Accepted Manuscript Posterior Reversible Encephalopathy and Cerebral Vasoconstriction in a patient with Hemolytic Uremic Syndrome Rajkumar Agarwal, MD Cresha Davis, MD Deniz Altinok, MD Fatema J. Serajee, MBBS PII:
S0887-8994(14)00026-5
DOI:
10.1016/j.pediatrneurol.2014.01.024
Reference:
PNU 8239
To appear in:
Pediatric Neurology
Received Date: 19 November 2013 Revised Date:
17 December 2013
Accepted Date: 5 January 2014
Please cite this article as: Agarwal R, Davis C, Altinok D, Serajee FJ, Posterior Reversible Encephalopathy and Cerebral Vasoconstriction in a patient with Hemolytic Uremic Syndrome, Pediatric Neurology (2014), doi: 10.1016/j.pediatrneurol.2014.01.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Title: Posterior Reversible Encephalopathy and Cerebral Vasoconstriction in a patient with Hemolytic Uremic Syndrome.
RI PT
Running title: PRES and RCVS
Authors:
SC
Rajkumar Agarwal1, MD, Cresha Davis1, MD, Deniz Altinok2, MD, Fatema J Serajee1, MBBS
Wayne State University, Detroit, MI
Address for Correspondence:
3901 Beaubien Street
EP
Detroit MI 48201
TE D
Rajkumar Agarwal, MD
M AN U
Department of Pediatrics1, Neurology1 and Radiology2, Children's Hospital of Michigan,
AC C
Telephone: 313-745-5788
Fax: 313-745-0955
Email: [email protected]
Word Count: 1567
PRES and RCVS
1
ACCEPTED MANUSCRIPT
Abstract
BACKGROUND: We report a patient with hemolytic uremic syndrome (HUS) who with
radiological
manifestations
suggestive
of
posterior
reversible
RI PT
presented
encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS). PATIENT: A 13 year old girl presented with fever and bloody diarrhea and
SC
progressed to develop HUS. She subsequently developed encephalopathy, aphasia and right sided weakness. RESULTS: Brain MRI showed presence of vasogenic edema in
M AN U
the left frontal lobe, in addition to T2 and FLAIR changes in white matter bilaterally, compatible with PRES. MRA showed beading of the cerebral vessels suggestive of RCVS. Neurological deficits reversed 8 days after symptom onset, with resolution of the beading pattern on follow up MRA after 3 weeks. CONCLUSIONS: Both PRES and RCVS may represent manifestations of similar underlying pathophysiologic mechanisms.
TE D
Recognition of the co-existence of these processes in patients with HUS may aid in judicious management of these patients and avoidance of inappropriate therapeutic
AC C
EP
interventions.
Key words: hemolytic-uremic syndrome, PRES, RCVS, vasospasm
PRES and RCVS
2
ACCEPTED MANUSCRIPT
Introduction
Neurological involvement is the most common extra-renal manifestation of hemolytic 1
The clinical presentation in these patients could range from
RI PT
uremic syndrome (HUS).
seizures to mental status alteration and focal neurological deficits. 2
SC
Case report
A previously healthy thirteen year old right-handed Caucasian female was admitted to the
M AN U
hospital with a three day history of fever, abdominal pain and bloody diarrhea. During the course of her admission, she developed oliguria, azotemia, thrombocytopenia and acute renal failure. Laboratory studies revealed escalating creatinine levels (up to 8.3 mg/dL), necessitating initiation of peritoneal dialysis after a week of hospitalization. Soon after initiation of dialysis, she started to have intermittent elevations in her blood pressure,
TE D
with systolic blood pressure reaching as high as 155 mg Hg (>95th percentile). She had fluctuations in her mental status with periods of agitation and confusion. On day 4 of
EP
dialysis, she developed global aphasia, right sided facial droop and right hemiparesis. The blood pressure in the 12 hours prior to these symptoms was consistently elevated with
AC C
systolic blood pressure ranging between 148 mm Hg and 188 mg Hg.
A computed tomogram (CT) of her head revealed a hypodensity in the left frontal region. Magnetic Resonance Imaging (MRI) of the brain (Figure 1) showed multiple patchy areas of increased T2 and FLAIR signal abnormalities in bilateral frontal and parietal subcortical white matter. The most prominent lesion was seen in the left frontal lobe. There was no diffusion restriction on Diffusion Weighted images (DWI), but an elevated
PRES and RCVS
3
ACCEPTED MANUSCRIPT
Apparent Diffusion Co-efficient (ADC) was noted in the lesion. In addition, there were punctate hemorrhagic foci in the left frontal region. Magnetic resonance spectroscopy (MRS) lacked a lactate or choline peak. Magnetic Resonance Angiography (MRA)
RI PT
showed smaller than expected caliber of the posterior cerebral arteries. "Beading" was noted in the right posterior cerebral artery and distal branches of right middle cerebral artery (Figure 2). Magnetic resonance venography (MRV) was normal. Serological tests
SC
for HIV, ANA, Anti-ds-DNA antibody, Cardiolipin antibody and ANCA were negative. Complement levels (C3 and C4) were normal. Cerebrospinal fluid studies were
M AN U
unremarkable, including absence of oligoclonal bands.
Hypertension was controlled with nicardipine drip followed by use of oral antihypertensive agents. The radiological abnormalities seen on MRA raised a concern for vasculitis. Hence, she received a course of intravenous immunoglobulin (IVIG) followed
TE D
by high dose methylprednisolone. Eight days after she developed hemiparesis, her neurological deficits resolved. Oral prednisone was continued post discharge. Three
EP
weeks after the onset of her symptoms, her brain MRI demonstrated marked improvement in the subcortical hyperintensities with no beading or focal narrowing
AC C
(Figure 3).
Discussion
Hemolytic-uremic syndrome (HUS) is characterized by a triad of clinical features consisting of microangiopathic hemolytic anemia, thrombocytopenia and uremia. The most common cause of HUS in children is infection with verotoxin producing enteric pathogens. 2 Neurological symptoms may be seen in 20% - 50% of patients with HUS.1 A
PRES and RCVS
4
ACCEPTED MANUSCRIPT
commonly implicated factor in neurological injury is a direct verotoxin induced damage to the endothelium.
1
An alternative hypothesis is neuro-inflammation resulting from
massive cytokine release by the endothelial cells to which the toxin attaches. 2 There are
RI PT
other metabolic changes like hyponatremia, azotemia and fluid imbalance which may complicate the course of HUS and can affect the neural homeostasis directly or indirectly. Hypertension may also be a manifestation of HUS, and could lead to disturbances in
M AN U
diverse neurological manifestations in a given patient. 2
SC
cerebral autoregulation. All these factors in isolation or in combination can lead to
Neuroimaging in patients with HUS most frequently reveals involvement of the basal ganglia in the form of edema, infarction or hemorrhage.
3
Other manifestations include
cortical edema or infarcts and changes in the white matter consistent with PRES. 3, 4, 5 The symptomatic lesion in our patient was present in the left frontal lobe. It did not show
TE D
diffusion restriction, making it unlikely to be cytotoxic edema or infarction. The absence of lactate peak on MRS and the eventual complete resolution of the lesion on follow up imaging argue against a thromboembolic or vasculitic infarct. Elevated ADC was
EP
suggestive of vasogenic edema which is seen in PRES. 6
AC C
The underlying pathophysiology for development of PRES in patients with HUS is controversial. Severe hypertension with failed autoregulation, injury to the capillary bed, and hyperperfusion remain the most popular theory for the brain edema in PRES.
7, 8
Earlier descriptions of PRES illustrated involvement of symmetrical areas supplied by posterior cerebral arteries, leading to the nomenclature “posterior” reversible encephalopathy syndrome. 6 The preferential involvement of the parieto-occipital region
PRES and RCVS
5
ACCEPTED MANUSCRIPT
is hypothesized to be due to decreased adrenergic tone of the posterior circulation as compared to the anterior circulation. Nonetheless, numerous reports have described patients with PRES involving the anterior circulation and in an asymmetrical pattern, as 5, 7
The dynamic changes in blood pressure are not adequate to
RI PT
was seen in our patient.
explain the development of PRES in all cases, as PRES is known to develop in normotensive patients and in patients with mild elevation of blood pressure.
8
The
SC
pathophysiology in these patients is believed to be a “systemic process” with cytokine production, endothelial injury and microcirculatory disturbances,
8
as in HUS. The
M AN U
presence of hypertension in combination with the toxin-mediated vascular dysfunction could be causative of PRES in our patient.
The “beaded” appearance of large and medium sized arteries in patients with “thunderclap headache” has been very well described.
9
The underlying pathology,
TE D
termed as "Reversible Cerebral Vasoconstriction Syndrome" (RCVS), has now been implicated in many different neurological syndromes. The proposed criteria for diagnosis
EP
of RCVS include presence of segmental cerebral artery vasoconstriction, absence of aneurysmal subarachnoid hemorrhage, normal or near-normal cerebrospinal fluid
AC C
analysis, severe and acute headache and documentation of reversibility of the angiographic abnormalities within 12 weeks after symptom onset.
9
Our patient met the
diagnostic criteria for RCVS, except for the presence of headache. The absence of a reported headache could be related to the underlying encephalopathy at the time of manifestation of the acute right sided weakness.
PRES and RCVS
6
ACCEPTED MANUSCRIPT
The basic pathophysiological mechanism in both PRES and RCVS is a disturbance in the regulation of the cerebral arterial tone. PRES is believed to be a disorder of small sized arterioles, whereas RCVS is primarily vasoconstriction detected in medium-to-large sized 10
About 9% - 14% of patients with RCVS may be associated with PRES.
RI PT
arterioles.
11
Similarly, patients with PRES have been described to have diffuse vasoconstriction or focal vasculopathy.
8, 11
It has thus been suggested that PRES and RCVS may resemble
SC
the end points of a similar pathophysiologic process. Whether a patient develops PRES, RCVS or an “overlapping syndrome”, is determined by differences in the vascular tone at
M AN U
various levels of circulation. 10 The simultaneous occurrence of both these entities in our patient reiterates the shared pathophysiology of these disorders. It is also plausible that the PRES-like vasogenic edema is a manifestation of the vasospasm seen in RCVS and not necessarily a distinct phenomenon. 11 The combination of PRES and RCVS, although 10, 12
has not been described previously in a patient with
TE D
reported with other etiologies,
HUS. The absence of this finding in previous reports of HUS could be due to the limitation of the imaging modality or due to timing of the study, as it is known that
EP
vasoconstriction seen in RCVS could be fluctuating. 10
AC C
The focal areas of "beading" noted on the MRA raised the suspicion for an immunemediated vasculitic process. The serological markers for an autoimmune condition were negative. Further evaluation in the form of catheter angiography or brain biopsy could not be pursued due to the underlying medical condition and presence of coagulopathy. She received empirical treatment with IVIG and intravenous steroids. However, the sudden onset of symptoms, normal CSF analysis, absence of infarcts and the completely reversible angiographic changes would be very unlikely in the presence of central
PRES and RCVS
7
ACCEPTED MANUSCRIPT
nervous system vasculitis.
13, 14
We also acknowledge that catheter angiography is the
gold standard for diagnosis of RCVS;
9
as MRA tends to overestimate the degree of
RI PT
arterial narrowing. 15
The treatment of PRES relies on withdrawal of the offending agent, control of hypertension and symptomatic management.
7
For patients with RCVS, vasodilators 9
Both
SC
including calcium channel antagonists have been tried with reasonable success.
PRES and RCVS imply a “reversible” disease, with complete recovery. 7, 9 This is true in
M AN U
the majority of cases, as in our patient, where both clinically and radiologically, the manifestations are transient and improve in a short period. However, some patients with either disorder, might develop significant infarcts or hemorrhages, which could lead to mortality or long term morbidity. 7, 8, 9
TE D
Conclusion
In conclusion, we report a patient with HUS who presented with encephalopathy and
EP
focal neurological deficit. Neuroimaging was suggestive of vasogenic edema seen in PRES; with MRA consistent with RCVS. There have been no reports in the literature
AC C
describing the co-occurrence of these entities in a patient with HUS. It is likely that both PRES and RCVS are phenotypic manifestations of a similar pathophysiologic process. "Beading" of the vessels typically raises concern for vasculitis, especially in the setting of an underlying toxin-mediated immune process. However, the completely reversible nature of the beading with absence of infarcts and markers of neuroinflammation makes RCVS an important consideration in a patient who presents likewise. Availability of
PRES and RCVS
8
ACCEPTED MANUSCRIPT
similar reports in future may help improve the understanding of these disease processes
AC C
EP
TE D
M AN U
SC
RI PT
and judicious use of immune modulating therapy.
PRES and RCVS
9
ACCEPTED MANUSCRIPT
References
1. Toldo I, Manara R, Cogo P et al. Diffusion-Weighted Imaging Findings in Hemolytic
RI PT
Uremic Syndrome with central nervous system involvement. J Child Neurol. 2009; 24(2): 247-250.
2. Nathanson S, Kwon T, Elmaleh M, et al. Acute neurological involvement in diarrhea-
SC
associated hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2010; 5(7): 1218-1228.
M AN U
3. Steinborn M, Leiz S, Rudisser K, Griebel M, Harder T, Hahn H. CT and MRI in haemolytic uraemic syndrome with central nervous system involvement: distribution of lesions and prognostic value of imaging findings. Pediatr Radiol. 2004; 34(10): 805-810.
4. Taylor MB, Jackson A, Weller JM. Dynamic susceptibility contrast enhanced MRI in
TE D
reversible posterior leukoencephalopathy syndrome associated with haemolytic uraemic syndrome. Br J Radiol. 2000; 73(868): 438-442.
EP
5. Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: Fundamental imaging and clinical features. AJNR Am J Neuroradiol. 2008; 29(6): 1036-1042.
AC C
6. Lamy C, Oppenheim C, Méder JF, Mas JL. Neuroimaging in posterior reversible encephalopathy syndrome. J Neuroimaging. 2004; 14(2): 89-96.
7. Stott VL, Hurrell MA, Anderson TJ. Reversible posterior leukoencephalopathy syndrome: a misnomer reviewed. Intern Med J. 2005; 35(2): 83-90.
PRES and RCVS
10
ACCEPTED MANUSCRIPT
8. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: Controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol. 2008; 29(6):
RI PT
1043-1049.
9. Calabrese LH, Dodick DW, Schwedt TJ, Singhal AB. Narrative review: reversible cerebral vasoconstriction syndromes. Ann Intern Med. 2007; 146(1): 34-44.
SC
10. Singhal AB. Postpartum angiopathy with reversible posterior leukoencephalopathy.
M AN U
Arch Neurol. 2004; 61(3): 411-416.
11. Chen SP, Fuh JL, Wang SJ. Reversible cerebral vasoconstriction syndrome: current and future perspectives. Expert Rev Neurother. 2011; 11(9): 1265-1276.
12 Chatterjee N, Domoto-Reilly K, Fecci PE, Schwamm LH, Singhal AB. Licorice-
TE D
associated reversible cerebral vasoconstriction with PRES. Neurology. 2010; 75(21): 1939-1941.
EP
13. Hajj-Ali RA. Primary angiitis of the central nervous system: differential diagnosis and treatment. Best Pract Res Clin Rheumatol. 2010; 24(3): 413-426.
AC C
14. Singhal AB. Diagnostic challenges in RCVS, PACNS, and other cerebral arteriopathies. Cephalalgia 2011; 31(10): 1067-1070.
15. Lee BC, Park TS, Kaufman BA. MR angiography in pediatric neurological disorders. Pediatr Radiol. 1995; 25(6): 409-419.
PRES and RCVS
11
ACCEPTED MANUSCRIPT
Figure 1: MRI Brain at the onset of right sided weakness, demonstrating changes suggestive of PRES.
b) Elevated ADC seen in the left frontal region (White arrow).
RI PT
a) DWI image showing no diffusion restriction.
c) Axial FLAIR image showing large hyperintense region in the left frontal white matter (Black arrowhead).
occipital subcortical regions (black arrows).
SC
d) Axial FLAIR image showing hyperintensities in the left frontal and right parieto-
M AN U
e) Susceptibility weighted images suggestive of petechial hemorrhages in the left frontal
AC C
EP
TE D
lobe (white arrowhead).
PRES and RCVS
12
ACCEPTED MANUSCRIPT
Figure 2: MR Angiogram demonstrating changes suggestive of RCVS, with areas of
AC C
EP
TE D
M AN U
SC
RI PT
focal narrowing (black arrows) in the M3 branches of right MCA and in right PCA.
PRES and RCVS
13
ACCEPTED MANUSCRIPT
Figure 3: Follow up imaging 3 weeks from the development of right sided weakness. a) Axial FLAIR shows resolution of previously seen abnormalities. b) Stable Susceptibility images likely due to hemosiderin deposition (Black arrow).
AC C
EP
TE D
M AN U
SC
RI PT
c) MRA shows normal vascular flow pattern.
PRES and RCVS
14
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S0887-8994(14)00026-5
DOI:
10.1016/j.pediatrneurol.2014.01.024
Reference:
PNU 8239
To appear in:
Pediatric Neurology
Received Date: 19 November 2013 Revised Date:
17 December 2013
Accepted Date: 5 January 2014
Please cite this article as: Agarwal R, Davis C, Altinok D, Serajee FJ, Posterior Reversible Encephalopathy and Cerebral Vasoconstriction in a patient with Hemolytic Uremic Syndrome, Pediatric Neurology (2014), doi: 10.1016/j.pediatrneurol.2014.01.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Title: Posterior Reversible Encephalopathy and Cerebral Vasoconstriction in a patient with Hemolytic Uremic Syndrome.
RI PT
Running title: PRES and RCVS
Authors:
SC
Rajkumar Agarwal1, MD, Cresha Davis1, MD, Deniz Altinok2, MD, Fatema J Serajee1, MBBS
Wayne State University, Detroit, MI
Address for Correspondence:
3901 Beaubien Street
EP
Detroit MI 48201
TE D
Rajkumar Agarwal, MD
M AN U
Department of Pediatrics1, Neurology1 and Radiology2, Children's Hospital of Michigan,
AC C
Telephone: 313-745-5788
Fax: 313-745-0955
Email: [email protected]
Word Count: 1567
PRES and RCVS
1
ACCEPTED MANUSCRIPT
Abstract
BACKGROUND: We report a patient with hemolytic uremic syndrome (HUS) who with
radiological
manifestations
suggestive
of
posterior
reversible
RI PT
presented
encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS). PATIENT: A 13 year old girl presented with fever and bloody diarrhea and
SC
progressed to develop HUS. She subsequently developed encephalopathy, aphasia and right sided weakness. RESULTS: Brain MRI showed presence of vasogenic edema in
M AN U
the left frontal lobe, in addition to T2 and FLAIR changes in white matter bilaterally, compatible with PRES. MRA showed beading of the cerebral vessels suggestive of RCVS. Neurological deficits reversed 8 days after symptom onset, with resolution of the beading pattern on follow up MRA after 3 weeks. CONCLUSIONS: Both PRES and RCVS may represent manifestations of similar underlying pathophysiologic mechanisms.
TE D
Recognition of the co-existence of these processes in patients with HUS may aid in judicious management of these patients and avoidance of inappropriate therapeutic
AC C
EP
interventions.
Key words: hemolytic-uremic syndrome, PRES, RCVS, vasospasm
PRES and RCVS
2
ACCEPTED MANUSCRIPT
Introduction
Neurological involvement is the most common extra-renal manifestation of hemolytic 1
The clinical presentation in these patients could range from
RI PT
uremic syndrome (HUS).
seizures to mental status alteration and focal neurological deficits. 2
SC
Case report
A previously healthy thirteen year old right-handed Caucasian female was admitted to the
M AN U
hospital with a three day history of fever, abdominal pain and bloody diarrhea. During the course of her admission, she developed oliguria, azotemia, thrombocytopenia and acute renal failure. Laboratory studies revealed escalating creatinine levels (up to 8.3 mg/dL), necessitating initiation of peritoneal dialysis after a week of hospitalization. Soon after initiation of dialysis, she started to have intermittent elevations in her blood pressure,
TE D
with systolic blood pressure reaching as high as 155 mg Hg (>95th percentile). She had fluctuations in her mental status with periods of agitation and confusion. On day 4 of
EP
dialysis, she developed global aphasia, right sided facial droop and right hemiparesis. The blood pressure in the 12 hours prior to these symptoms was consistently elevated with
AC C
systolic blood pressure ranging between 148 mm Hg and 188 mg Hg.
A computed tomogram (CT) of her head revealed a hypodensity in the left frontal region. Magnetic Resonance Imaging (MRI) of the brain (Figure 1) showed multiple patchy areas of increased T2 and FLAIR signal abnormalities in bilateral frontal and parietal subcortical white matter. The most prominent lesion was seen in the left frontal lobe. There was no diffusion restriction on Diffusion Weighted images (DWI), but an elevated
PRES and RCVS
3
ACCEPTED MANUSCRIPT
Apparent Diffusion Co-efficient (ADC) was noted in the lesion. In addition, there were punctate hemorrhagic foci in the left frontal region. Magnetic resonance spectroscopy (MRS) lacked a lactate or choline peak. Magnetic Resonance Angiography (MRA)
RI PT
showed smaller than expected caliber of the posterior cerebral arteries. "Beading" was noted in the right posterior cerebral artery and distal branches of right middle cerebral artery (Figure 2). Magnetic resonance venography (MRV) was normal. Serological tests
SC
for HIV, ANA, Anti-ds-DNA antibody, Cardiolipin antibody and ANCA were negative. Complement levels (C3 and C4) were normal. Cerebrospinal fluid studies were
M AN U
unremarkable, including absence of oligoclonal bands.
Hypertension was controlled with nicardipine drip followed by use of oral antihypertensive agents. The radiological abnormalities seen on MRA raised a concern for vasculitis. Hence, she received a course of intravenous immunoglobulin (IVIG) followed
TE D
by high dose methylprednisolone. Eight days after she developed hemiparesis, her neurological deficits resolved. Oral prednisone was continued post discharge. Three
EP
weeks after the onset of her symptoms, her brain MRI demonstrated marked improvement in the subcortical hyperintensities with no beading or focal narrowing
AC C
(Figure 3).
Discussion
Hemolytic-uremic syndrome (HUS) is characterized by a triad of clinical features consisting of microangiopathic hemolytic anemia, thrombocytopenia and uremia. The most common cause of HUS in children is infection with verotoxin producing enteric pathogens. 2 Neurological symptoms may be seen in 20% - 50% of patients with HUS.1 A
PRES and RCVS
4
ACCEPTED MANUSCRIPT
commonly implicated factor in neurological injury is a direct verotoxin induced damage to the endothelium.
1
An alternative hypothesis is neuro-inflammation resulting from
massive cytokine release by the endothelial cells to which the toxin attaches. 2 There are
RI PT
other metabolic changes like hyponatremia, azotemia and fluid imbalance which may complicate the course of HUS and can affect the neural homeostasis directly or indirectly. Hypertension may also be a manifestation of HUS, and could lead to disturbances in
M AN U
diverse neurological manifestations in a given patient. 2
SC
cerebral autoregulation. All these factors in isolation or in combination can lead to
Neuroimaging in patients with HUS most frequently reveals involvement of the basal ganglia in the form of edema, infarction or hemorrhage.
3
Other manifestations include
cortical edema or infarcts and changes in the white matter consistent with PRES. 3, 4, 5 The symptomatic lesion in our patient was present in the left frontal lobe. It did not show
TE D
diffusion restriction, making it unlikely to be cytotoxic edema or infarction. The absence of lactate peak on MRS and the eventual complete resolution of the lesion on follow up imaging argue against a thromboembolic or vasculitic infarct. Elevated ADC was
EP
suggestive of vasogenic edema which is seen in PRES. 6
AC C
The underlying pathophysiology for development of PRES in patients with HUS is controversial. Severe hypertension with failed autoregulation, injury to the capillary bed, and hyperperfusion remain the most popular theory for the brain edema in PRES.
7, 8
Earlier descriptions of PRES illustrated involvement of symmetrical areas supplied by posterior cerebral arteries, leading to the nomenclature “posterior” reversible encephalopathy syndrome. 6 The preferential involvement of the parieto-occipital region
PRES and RCVS
5
ACCEPTED MANUSCRIPT
is hypothesized to be due to decreased adrenergic tone of the posterior circulation as compared to the anterior circulation. Nonetheless, numerous reports have described patients with PRES involving the anterior circulation and in an asymmetrical pattern, as 5, 7
The dynamic changes in blood pressure are not adequate to
RI PT
was seen in our patient.
explain the development of PRES in all cases, as PRES is known to develop in normotensive patients and in patients with mild elevation of blood pressure.
8
The
SC
pathophysiology in these patients is believed to be a “systemic process” with cytokine production, endothelial injury and microcirculatory disturbances,
8
as in HUS. The
M AN U
presence of hypertension in combination with the toxin-mediated vascular dysfunction could be causative of PRES in our patient.
The “beaded” appearance of large and medium sized arteries in patients with “thunderclap headache” has been very well described.
9
The underlying pathology,
TE D
termed as "Reversible Cerebral Vasoconstriction Syndrome" (RCVS), has now been implicated in many different neurological syndromes. The proposed criteria for diagnosis
EP
of RCVS include presence of segmental cerebral artery vasoconstriction, absence of aneurysmal subarachnoid hemorrhage, normal or near-normal cerebrospinal fluid
AC C
analysis, severe and acute headache and documentation of reversibility of the angiographic abnormalities within 12 weeks after symptom onset.
9
Our patient met the
diagnostic criteria for RCVS, except for the presence of headache. The absence of a reported headache could be related to the underlying encephalopathy at the time of manifestation of the acute right sided weakness.
PRES and RCVS
6
ACCEPTED MANUSCRIPT
The basic pathophysiological mechanism in both PRES and RCVS is a disturbance in the regulation of the cerebral arterial tone. PRES is believed to be a disorder of small sized arterioles, whereas RCVS is primarily vasoconstriction detected in medium-to-large sized 10
About 9% - 14% of patients with RCVS may be associated with PRES.
RI PT
arterioles.
11
Similarly, patients with PRES have been described to have diffuse vasoconstriction or focal vasculopathy.
8, 11
It has thus been suggested that PRES and RCVS may resemble
SC
the end points of a similar pathophysiologic process. Whether a patient develops PRES, RCVS or an “overlapping syndrome”, is determined by differences in the vascular tone at
M AN U
various levels of circulation. 10 The simultaneous occurrence of both these entities in our patient reiterates the shared pathophysiology of these disorders. It is also plausible that the PRES-like vasogenic edema is a manifestation of the vasospasm seen in RCVS and not necessarily a distinct phenomenon. 11 The combination of PRES and RCVS, although 10, 12
has not been described previously in a patient with
TE D
reported with other etiologies,
HUS. The absence of this finding in previous reports of HUS could be due to the limitation of the imaging modality or due to timing of the study, as it is known that
EP
vasoconstriction seen in RCVS could be fluctuating. 10
AC C
The focal areas of "beading" noted on the MRA raised the suspicion for an immunemediated vasculitic process. The serological markers for an autoimmune condition were negative. Further evaluation in the form of catheter angiography or brain biopsy could not be pursued due to the underlying medical condition and presence of coagulopathy. She received empirical treatment with IVIG and intravenous steroids. However, the sudden onset of symptoms, normal CSF analysis, absence of infarcts and the completely reversible angiographic changes would be very unlikely in the presence of central
PRES and RCVS
7
ACCEPTED MANUSCRIPT
nervous system vasculitis.
13, 14
We also acknowledge that catheter angiography is the
gold standard for diagnosis of RCVS;
9
as MRA tends to overestimate the degree of
RI PT
arterial narrowing. 15
The treatment of PRES relies on withdrawal of the offending agent, control of hypertension and symptomatic management.
7
For patients with RCVS, vasodilators 9
Both
SC
including calcium channel antagonists have been tried with reasonable success.
PRES and RCVS imply a “reversible” disease, with complete recovery. 7, 9 This is true in
M AN U
the majority of cases, as in our patient, where both clinically and radiologically, the manifestations are transient and improve in a short period. However, some patients with either disorder, might develop significant infarcts or hemorrhages, which could lead to mortality or long term morbidity. 7, 8, 9
TE D
Conclusion
In conclusion, we report a patient with HUS who presented with encephalopathy and
EP
focal neurological deficit. Neuroimaging was suggestive of vasogenic edema seen in PRES; with MRA consistent with RCVS. There have been no reports in the literature
AC C
describing the co-occurrence of these entities in a patient with HUS. It is likely that both PRES and RCVS are phenotypic manifestations of a similar pathophysiologic process. "Beading" of the vessels typically raises concern for vasculitis, especially in the setting of an underlying toxin-mediated immune process. However, the completely reversible nature of the beading with absence of infarcts and markers of neuroinflammation makes RCVS an important consideration in a patient who presents likewise. Availability of
PRES and RCVS
8
ACCEPTED MANUSCRIPT
similar reports in future may help improve the understanding of these disease processes
AC C
EP
TE D
M AN U
SC
RI PT
and judicious use of immune modulating therapy.
PRES and RCVS
9
ACCEPTED MANUSCRIPT
References
1. Toldo I, Manara R, Cogo P et al. Diffusion-Weighted Imaging Findings in Hemolytic
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Uremic Syndrome with central nervous system involvement. J Child Neurol. 2009; 24(2): 247-250.
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3. Steinborn M, Leiz S, Rudisser K, Griebel M, Harder T, Hahn H. CT and MRI in haemolytic uraemic syndrome with central nervous system involvement: distribution of lesions and prognostic value of imaging findings. Pediatr Radiol. 2004; 34(10): 805-810.
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reversible posterior leukoencephalopathy syndrome associated with haemolytic uraemic syndrome. Br J Radiol. 2000; 73(868): 438-442.
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5. Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: Fundamental imaging and clinical features. AJNR Am J Neuroradiol. 2008; 29(6): 1036-1042.
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8. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: Controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol. 2008; 29(6):
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15. Lee BC, Park TS, Kaufman BA. MR angiography in pediatric neurological disorders. Pediatr Radiol. 1995; 25(6): 409-419.
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Figure 1: MRI Brain at the onset of right sided weakness, demonstrating changes suggestive of PRES.
b) Elevated ADC seen in the left frontal region (White arrow).
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a) DWI image showing no diffusion restriction.
c) Axial FLAIR image showing large hyperintense region in the left frontal white matter (Black arrowhead).
occipital subcortical regions (black arrows).
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d) Axial FLAIR image showing hyperintensities in the left frontal and right parieto-
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e) Susceptibility weighted images suggestive of petechial hemorrhages in the left frontal
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lobe (white arrowhead).
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Figure 2: MR Angiogram demonstrating changes suggestive of RCVS, with areas of
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focal narrowing (black arrows) in the M3 branches of right MCA and in right PCA.
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Figure 3: Follow up imaging 3 weeks from the development of right sided weakness. a) Axial FLAIR shows resolution of previously seen abnormalities. b) Stable Susceptibility images likely due to hemosiderin deposition (Black arrow).
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c) MRA shows normal vascular flow pattern.
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