EDITORIAL
Hypertensive crisis Reversible edema in leukoencephalopathy, retinopathy, now myelopathy?
Gregory Kapinos, MD, MS Pina C. Sanelli, MD, MPH, FACR
Correspondence to Dr. Kapinos: [email protected] Neurology® 2014;83:1996–1997
The definition of the clinicoradiologic syndrome posterior reversible leukoencephalopathy syndrome (PRES) has been stretched over the last decade.1 Many regard PRES as a final common denominator for various cerebral insults, without a single etiopathogenic trigger.1,2 The hallmark of classic PRES is hydrostatic pressure breakthrough causing cerebral vasogenic edema, commonly coupled with a history of refractory hypertension, ictal surge in blood pressure (BP), and a concomitant systemic inflammatory or uremic process.1 High BP may be absent in PRES if there is renal failure; infection or any systemic inflammatory response syndrome; or immunomodulation as seen in eclampsia, autoimmune disorders, or chemotherapy.1–3 PRES may thus be better defined as a “neurotoxic syndrome”2 with blood–brain barrier opening or with disruption of cerebral autoregulation leading to dysperfusion with either vasogenic or cytotoxic edema.2,3 The phenotypic umbrella of PRES now includes transient, isolated splenial edematous lesions4 and extensive spinal cord edema. A mounting number of cases of longitudinally extensive central cord edema in the absence of infectious, demyelinating, or ischemic causes or venous engorgement from an arteriovenous fistula now warrant codifying this entity as a discrete clinical syndrome and perusal for specific risk factors. In this issue of Neurology®, de Havenon et al.5 analyzed the semiology and potential cause for a newly recognized subset of patients with PRES. They present 2 cases and integrate the data into a broader analysis of 6 other case reports, where patients had risk factors for classic PRES and no other cause for reversible spinal cord edema. They coined PRES-SCI (with spinal cord involvement) as a syndromic entity and found that severe acute hypertension, grade IV hypertensive retinopathy, younger age, and male gender are key features for this subtype of PRES. Lesions invariably manifested as confluent central cord T2 hyperintensity, involving at least 4 spinal segments, originating at the cervicomedullary junction.5 We laud the authors for describing the clinicoradiologic characteristics and attempting to find a single etiopathogenesis underpinning this syndrome, such as severe hypertension as a leading cause and the uniform
presence of hypertensive retinopathies.5 However, many treatments in this cohort were directed at aggressive BP reduction and amelioration of the renal function, reflecting the prominence of both hypertension and uremia in this cohort. One patient received steroids, probably for vasogenic edema, confounding the primacy of severe hypertension as the root cause. The main messages drawn from this study5 might include the following: (1) in confirmed cases of PRES, mild signs of myelopathy should prompt imaging of the cord, and if edema is found, a less extensive workup for other causes may be possible; or (2) all patients with PRES should be screened for cord edema, because only half of this cohort expressed symptoms or signs of myelopathy; and (3) when facing cryptogenic isolated extensive central cord edema, if PRES clinical risk factors are present, PRES-SCI should be listed in the differential diagnosis, permitting a less extensive workup and avoidance of empirical treatment for myelitis. These conclusions would be too hasty, however. One cannot emphasize enough that clinicians and radiologists facing isolated central cord edema in hypertensive patients, or even cord edema in confirmed cases of PRES, must still exclude dangerous causes with a standard myelitis workup. Given that this review failed to identify any pathognomonic features, a careful review of clinical history, CSF analysis, and MRI of the neuraxis remains imperative before claiming that lowering the BP will necessarily lead to a favorable outcome.5 Perspicacious analysis of cause or consequence is also warranted before claiming PRES is causing any cord edema. Indeed, a separate primary lesion in the cervical cord can cause local cord edema, which in turn can disrupt the autonomic nervous system, with sympathetic overtone, leading to supratentorial PRES manifestations.6,7 This study5 will likely prompt subsequent investigations to compare various risk factor profiles in subtypes of PRES. As with typical PRES, the new pathophysiology of PRES-SCI may occur in a substantial number of patients without hypertension, even though all reported cases seem to be associated with severe acute hypertension. Patients with eclampsia or on chemotherapeutic drugs, or patients with severe hypertension and uremia or infection, could be selected as cohorts to be screened
See page 2002 From the Departments of Neurosurgery & Neurology (G.K.) and Radiology (P.C.S.), Hofstra North Shore–LIJ School of Medicine, Manhasset, NY. 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 editorial. 1996
© 2014 American Academy of Neurology
for cord edema, before the neurologic community claims that it is a distinct PRES variant worth attributing solely to hypertensive crisis, as suggested by de Havenon et al.5 Vasoreactivity, perfusion and diffusion-weighted imaging, as well as blood–brain barrier (BBB)/blood–cord barrier (BCB) permeability imaging8 are crucial to parse this pleomorphic entity of acute idiopathic reversible CNS edema.2 While the authors diligently commented that absence of enhancement indicates no BCB alteration, dedicated BBB/ BCB permeability mapping may yield some interesting results, as mild BBB alterations lead to permeability abnormality prior to total disruption of BBB seen with parenchymal enhancement.8–10 Management of patients with PRES is now more complicated than simply lowering BP because of hydrostatic breakthrough edema, as the PRES spectrum spans edema and ischemia, immunologic alteration, BBB disruption, and loss of cerebral autoregulation.2–4 The fact that all patients with PRES-SCI seem to improve with aggressive BP reduction and return to premorbid baseline5 is encouraging, but some patients may have sequelae from this transient and not so benign edema.1,2 AUTHOR CONTRIBUTIONS Gregory Kapinos: drafting/revising the manuscript, study concept or design, analysis or interpretation of data. Pina C. Sanelli: drafting/revising the manuscript.
STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Lamy C, Oppenheim C, Mas JL. Posterior reversible encephalopathy syndrome. Handb Clin Neurol 2014; 121:1687–1701. 2. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. ANJR Am J Neuroradiol 2008;29:1043–1049. 3. Wartenberg KE, Patsalides AD, Yepes M. Transient diffusionweighted imaging changes in a patient with reversible leukoencephalopathy syndrome. Acta Radiol 2004;45:674–678. 4. Garcia-Monco JC, Martínez A, Brochado AP, Saralegui I, Cabrera A, Beldarrain MG. Isolated and reversible lesions of the corpus callosum: a distinct entity. J Neuroimaging 2010; 20:1–2. 5. de Havenon A, Joos Z, Longenecker L, Shah L, Ansari S, Digre K. Posterior reversible encephalopathy syndrome with spinal cord involvement. Neurology 2014;83:2002– 2006. 6. Gopalakrishnan CV, Vikas V, Nair S Posterior reversible encephalopathy syndrome in a case of postoperative spinal extradural haematoma: case report and review of literature. Asian Spine J 2011;5:64–67. 7. Matias AC, Rocha J, Cerqueira ME, Pereira JM. Autonomic dysreflexia and posterior reversible encephalopathy syndrome. Am J Phys Med Rehabil 2013;92:453–458. 8. Fang R, Karlsson K, Chen T, Sanelli PC. Improving lowdose blood-brain barrier permeability quantification using sparse high-dose induced prior for Patlak model. Med Image Anal 2014;18:866–880. 9. Leigh R, Jen SS, Hillis AE, Krakauer JW, Barker PB; STIR, VISTA Imaging Investigators. Pretreatment blood-brain barrier damage and post-treatment intracranial hemorrhage in patients receiving intravenous tissue-type plasminogen activator. Stroke 2014;45:2030–2035. 10. Roberts HC, Roberts TP, Bollen AW, Ley S, Brasch RC, Dillon WP. Correlation of microvascular permeability derived from dynamic contrast-enhanced MR imaging with histologic grade and tumor labeling index: a study in human brain tumors. Acad Radiol 2001;8:384–391.
Neurology 83
November 25, 2014
1997
Hypertensive crisis: Reversible edema in leukoencephalopathy, retinopathy, now myelopathy? Gregory Kapinos and Pina C. Sanelli Neurology 2014;83;1996-1997 Published Online before print October 29, 2014 DOI 10.1212/WNL.0000000000001035 This information is current as of October 29, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/22/1996.full.html
References
This article cites 10 articles, 3 of which you can access for free at: http://www.neurology.org/content/83/22/1996.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Other cerebrovascular disease/ Stroke http://www.neurology.org//cgi/collection/other_cerebrovascular_diseas e__stroke
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
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.
Hypertensive crisis Reversible edema in leukoencephalopathy, retinopathy, now myelopathy?
Gregory Kapinos, MD, MS Pina C. Sanelli, MD, MPH, FACR
Correspondence to Dr. Kapinos: [email protected] Neurology® 2014;83:1996–1997
The definition of the clinicoradiologic syndrome posterior reversible leukoencephalopathy syndrome (PRES) has been stretched over the last decade.1 Many regard PRES as a final common denominator for various cerebral insults, without a single etiopathogenic trigger.1,2 The hallmark of classic PRES is hydrostatic pressure breakthrough causing cerebral vasogenic edema, commonly coupled with a history of refractory hypertension, ictal surge in blood pressure (BP), and a concomitant systemic inflammatory or uremic process.1 High BP may be absent in PRES if there is renal failure; infection or any systemic inflammatory response syndrome; or immunomodulation as seen in eclampsia, autoimmune disorders, or chemotherapy.1–3 PRES may thus be better defined as a “neurotoxic syndrome”2 with blood–brain barrier opening or with disruption of cerebral autoregulation leading to dysperfusion with either vasogenic or cytotoxic edema.2,3 The phenotypic umbrella of PRES now includes transient, isolated splenial edematous lesions4 and extensive spinal cord edema. A mounting number of cases of longitudinally extensive central cord edema in the absence of infectious, demyelinating, or ischemic causes or venous engorgement from an arteriovenous fistula now warrant codifying this entity as a discrete clinical syndrome and perusal for specific risk factors. In this issue of Neurology®, de Havenon et al.5 analyzed the semiology and potential cause for a newly recognized subset of patients with PRES. They present 2 cases and integrate the data into a broader analysis of 6 other case reports, where patients had risk factors for classic PRES and no other cause for reversible spinal cord edema. They coined PRES-SCI (with spinal cord involvement) as a syndromic entity and found that severe acute hypertension, grade IV hypertensive retinopathy, younger age, and male gender are key features for this subtype of PRES. Lesions invariably manifested as confluent central cord T2 hyperintensity, involving at least 4 spinal segments, originating at the cervicomedullary junction.5 We laud the authors for describing the clinicoradiologic characteristics and attempting to find a single etiopathogenesis underpinning this syndrome, such as severe hypertension as a leading cause and the uniform
presence of hypertensive retinopathies.5 However, many treatments in this cohort were directed at aggressive BP reduction and amelioration of the renal function, reflecting the prominence of both hypertension and uremia in this cohort. One patient received steroids, probably for vasogenic edema, confounding the primacy of severe hypertension as the root cause. The main messages drawn from this study5 might include the following: (1) in confirmed cases of PRES, mild signs of myelopathy should prompt imaging of the cord, and if edema is found, a less extensive workup for other causes may be possible; or (2) all patients with PRES should be screened for cord edema, because only half of this cohort expressed symptoms or signs of myelopathy; and (3) when facing cryptogenic isolated extensive central cord edema, if PRES clinical risk factors are present, PRES-SCI should be listed in the differential diagnosis, permitting a less extensive workup and avoidance of empirical treatment for myelitis. These conclusions would be too hasty, however. One cannot emphasize enough that clinicians and radiologists facing isolated central cord edema in hypertensive patients, or even cord edema in confirmed cases of PRES, must still exclude dangerous causes with a standard myelitis workup. Given that this review failed to identify any pathognomonic features, a careful review of clinical history, CSF analysis, and MRI of the neuraxis remains imperative before claiming that lowering the BP will necessarily lead to a favorable outcome.5 Perspicacious analysis of cause or consequence is also warranted before claiming PRES is causing any cord edema. Indeed, a separate primary lesion in the cervical cord can cause local cord edema, which in turn can disrupt the autonomic nervous system, with sympathetic overtone, leading to supratentorial PRES manifestations.6,7 This study5 will likely prompt subsequent investigations to compare various risk factor profiles in subtypes of PRES. As with typical PRES, the new pathophysiology of PRES-SCI may occur in a substantial number of patients without hypertension, even though all reported cases seem to be associated with severe acute hypertension. Patients with eclampsia or on chemotherapeutic drugs, or patients with severe hypertension and uremia or infection, could be selected as cohorts to be screened
See page 2002 From the Departments of Neurosurgery & Neurology (G.K.) and Radiology (P.C.S.), Hofstra North Shore–LIJ School of Medicine, Manhasset, NY. 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 editorial. 1996
© 2014 American Academy of Neurology
for cord edema, before the neurologic community claims that it is a distinct PRES variant worth attributing solely to hypertensive crisis, as suggested by de Havenon et al.5 Vasoreactivity, perfusion and diffusion-weighted imaging, as well as blood–brain barrier (BBB)/blood–cord barrier (BCB) permeability imaging8 are crucial to parse this pleomorphic entity of acute idiopathic reversible CNS edema.2 While the authors diligently commented that absence of enhancement indicates no BCB alteration, dedicated BBB/ BCB permeability mapping may yield some interesting results, as mild BBB alterations lead to permeability abnormality prior to total disruption of BBB seen with parenchymal enhancement.8–10 Management of patients with PRES is now more complicated than simply lowering BP because of hydrostatic breakthrough edema, as the PRES spectrum spans edema and ischemia, immunologic alteration, BBB disruption, and loss of cerebral autoregulation.2–4 The fact that all patients with PRES-SCI seem to improve with aggressive BP reduction and return to premorbid baseline5 is encouraging, but some patients may have sequelae from this transient and not so benign edema.1,2 AUTHOR CONTRIBUTIONS Gregory Kapinos: drafting/revising the manuscript, study concept or design, analysis or interpretation of data. Pina C. Sanelli: drafting/revising the manuscript.
STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Lamy C, Oppenheim C, Mas JL. Posterior reversible encephalopathy syndrome. Handb Clin Neurol 2014; 121:1687–1701. 2. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. ANJR Am J Neuroradiol 2008;29:1043–1049. 3. Wartenberg KE, Patsalides AD, Yepes M. Transient diffusionweighted imaging changes in a patient with reversible leukoencephalopathy syndrome. Acta Radiol 2004;45:674–678. 4. Garcia-Monco JC, Martínez A, Brochado AP, Saralegui I, Cabrera A, Beldarrain MG. Isolated and reversible lesions of the corpus callosum: a distinct entity. J Neuroimaging 2010; 20:1–2. 5. de Havenon A, Joos Z, Longenecker L, Shah L, Ansari S, Digre K. Posterior reversible encephalopathy syndrome with spinal cord involvement. Neurology 2014;83:2002– 2006. 6. Gopalakrishnan CV, Vikas V, Nair S Posterior reversible encephalopathy syndrome in a case of postoperative spinal extradural haematoma: case report and review of literature. Asian Spine J 2011;5:64–67. 7. Matias AC, Rocha J, Cerqueira ME, Pereira JM. Autonomic dysreflexia and posterior reversible encephalopathy syndrome. Am J Phys Med Rehabil 2013;92:453–458. 8. Fang R, Karlsson K, Chen T, Sanelli PC. Improving lowdose blood-brain barrier permeability quantification using sparse high-dose induced prior for Patlak model. Med Image Anal 2014;18:866–880. 9. Leigh R, Jen SS, Hillis AE, Krakauer JW, Barker PB; STIR, VISTA Imaging Investigators. Pretreatment blood-brain barrier damage and post-treatment intracranial hemorrhage in patients receiving intravenous tissue-type plasminogen activator. Stroke 2014;45:2030–2035. 10. Roberts HC, Roberts TP, Bollen AW, Ley S, Brasch RC, Dillon WP. Correlation of microvascular permeability derived from dynamic contrast-enhanced MR imaging with histologic grade and tumor labeling index: a study in human brain tumors. Acad Radiol 2001;8:384–391.
Neurology 83
November 25, 2014
1997
Hypertensive crisis: Reversible edema in leukoencephalopathy, retinopathy, now myelopathy? Gregory Kapinos and Pina C. Sanelli Neurology 2014;83;1996-1997 Published Online before print October 29, 2014 DOI 10.1212/WNL.0000000000001035 This information is current as of October 29, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/22/1996.full.html
References
This article cites 10 articles, 3 of which you can access for free at: http://www.neurology.org/content/83/22/1996.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Other cerebrovascular disease/ Stroke http://www.neurology.org//cgi/collection/other_cerebrovascular_diseas e__stroke
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
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.
