ARTICLES

Adam de Havenon, MD Zachary Joos, MD Loren Longenecker, MD Lubdha Shah, MD Safdar Ansari, MD Kathleen Digre, MD

Correspondence to Dr. de Havenon: [email protected]

Posterior reversible encephalopathy syndrome with spinal cord involvement

ABSTRACT

Objective: To characterize a cohort of patients with the signs and symptoms of posterior reversible encephalopathy syndrome (PRES), but with clinical and radiologic involvement of the spinal cord.

Methods: We report 2 cases of PRES with spinal cord involvement and identified an additional 6 cases in the Medline database using various search terms related to “spinal PRES,” “spinal reversible posterior leukoencephalopathy syndrome,” and “spinal hypertensive encephalopathy.” We analyzed the clinical and imaging characteristics of the 8 cases.

Results: Average age was 31 years, with 5 male and 3 female patients. All patients had severe acute hypertension and a confluent, expansile central spinal cord T2 hyperintensity spanning at least 4 spinal segments, originating at the cervicomedullary junction. Of 8 patients, 7 had hypertensive retinopathy, a favorable clinical course with only antihypertensive treatment, and resolution of the spinal cord lesions on follow-up imaging. A total of 4 of 8 patients had symptoms referable to the spinal cord lesions and only 1 of 8 had a seizure. Conclusion: In light of the already wide definition of PRES, we propose a new syndrome named PRES with spinal cord involvement (PRES-SCI). Clinicians should suspect PRES-SCI when patients with PRES have neurologic signs referable to the spinal cord, extreme elevation in blood pressure, MRI lesions that extend to the cervicomedullary junction, or grade IV hypertensive retinopathy. These clinical scenarios should prompt a cervical spine MRI to help guide patient management decisions and prognostication. When clinicians evaluate longitudinally extensive spinal T2 hyperintensities, they should consider PRES-SCI, which, if diagnosed, would spare patients the morbidity of a standard myelitis workup and empiric treatment. Neurology® 2014;83:2002–2006 GLOSSARY FLAIR 5 fluid-attenuated inversion recovery; HE 5 hypertensive encephalopathy; PRES 5 posterior reversible encephalopathy syndrome; PRES-SCI 5 posterior reversible encephalopathy syndrome with spinal cord involvement.

In 1996, Hinchey et al.1 published a case series of 15 patients with the neurologic symptoms of hypertensive encephalopathy (HE) and CT or MRI findings of cerebral white matter edema in a predominantly posterior distribution. These patients had a benign course, and she termed the entity “a reversible posterior leukoencephalopathy syndrome.” The majority of patients, 12 of 15, were hypertensive at the time of presentation, but several also had eclampsia or took the immunosuppressants cyclosporine and tacrolimus. This landmark case series led to the establishment of the clinicoradiologic diagnosis now primarily known as posterior reversible encephalopathy syndrome (PRES). The MRI signal abnormality corresponding to edema is classically parieto-occipital, but there is commonly involvement of the frontal and temporal lobes, basal ganglia, cerebellum, and brainstem. Classic PRES is subcortical vasogenic edema without hemorrhage, but complicated or atypical PRES can show cortical edema, hemorrhage, postcontrast enhancement, and ischemia.2 Since 1996, PRES has become such a heterogeneous syndrome that the majority of cases are clinically or radiologically atypical based on the original description. We widen that spectrum further by describing a cohort of patients with PRES and spinal cord involvement. Editorial, page 1996 From the Department of Neurology (A.d.H.), University of Washington, Seattle; and the Departments of Ophthalmology (Z.J., K.D.), Radiology (L.L., L.S.), and Neurology (S.A., K.D.), University of Utah, Salt Lake City. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 2002

© 2014 American Academy of Neurology

METHODS We report 2 cases of PRES with spinal cord involvement and identified an additional 6 cases in the Medline database using various search terms related to “spinal PRES,” “spinal reversible posterior leukoencephalopathy syndrome,” and “spinal hypertensive encephalopathy.”

Case reports. Our first case is a 50-year-old man with a history of hypertension and chronic kidney disease who took no medication and presented with 1 week of worsening vision, urinary incontinence, lower extremity weakness, altered mental Figure

Characteristic imaging findings in posterior reversible encephalopathy syndrome with spinal cord involvement

status, and systolic blood pressures in the low 200s mm Hg. Laboratory testing revealed renal insufficiency, but was negative for infectious or noninfectious inflammatory diseases. On neurologic examination, he demonstrated bilateral hypertensive retinopathy and mild lower extremity weakness with spasticity. MRI of the brain showed T2 and fluid-attenuated inversion recovery (FLAIR) hyperintensity in the bilateral parietal and occipital lobes, cerebellum, pons, medulla, and upper cervical spinal cord that extended to the upper thoracic spine (figure, A and B). Lumbar puncture had an opening pressure of 29 cm H2O with normal cell indices and no evidence of demyelination. After aggressively lowering the patient’s blood pressure, his symptoms rapidly improved. Repeat MRI brain 1 week after admission showed markedly decreased T2/FLAIR hyperintensities, which were nearly resolved 5 months later on a second repeat MRI brain and spine (figure, F). His examination at 10 months was significant for only mild left lower extremity weakness. The second case is a 25-year-old man with a history of type 1 membranoproliferative glomerulonephritis and hypertension who was nonadherent to antihypertensive medication and presented with 2 weeks of headache and vision loss in the left eye. Blood pressure on presentation was 225/159 mm Hg. Laboratory testing also revealed renal insufficiency, but was negative for infectious or noninfectious inflammatory diseases. Neurologic examination was significant for bilateral hypertensive retinopathy (figure, G). MRI of the brain showed T2 hyperintensity in the medulla and cervicomedullary junction, prompting an MRI of the spine, which showed T2 hyperintensity in the entire central spinal cord (figure, C and D). A lumbar puncture had normal opening pressure, unremarkable cell indices, and no evidence of demyelination. We treated the patient with aggressive blood pressure reduction and a 3-day course of methylprednisolone. His vision rapidly improved, and MRIs of the brain and spine after 3 months had normal results (figure, E).

Demographic and clinical data of the 8 patients are shown in table 1. In addition to the classic imaging findings of PRES, all patients had T2/FLAIR signal abnormalities involving the posterior fossa or brainstem, and 7 of 8 patients showed abnormal medullary signal (table 2). All patients had confluent, slightly expansile central spinal cord T2 hyperintensity spanning at least 4 spinal segments, originating at the cervicomedullary junction. In 4 of 8 patients in whom this was evaluated, the spinal cord lesions did not have contrast enhancement or, in 3 of 8, diffusion restriction. Followup spinal MRI, done as early as 2 weeks or as late as 6 months, was normal in 7 of 8 patients.

RESULTS

(A) Patient 1, axial fluid-attenuated inversion recovery (FLAIR) hyperintensity of the bilateral occipital lobes (black arrows). (B) Patient 1, axial FLAIR hyperintensity of the bilateral cerebellum and medulla, and sagittal T2 hyperintensity extending along the length of the spinal cord (black arrows). This patient had symptoms referable to his spinal lesions. (C, D) Patient 2, FLAIR/short tau inversion recovery hyperintensity in ventral medulla and the central spinal cord without supratentorial lesions. This patient had no symptoms referable to the spinal cord lesions (white arrows). (E) Patient 2, follow-up MRI at 3 months shows resolution of the T2 hyperintensity in the ventral medulla and cervical spinal cord (dotted white arrow, compare to C and D), which was also true on the spinal cord MRI (not shown). (F) Patient 1, follow-up MRI at 5 months, axial FLAIR through the cerebellum shows significant decrease in signal in the cerebellum and medulla and sagittal T2 of the thoracic spine shows resolution of the prior hyperintensity (dotted black arrows, compare to B). (G) Patient 2, montage fundus photograph of left eye shows optic nerve edema, arteriolar narrowing, flame hemorrhages, macular star pattern of exudates in the macula, and cotton-wool spots. (H) Patient 2, montage fundus photograph of left eye 4 months after presentation shows partial resolution of prior abnormalities.

Although our cohort is small, several clinical and imaging characteristics distinguish classic PRES from the syndrome we describe, the most obvious being involvement of the spinal cord. None of our patients was normotensive, which is the case in 20%–30% of PRES cases; took medications known to cause PRES; or had commonly associated medical illnesses like eclampsia or systemic lupus erythematous. This cohort had an exceptionally high mean blood pressure of 217/135 mm Hg, as compared to a mean of 165/97 mm Hg in the article by Hinchey et al.1 and 160/99 mm Hg in a more recent case series of patients with PRES.3 Only 1 patient, who DISCUSSION

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Table 1

Demographics and clinical characteristics of 8 patients with PRES-SCI

Age, Patient y/sex

Diagnosis

Clinical findings

Highest blood pressure

Ophthalmologic examination

Neurologic examination

Laboratory abnormalities

1

50/M

Untreated hypertension, chronic renal failure

Hypertension, headache, vomiting, confusion, vision loss

SBP over 200 mm Hg at home, 180/ 110 mm Hg in hospital

Hypertensive retinopathy with minimal papilledema

Bilateral LE weakness, BUN 83 mg/dL, brisk DTR, Babinski creatinine 3.5 mg/dL sign, and incontinence

2

25/M

Untreated hypertension, MPGN type I

Hypertension, headache, vision loss

225/160 mm Hg

Hypertensive retinopathy with papilledema

Normal

BUN 50 mg/dL, creatinine 4.6 mg/dL, CSF reported normal

35

17/M

IgA nephropathy

Hypertension, headache, vomiting, visual disturbance

240/130 mm Hg

Hypertensive retinopathy with papilledema

Normal

BUN 86 mg/dL, creatinine 3.7 mg/dL

46

14/F

Fibromuscular dysplasia and renal artery stenosis

Hypertension, headache, vomiting, vision loss, GCS 11

185/145 mm Hg

Hypertensive retinopathy with papilledema

Brisk DTR, negative Babinski

CSF protein 89 mg/dL, 31 proteinuria

57

39/F

Untreated hypertension, chemotherapy with gemcitabine 3 weeks prior

Hypertension, headache, vomiting, blurred vision, drowsy

220/120 mm Hg

Hypertensive retinopathy

Normal

Serum reported normal

68

38/M

Untreated hypertension Hypertension, headache, vision loss

230/140 mm Hg

Hypertensive retinopathy with papilledema

Isolated bilateral Babinski sign

Serum and CSF reported normal

79

44/F

Untreated hypertension Hypertension, headache, LE weakness, urinary urgency, blurred vision, drowsy

240/140 mm Hg

Hypertensive retinopathy

Bilateral LE weakness, Serum and CSF brisk DTR, Hoffman reported normal and Babinski sign

810

23/M

Cocaine-induced hypertension

“Very high”

Not documented

“Clinical symptoms of a spinal cord syndrome”

Hypertension, confusion, seizure

Not documented

Abbreviations: BUN 5 blood urea nitrogen; DTR 5 deep tendon reflexes; GCS 5 Glasgow Coma Scale score; LE 5 lower extremity; MPGN 5 membranoproliferative glomerulonephritis; PRES-SCI 5 posterior reversible encephalopathy syndrome with spinal cord involvement; SBP 5 systolic blood pressure. Patients 1 and 2 are reported in this article.

was using cocaine, had seizure, compared to rates of seizure with PRES ranging from 70% to 92%.2 Our patients are younger, with a mean age of 31 years vs 39–47 years in PRES, and are not predominantly women, as is the case with PRES.2 Hypertensive retinopathy was present in 7 of 7 patients and 5 of 7 had grade IV hypertensive retinopathy, accounting for 71%, compared to only 23% of patients with HE, most of whom would have PRES if imaged with MRI.4 This cohort rapidly improved with blood pressure reduction, although 1 patient also received a short course of a corticosteroid, and 7 of 8 returned to their premorbid baseline. The differential diagnosis of longitudinally extensive spinal T2 hyperintensity includes myelitidies secondary to autoimmune disease, CNS infection, malignancy, or vascular myelopathy from a dural arteriovenous fistula, none of which would be expected to have a benign course without specific treatment. The spinal lesions did not have contrast enhancement, further arguing against myelitis, and on diffusion-weighted imaging there was no evidence of cytotoxic edema to suggest ischemia. It would also be unusual for myelitis to cause dramatic imaging abnormalities without marked clinical symptoms, as was the case in 4 of 8 of our cohort. The most frequently proposed mechanism of PRES is a failure of cerebrovascular autoregulation in the 2004

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presence of acute hypertension and the vertebrobasilar system is considered particularly sensitive to this process.2 The anterior spinal artery arises from the vertebrobasilar system, which may explain our patients’ high prevalence of lesions in the cervical cord. Our patients are on the severe hypertensive end of the spectrum of PRES syndromes, in keeping with prior studies that demonstrated an association between more extreme hypertension and involvement of the brainstem in PRES.3 In light of the already wide definition of PRES, we propose a new syndrome named PRES with spinal cord involvement (PRES-SCI). PRES-SCI shares many clinical, radiographic, and, presumably, pathophysiologic attributes with PRES, but is a unique disorder that also affects the spinal cord of younger, often male, patients, who thus far have presented with severe acute hypertension as well as headache, nausea/ vomiting, encephalopathy, visual disturbance, renal failure, and hypertensive retinopathy, but not necessarily seizure. Half of the patients have symptoms referable to the spinal cord. Serologic and CSF analyses are not diagnostic of PRES-SCI but are necessary to rule out infectious and noninfectious etiologies of myelitis. Most patients have a full recovery. Clinicians should suspect PRES-SCI when patients with PRES have neurologic signs referable to

Table 2

Imaging, treatment, and outcome of 8 patients with PRES-SCI syndrome

Patient T2 Lesions on MRI brain

T2 Lesions on MRI spine

Other imaging characteristics

Clinical course after normalization of blood pressure

Repeat imaging

Clinical outcome

1

Occipital lobe (bilateral), posterior parietal (bilateral), cerebellum (bilateral), medulla

Confluent, central cord, entire spinal cord

Cord expansion, left parietal punctate hemorrhage, normal spine ADC values

Rapid improvement of encephalopathy, slow improvement of LE symptoms

MRI at 5 months: resolution of brain abnormalities, near normalization of spine

Persistence of mild LE weakness

2

Medulla

Confluent, central cord, entire spinal cord

Cord expansion, normal spine ADC values

Rapid improvement

MRI at 3 months: normal

Resolution of symptoms

35

Occipital lobe (bilateral), posterior parietal (bilateral), cerebellum (left), medulla

Confluent, central cord, from cervicomedullary junction to C5

Cord expansion, normal spine ADC values

Rapid improvement

MRI at 1 month: normal

Resolution of symptoms

46

Cerebellum (bilateral), pons, medulla

Confluent, central cord, from cervicomedullary junction to T8

Cord expansion, no contrast enhancement

Rapid improvement

MRI at 5 months: normal

Resolution of symptoms

57

Frontal lobe (right), occipital lobe (bilateral), posterior parietal (bilateral), cerebellum (bilateral)

Confluent, central cord, from cervicomedullary junction to C8

Cord expansion, no contrast enhancement

Rapid improvement

MRI at 2 weeks: normal spine and near normal brain

Resolution of symptoms

68

Occipital lobe (bilateral), cerebellum (bilateral), pons, medulla

Confluent, central cord, entire spinal cord

Cord expansion, no contrast enhancement

Visual impairment for several months

MRI at 2 weeks: normal

Resolution of symptoms

79

Pons, medulla

Confluent, central cord, from cervicomedullary junction to C5

Cord expansion, no contrast enhancement

Gradual improvement of LE weakness

MRI at 6 months normal

Resolution of symptoms

810

Occipital lobe (bilateral), posterior parietal (bilateral), pons, medulla

Confluent, central cord, entire spinal cord

Cord expansion

Rapid improvement

MRI at 1 month: normal

Resolution of symptoms

Abbreviations: ADC 5 apparent diffusion coefficient; LE 5 lower extremity; PRES-SCI 5 posterior reversible encephalopathy syndrome with spinal cord involvement. Patients 1 and 2 are reported in this article.

the spinal cord, extreme elevation in blood pressure, MRI lesions that extend to the cervicomedullary junction, or grade IV hypertensive retinopathy. These clinical scenarios should prompt a cervical spine MRI to help guide patient management and prognostication. In addition, when clinicians evaluate longitudinally extensive spinal T2 hyperintensities, they should consider PRES-SCI, which, if diagnosed, may spare patients the morbidity of a standard myelitis workup and empiric treatment. PRES-SCI is likely underdiagnosed. As clinicians become aware of PRES-SCI, we will better characterize it and may ultimately find that, like PRES, it can also affect normotensive patients with renal failure, specific drug exposures, or inflammatory diseases. AUTHOR CONTRIBUTIONS Adam de Havenon is the first author and did the majority of the drafting and editing of the manuscript. Zachary Joos made a significant contribution to the drafting and editing of the manuscript. Loren Longenecker made a significant contribution to the drafting and editing of the manuscript. Lubdha Shah made a significant contribution to the editing of the manuscript. Safdar Ansari made a significant contribution to the editing of the manuscript. Kathleen Digre made a significant contribution to the editing of the manuscript.

ACKNOWLEDGMENT Dr. de Havenon thanks Will Longstreth, MD, and David Tirschwell, MD, for their assistance with editing of the manuscript.

STUDY FUNDING No targeted funding reported.

DISCLOSURE A. de Havenon reports no disclosures relevant to the manuscript. Z. Joos is supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, to the Department of Ophthalmology & Visual Sciences, University of Utah. L. Longenecker, L. Shah, and S. Ansari report no disclosures relevant to the manuscript. K. Digre is supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, to the Department of Ophthalmology & Visual Sciences, University of Utah. Go to Neurology.org for full disclosures.

Received March 12, 2014. Accepted in final form June 30, 2014. REFERENCES 1. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494–500. 2. Legriel S, Pico F, Azoulay E. Understanding posterior reversible encephalopathy syndrome. In: Vincent J-L, ed. Annual Update in Intensive Care and Emergency Medicine 2011. Berlin: Springer; 2011:631–653. 3. Moon S-N, Jeon SJ, Choi SS, et al. Can clinical and MRI findings predict the prognosis of variant and classical type of posterior reversible encephalopathy syndrome (PRES)? Acta Radiol 2013;54:1182–1190. 4. Amraoui F, van Montfrans GA, van den Born BJ. Value of retinal examination in hypertensive encephalopathy. J Hum Hypertens 2010;24:274–279. 5. Choh NA, Jehangir M, Rasheed M, Mira T, Ahmad I, Choh S. Involvement of the cervical cord and medulla in Neurology 83

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posterior reversible encephalopathy syndrome. Ann Saudi Med 2011;31:90–92. Nagato M, Takahashi Y, Yoshioka M, Nambu M. A case of hypertensive encephalopathy with extensive spinal lesions on MRI. Brain Dev 2010;32:598–601. Briganti C, Caulo M, Notturno F, Tartaro A, Uncini A. Asymptomatic spinal cord involvement in posterior reversible encephalopathy syndrome. Neurology 2009;73:1507–1508.

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This Week’s Neurology® Podcast Mystery Case: Heidenhain variant of Creutzfeldt-Jakob disease (see p. e187) This podcast begins and closes with Dr. Robert Gross, Editor-inChief, briefly discussing highlighted articles from the November 25, 2014, issue of Neurology. In the second segment, Dr. Andy Southerland talks with Ms. Esmeralda Santiago about her experiences and observations dealing with stroke recovery and rehabilitation. Dr. Adam Numis then reads the e-Pearl of the week about variants of sporadic Creutzfeld-Jakob disease. In the next part of the podcast, Dr. David Taplinger focuses his interview with Dr. Steven Frucht on the movement disorder emergency “tic status.” Disclosures can be found at Neurology.org. At Neurology.org, click on “RSS” in the Neurology Podcast box to listen to the most recent podcast and subscribe to the RSS feed. CME Opportunity: Listen to this week’s Neurology Podcast and earn 0.5 AMA PRA Category 1 CME Credits™ by answering the multiple-choice questions in the online Podcast quiz.

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2006

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Posterior reversible encephalopathy syndrome with spinal cord involvement Adam de Havenon, Zachary Joos, Loren Longenecker, et al. Neurology 2014;83;2002-2006 Published Online before print October 29, 2014 DOI 10.1212/WNL.0000000000001026 This information is current as of October 29, 2014

Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

Posterior reversible encephalopathy syndrome with spinal cord involvement.

To characterize a cohort of patients with the signs and symptoms of posterior reversible encephalopathy syndrome (PRES), but with clinical and radiolo...
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