour Holter monitor was performed in 18 pa-tients, and no specific contributing arrhythmia was identi-fied. An echocardiogram in 52 patients (transesophageal, 35;transthoracic, 17) revealed the following findings: patent fo-ramen ovale, 10; atrial enlargement, 3; Lambl excrescence, 2;spontaneous echo contrast, 1; atrial septal aneurysm, 1.

The following laboratory values were evaluated and ab-normal: hemoglobin A1C (>5.6%; to convert to proportions oftotal hemoglobin, multiply by 0.01), 10 of 21 patients (48%);elevated low-density lipoprotein (>100 mg/dL; to convert tomillimoles per liter, multiply by 0.0259), 29 of 55 patients(53%); hypercoagulable profile, 7 of 63 patients (11%) (antiphos-pholipid antibody positivity, 4; heterozygous prothrombin genemutation, 2; low antithrombin, 1); connective tissue diseaseevaluation, 11 of 78 patients (14%) (mildly elevated anti-nuclear antibody, 10; cyclic citrullinated peptide elevation, 1);anti–neutrophil cytoplasmic antibody panel for vasculitis, 2 of45 patients (4%) (both perinuclear anti–neutrophil cytoplas-mic antibody positive); paraneoplastic autoantibody evalua-

tion, 8 of 44 patients (nonspecific low titer elevations of noclinical significance in all). Aquaporin-4-IgG was negative in54 patients evaluated. Electromyography/nerve conductionstudies were performed in 19 patients, with neurogenic changes(large motor units, fibrillations) correlating to the area of is-chemia in 13 of 19 patients (68%).

Suspected Mechanism of InfarctionThe suspected mechanism of SCI was idiopathic with athero-sclerotic risk factors, 91 (68%); fibrocartilaginous embolism,19 (14%); aortic dissection, 7 (5%); hypercoaguability, 5 (4%);vertebral artery dissection, 4 (3%); systemic hypotension, 3(2%); cardioembolic, 2 (2%); and vasculitis, 2 (2%).

TreatmentImmunotherapy was used for a suspected immune-mediatedcondition in 74 patients (56%): corticosteroids, 71; intrave-nous immunoglobulin, 16; plasma exchange, 12; azathio-prine, 1; mycophenolate mofetil, 1; and rituximab, 1. Blood pres-sure augmentation was used in 9, lumbar drain in 8, andintravenous tissue plasminogen activator was administered to2 patients. Anticoagulation was initiated in 11 patients, and atleast 1 antiplatelet agent was used in 92 patients. Other treat-ments for suspected alternative diagnoses included spinal de-compression, 3 (all patients worsened after surgery); cardiacstent placement, 1; and epidural corticosteroid injection for ra-diculopathy, 1.

Outcomes and Follow-upAt final follow-up at our facility, American Spinal Injury As-sociation Impairment Scale outcomes were graded as fol-lows: A, 12; B, 5; C, 23; and D, 93. Ambulatory outcome at lastfollow-up was: no gait aid, 63 (47%); cane, 13 (10%); walker,20 (15%); wheelchair, 34 (26%); and death, 3 (2%). No pa-tients developed recurrent episodes of SCI during follow-up.

Proposed Diagnostic CriteriaWe propose diagnostic criteria for SCI in the Box, using the termsdefinite, probable, and possible SCI. Patients in our study metthe following criteria: definite, 39 (29.3%); probable, 83 (62.4%);and possible SCI, 10 (7.5%). One patient did not meet diagnos-tic criteria, having severe pain without significant deficits.

Validation CohortOf 280 patients from our validation cohort, 9 patients (3.2%)met criteria for possible SCI at presentation, but diagnosticevaluation revealed an alternative diagnosis was more likelyin all: spinal dural arteriovenous fistula, 5 (MRI flow voids);multiple sclerosis, 2 (multiple demyelinating lesions on MRI);sarcoidosis, 1 (inflammatory CSF, enhancement pattern); andcytomegalovirus, 1 (inflammatory CSF). No patients met cri-teria for definite or probable SCI.

DiscussionWe describe the clinical and neuroimaging details of a large se-ries of spontaneous SCIs, propose diagnostic criteria, and use

Box. Proposed Spinal Cord Infarction (SCI) Diagnostic Criteria

Criteria1. Acute nontraumatic myelopathy (no preceding progressive

myelopathy)Onset to nadir severe deficitsa 12 h or lessIf stuttering course is more than 12 h, severe deficits

arapidly

develop 12 h or less2. Magnetic resonance imaging

A. No spinal cord compressionB. Supportive: Intramedullary T2-hyperintense spinal cord

lesion (eBox 2 in the Supplement)C. Specific (1 of): diffusion-weighted imaging/apparent

diffusion coefficient restriction, associated vertebral bodyinfarction, arterial dissection/occlusion adjacent to lesion

3. Cerebrospinal fluidNoninflammatory (normal cell count, IgG index and nooligoclonal bands)

4. Alternative diagnosesAlternative diagnosis is not more likely (eBox 1 in theSupplement)

Type of SCIDefinite spontaneous SCI (1, 2A, 2B, 2C, 4)

Probable spontaneous SCI (1, 2A, 2B, 3, 4)

Possible spontaneous SCI (1, 4)

Definite periprocedural SCI (1, 2A, 2B, 4)

Probable periprocedural SCI (1, 4)

a A severe acute deficit (motor and/or sensory) typically consists of loss ofantigravity strength or worse, severe objective sensory loss impairingfunction (eg, severe sensory ataxia).

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a validation cohort to assess their utility. Features often con-sidered to be atypical (eg, >4 hours to nadir, MRI and clinicalevidence outside the anterior spinal artery territory, gado-linium enhancement) are actually common and should not pre-clude physicians from making the diagnosis of SCI. Spinal cordinfarction is underrecognized and frequently misdiagnosed astransverse myelitis,4,5 highlighting the need for diagnostic cri-teria that can be broadly applied to patients with spontane-ous and periprocedural SCI.

The proposed SCI diagnostic criteria emphasize 3 majorcomponents: (1) clinical: rapid development of severe defi-cits within 12 hours; (2) MRI spine: exclusion of compression(2A) with supportive features (2B), and specific imaging find-ings (2C); and (3) CSF: highlighting noninflammatory find-ings in most. The most critical component is the rapid accu-mulation of severe deficits within 12 hours because moregradual worsening favors alternative etiologies. In our valida-tion cohort, this was the most powerful diagnostic discrimi-nator, similar to what others have found4; it is rare for alter-native myelopathy etiologies to present this rapidly with asevere deficit. A noninflammatory CSF profile is helpful to dif-ferentiate from infectious and inflammatory etiologies, al-though mild abnormalities might be encountered in SCI as seenin 8% of our patients. As with most other diagnostic criteria,a patient should not have a more likely alternative diagnosis(eBox 1 in the Supplement) based on the careful interpreta-

tion of all diagnostic information. Our validation cohort withonly 9 patients (3.2%) initially meeting criteria for possible SCIsuggests these criteria will be very helpful in discriminatingSCI from other myelopathy etiologies. In addition, the crite-ria may have utility for enrollment in clinical trials and con-sensus of definitions for research in SCI.

Many prior cases of SCI have demonstrated a prolongedtime to nadir over many hours, including autopsy-proven casesand periprocedural SCI.2,4,9 The slower evolution of deficitsthan in cerebral infarction might be explained by diversecollateralization of spinal arterial supply10 with transientpreservation of tissue viability before infarction, while therelatively small area of the spinal cord may also make it moresusceptible to the effects of edema contributing to clinicalworsening.11,12 Pain was common at presentation (72%); it maybe explained by SCI activation of the spinothalamic tract or bythe contributing mechanism (fibrocartilaginous embolism, ar-tery dissection).9,13,14

Given the high proportion of older patients with vascularrisk factors in our study, traditional stroke mechanisms (ath-erothrombosis) likely have an important role in SCI,15 whichmay likely affect more proximal arteries than the spinal arter-ies themselves.16 Cervical artery dissections may be underdi-agnosed given limitations of assessment with standard angio-graphic imaging techniques; T1 fat suppression imaging mayvisualize a vessel wall hematoma (Figure 2) and confirm a

Figure 2. Confirmatory Magnetic Resonance Imaging Findings and Typical Gadolinium Enhancement Patternin Spinal Cord Infarctions

Vertebral body infarctionA

Diffusion restrictionC Contrast enhancementD Axial contrastenhancement

E

Cervical artery dissectionB

Confirmatory spinal cord infarction(SCI) findings are shown, includingvertebral body infarction on short-τinversion recovery imaging withassociated gadolinium enhancementof the vertebral body infarct, SCI, andanterior cauda equina (A); cervicalartery dissection with significantlydecreased left vertebral flow withconfirmed intramural hematomashown on T1-fat suppression imaging(B) adjacent to SCI; and diffusionrestriction on diffusion-weightedimaging with correlation on apparentdiffusion coefficient (C). Spinal cordinfarction gadolinium enhancementdemonstrated with a typicalcraniocaudal linear strip on sagittalviews (D) and corresponding anteriorpredominant gray matter andanteromedial spot (E) patterns onaxial views, highlighting thepredominant areas of ischemia.

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dissection.17 Detection of local disc protrusions may suggesta fibrocartilaginous embolism as the mechanism of SCI,9 whichis still captured within and consistent with our diagnostic cri-teria; however, degenerative disc disease is very common inthe general population.18

Although some MRI features confirm SCI (criterion 2C),these features are often absent or sequences to detect thesefindings are not undertaken. Physicians should request DWIin patients with acute myelopathy in an attempt to confirmthe diagnosis of SCI; however, DWI has incomplete sensitiv-ity in SCI given limitations of spatial resolution and suscepti-bility artifacts, as has been shown in definite cases of peripro-cedural SCI.2 Classic findings of owl eyes19,20 or pencil-likehyperintensity21 are helpful in suspecting SCI but are neitherspecific20 nor required for the diagnosis. A variety of otherT2-hyperintensity patterns can also be seen (Figure 1, Table 2,and eBox 2 in the Supplement), as previously characterized inthe periprocedural setting.2 Magnetic resonance imaging is of-ten normal acutely in SCI (24%), and thus repeating imagingdays later is recommended. Although gadolinium enhance-ment is usually considered suggestive of transverse myelitisor other etiologies, many periprocedural SCIs (43%)2 and spon-taneous SCIs (39%) demonstrate definite enhancement.A linear craniocaudal strip of enhancement is typical of SCI(Figure 2), highlighting the most predominant ischemic area(gray matter, arterial territory), and such a pattern is unusualwith inflammatory etiologies. Other patterns of enhance-ment should lead clinicians to alternative diagnoses. When SCIremains in question after initial evaluation, follow-up imagingdemonstrating chronic focal cystic myelomalacia (Figure 1) sup-ports vascular sequelae as opposed to myelitis.22

Unfortunately, no therapies are proven as effective to treatspontaneous SCI.23,24 Lumbar drainage and blood pressure aug-mentation are used for SCI in the setting of aortic surgery,23,25,26

but there are no data to support these strategies in spontane-ous SCI. Although previous cases15 and 2 of these patients re-ceived intravenous tissue plasminogen activator without harm,there is no evidence for efficacy in SCI. Empirical intrave-

nous methylprednisolone treatment is reasonable when con-cern remains for a possible inflammatory myelopathy. How-ever, some treatments, such as plasma exchange (which canreduce cord perfusion)27-29 and intravenous immunoglobu-lin (which is prothrombotic),30-32 could be harmful and shouldbe avoided. Aggressive rehabilitation should be pursued,1 andmany patients achieve a good outcome (47% without gait aid).

LimitationsOur study is limited by its retrospective design. The absenceof a criterion standard for diagnosis of spontaneous SCI againstwhich our diagnostic criteria can be assessed is the main limi-tation. The possibility exists that some cases with alternativemyelopathy etiologies were misdiagnosed as SCI. The exhaus-tive workup undertaken to exclude alternative etiologieshelped reduce this risk of misdiagnosis. Patients did not re-ceive a standard battery of tests in all cases. Forty-six pa-tients were excluded because they had incomplete data andthus did not meet inclusion criteria. The predominance of whiteindividuals likely reflects our upper Midwest patient catch-ment area, which is also predominantly white (80%-90%) andimpacts the generalizability to other racial/ethnic groups.33 Theimaging sequences performed varied, as did their timing. Alarger number of patients with DWI may change the apparentsensitivity, but the absence of diffusion restriction does not ex-clude SCI as shown in the periprocedural setting.2 Validationof these criteria will be needed in other cohorts and ideallywould include greater racial/ethnic diversity.

ConclusionsIn conclusion, our comprehensive review of a large series ofpatients with SCI identified several clinical and radiologicalclues to SCI and refines our understanding of the spectrum ofSCI presentation. We proposed and validated a set of diagnos-tic criteria that may improve recognition of SCI cases, guideacute management, and facilitate future research.

ARTICLE INFORMATION

Accepted for Publication: July 14, 2018.

Published Online: September 24, 2018.doi:10.1001/jamaneurol.2018.2734

Author Contributions: Drs Zalewski and Flanaganhad full access to all of the data in the study andtake responsibility for the integrity of the data andthe accuracy of the data analysis.Concept and design: Zalewski, Rabinstein,Kaufmann, Blessing, Flanagan.Acquisition, analysis, or interpretation of data:Zalewski, Krecke, Brown, Wijdicks, Weinshenker,Kaufmann, Morris, Aksamit, Bartleson, Lanzino,Flanagan.Drafting of the manuscript: Zalewski, Morris.Critical revision of the manuscript for importantintellectual content: All authors.Statistical analysis: Zalewski.Administrative, technical, or material support:Kaufmann, Morris, Bartleson.Supervision: Rabinstein, Wijdicks, Morris, Aksamit,Lanzino, Flanagan.

Conflict of Interest Disclosures: Dr Weinshenkerreceives royalties from RSR Ltd, University ofOxford, Hospices Civils de Lyon, and MVZ Labor PDDr Volkmann und Kollegen GbR for a patent ofneuromyelitis optica–IgG as a diagnostic test forneuromyelitis optica and related disorders; servesas a member of an adjudication committee forclinical trials in neuromyelitis optica beingconducted by MedImmune and AlexionPharmaceuticals; is a consultant for CaladriusBiosciences and BrainStorm Cell Therapeuticsregarding potential clinical trials for neuromyelitisoptica; and serves as a member of a data safetymonitoring committee for clinical trials conductedby Novartis. Dr Lanzino is a consultant forMedtronic.

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