Rev Chil Pediatr. 2017;88(5):640-646
DOI: 10.4067/S0370-41062017000500011

Clinical Case

Acute Cerebrovascular events associated to hemolytic uremic
syndrome: Description of two pediatric cases
Compromiso cerebrovascular agudo en síndrome hemolítico urémico:
descripción de dos casos pediátricos
López M.a, Huete I.b, Marta Hernándeza
Unit of Pediatric Neurology, Division of Pediatrics
Department of Radiology. School of Medicine, Pontificia Universidad Católica de Chile (PUC)

a

b

Received: 01-11-2016; Accepted: 01-03-2017

Abstract
Introduction: Diarrhea-associated Hemolytic Uremic Syndrome (D+HUS) is a multisystem disorder
in which neurological involvement (35 to 50%) is associated to adverse outcome. An important cause
of a permanent neurological impairment is the cerebrovascular pathology. Objective: To report two
pediatric cases of D+HUS with severe neurological involvement due to cerebrovascular disease, and
review available literature. Clinical cases: Two previously healthy 15- and 21-month-old children
debuted with seizures and impairment of consciousness within the first week of a D+HUS. Both presented hypertension, severe acute renal failure, and focal motor deficit. One child showed significant
improvement in neurologic status after five sessions of plasmapheresis. Brain magnetic resonance
showed in the first child multiple bilateral infarcts of small vessels and lesions of white matter. In
the second patient, large bilateral infarcts on both middle cerebral arteries territories were identified. One year after the acute event, both children showed functional impairment; The first patient
evolved with language delay and spastic hemiparesis; the second patient with spastic quadriparesis,
epilepsy with poor seizure control and marked functional impairment. Conclusion: Although most
of the children with D+HUS and brain involvement do not have long-term sequelae, cerebrovascular
disease in the acute period causes permanent damage, and in addition to the management of electrolyte disturbances, hypertension, and renal failure, therapies directed at specific pathophysiological
mechanisms that trigger vascular compromise may improve prognosis.

Correspondence:
Marta Hernández
mhernand@med.puc.cl

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Keywords:
Pediatric stroke,
acute renal failure,
thrombotic
microangiopathy,
disability,
Hemolytic Uremic
Syndrome

Clinical Case
Hemolytic uremic syndrome - M. López et al

Introduction
Diarrhea-associated Hemolytic Uremic Syndrome
(D+HUS) is a multisystem disorder and the leading
cause of acute renal failure in children aged < 4 years.
It is triggered by gastrointestinal infection, commonly
due to a Shiga toxin-producing Escherichia Coli (E.
Coli) serotype O157:H7. A distinctive triad characterized by acute renal failure, intravascular hemolytic
anemia, and thrombocytopenia constitutes the basis of
diagnosis. Thrombotic microangiopathy has a central
role in the pathophysiology of hemodynamic alterations of D+HUS. These disturbances can include the
central nervous system (CNS), gastrointestinal tract,
pancreas, liver, and kidney1-4.
Neurological involvement occurs in 35 to 50% of
D+HUS cases. Endothelial dysfunction (associated
with complement activation induced by Shiga toxin),
arterial hypertension, and hydroelectrolytic disorders
(commonly hyponatremia) are involved in CNS dysfunction. Although neurological manifestations can go
back with the standard treatment of D+HUS, in cases
of brain parenchymal injury the long-term neurological morbidity reaches up to 50%. Thus, an early brain
magnetic resonance imaging (MRI) allows identifying
ischemic lesions and vasogenic edema of the brain parenchyma5,6.
To date, no clinical studies are reporting a specific
therapy for D+HUS. Hemodynamic stabilization, hydroelectrolytic balance, and acute renal failure management (including renal replacement therapy to support critically ill patients) are the basis of treatment.
Furthermore, some immune-therapies such as plasmapheresis and use of antibodies against complement
proteins may be useful alternatives in patients with severe CNS involvement7-10.
According to Zambrano and Prado, the incidence of D+HUS in Chile is around 34/ 100,000 children
aged < 4 years, with a mortality of 2,9%11,12. There are
no reports of clinical characteristics or outcomes of
D+HUS children with neurological involvement on
acute period. The objective of this report is to describe clinical manifestations, neuroimaging features, and
neurological status at 24 months of 2 D+HUS children
with severe CNS involvement due to cerebrovascular
dysfunction. We discussed respect to the existing therapeutic alternatives for neurological impairment in
these patients. The Research Ethics Broads of the Pontificia Universidad Católica approved this study.

Clinical cases
Case 1
A 15-months old previously healthy boy who had
traveled outside the metropolitan region was admit-

ted to a rural hospital. He was receiving treatment for
acute non-dysenteric diarrhea, hyperemesis, and recurrent episodes of tonic-clonic seizures managed with
phenobarbital. Laboratory findings were consistent
with D+HUS. As his condition gradually progressed to
renal failure and persistently elevated blood pressure,
he was referred to our hospital for renal replacement
therapy. During his stay in our institution, he presented progressive renal and hemodynamic improvement
with pharmacological management (furosemide, hydralazine, and nifedipine), so he did not require dialysis. However, on the 9th day of evolution, he required
invasive mechanical ventilation (IMV) due to impairment of consciousness and generalized seizures. MRI
prior IMV showed acute white matter ischemic lesions
in the corona radiata, periventricular, and parieto-occipital areas (Figure 1). Five sessions of plasmapheresis
were performed due to the adverse neurological evolution, with a progressive improvement of mental status
and seizure control. At 6 and 12 months of discharge, the boy presented a right spastic hemiparesis and a
moderate delay in language. Because he did not present
any seizures at 24 months, the antiepileptic treatment
was progressively discontinued, without recurrence of
seizures (Table 1).

Case 2
A 21-months old previously healthy boy from
rural areas who presented acute dysenteric diarrhea
and hyperemesis was initially treated with furazolidone, however, due to the presence of severe dehydration was admitted in a primary hospital at the third
day of evolution with a normal hemogram and renal
function study. At the sixth day, the boy had a sudden
onset of impairment of consciousness, pallor, generalized edema and oliguria. Laboratory findings were
consistent with D+HUS. He presented a progressive
renal and respiratory failure due to an intercurrent
infection. Thus he required renal replacement therapy (peritoneal dialysis) and IMV for four days. After extubation, the patient developed impairment of
consciousness, generalized tonic seizures, and focal
motor deficits. A first brain CT and posterior MRI
with MRA showed extensive infarctions in the territory of both middle cerebral arteries (Figure 2). He
was referred to our hospital for the management of
refractory epilepsy. At admission, he had a qualitative
alteration of consciousness, spastic quadriparesis, and
a severe swallowing disorder which required a gastrostomy and fundoplication. At two years of follow-up,
the boy persisted with spastic quadriparesis, epilepsy
with poor seizures control and a marked functional
deterioration, but with oral feeding and preserved eye
contact (Table 1).
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Clinical Case
Hemolytic uremic syndrome - M. López et al

Figure 1. Patient 1: MRI taken
on the 18 h after neurological
symptoms showing diffusion
restriction in bilateral centrum
semi-ovale (figure a y b White
and black arrow) and bilateral
corticospinal tracts (figure c and
d; White and black arrow). In
T2 (e, dotted arrow) and FLAIR
(f, head arrow) show bilaterales
hyperintensities of capsula externa (e) and parieto-occipitales
zones (f).

Table 1. Clinical and laboratory characteristics of two boys with acute neurologic disease and hemolytic–uremic syndrome
Patient 1

Patient 2

Age (months)

15

21

Diarrhea

no bloody

bloody

Time between enteritis and neurological symptoms (days)
Alteration of conscience

7

6

Seizures

7

13

Time between enteritis and mechanical ventilation

9

8

Max blood pressure (mmHg)

129/77

121/78

Stool culture

(-)

(-)

PCR for verotoxin 1 y 2

day 12 (-)

day 20 (-)

ADAMTS-13 (metaloproteasa)

normal

normal

White blood cell counts (103/mm3)

14

17.9

Hematocrit (%)

22

26

Blood count

Schistocytes

(++)

(++)

Platelet (103/mm3)

41

16

Creatinine (mg/dL)

3,4

3,6

Renal replacement therapy

no

peritoneal dialysis

Plasmapheresis (nº)

5

no

PCR: polymerase chain reaction.

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Clinical Case
Hemolytic uremic syndrome - M. López et al

Figure 2. Axial (a) and coronal view (b) of CT brain, in patient 2. In the 8th day; extensive signal hypointensities changes of both middle cerebral
artery (white arrow). MRI-FLAIR in the 21th day, show involvement bilateral of cortical, subcortical zones y basal ganglia by ischaemic lesions (c, d,
white arrow). Conventional Angiogram shows occlusion branche M2 of right MCA (up, black arrow negra) and occlusion of the segment M1 in
the left MCA (abajo, dotted black arrow).

Discussion
About half of patients with D+HUS have acute
neurological manifestations such as headaches, qualitative and quantitative compromise of consciousness,
language disturbances, movement disorders, weakness and epileptic seizures, which are usually due to
cerebral edema caused by hyponatremia. Although in
pediatrics the acute CNS involvement is described as
transient and reversible, studies in adults suggest that
the frequency of cognitive impairment in children is
probably underestimated13.
Our patients presented severe neurological disturbances associated with D+HUS, developing in both
cases permanent motor and cognitive sequelae in
addition to epilepsy. Although in these children, the
neurological deterioration was evident, it is relevant to
perform a standardized neuropsychological study to all
patients with neurological manifestations in the course
of D+HUS to determine the requirement for specific
therapies. Retrospective studies of clinical series with
a high number of pediatric patients have found a severe neurological involvement during the acute period
of D+HUS in 25.6% of cases, with persistent deficits
in one-fifth of them and mortality of 17%. Adverse

outcomes would be associated with demyelinating lesions and brain ischemia4,14.
In our patients, MRI showed symmetrical and bilateral ischemic lesions. Patient 1 also showed diffuse
white matter lesions in the subacute-chronic period.
Patient 2 presented a stenosis of the M1 and M2 branches of both middle cerebral arteries, probably in the
context of endothelial damage due to Shiga toxin. A
retrospective study that included 52 children with
diarrhea and severe neurological involvement14, demonstrated a high frequency of focal lesions in terminal brain circulation. In this study, there was no statistically significant association between the location
of the lesion and the prognosis, unlike to our cases in
which MRI lesions had a high concordance with the
long-term neurological sequels.
Cerebrovascular lesions observed in MRI depend
on the underlying pathophysiological changes on the
course of the disease. There are, in general, 3 types of
lesions: (1) Hemodynamic infarcts with or without hemorrhagic transformation of terminal vessels located
in the basal ganglia and periventricular white matter
during the acute phase. (2) Cortical cytotoxic edema
due to coagulative necrosis with irregular distribution
during the subacute phase, mainly due to large to lar643

Clinical Case
Hemolytic uremic syndrome - M. López et al

ge vessel microangiopathy. (3) Symmetrical vasogenic
edema predominantly in the parieto-occipital regions
due to multifactorial endothelial damage (strongly
associated with prolonged or ictal hypertension) during the late phase (encephalopathy due to brain hyperperfusion, formerly known as posterior reversible
leukoencephalopathy)13,15-18.
Currently, new techniques in brain MRI have been
described as the susceptibility sequences (SWI: Susceptibility-Weighted Imaging). These sequences detect
hemodynamic brain changes in up to 92% of symptomatic patients, visualized as loss of venous contrast
that would reflect the increase in cerebral blood flow
due to severe acute anemia. This new technique would
allow the early detection of children at high risk of brain damage by low flow, allowing optimal management
of their disease19.
As previously mentioned, the correction of hemodynamic alterations, hydroelectrolytic misbalances,
and acute renal failure is the basis of the treatment of
neurological compromise in D+HUS. However, some
specific therapies linked to the underlying pathophysiological changes could improve symptoms in the
acute period and reduce long-term neurological morbidity. In one of our patients, the use of 5 sessions of
plasmapheresis was correlated with rapid and significant symptomatic improvement. Although Colic et al,
in 2011, demonstrated the decrease of CNS complications in adults with D+HUS undergoing plasmapheresis, these results have not been replicated successfully
in pediatric populations20, so the indication must be
evaluated case by case.
In recent years there has been increasing interest in
the potential benefit of the use of complement protein
antagonists, such as eculizumab (a monoclonal antibody that would specifically and irreversibly block the
C5 component) that would stop the cascade leading
to the development of thrombotic microangiopathy.
Moreover, that has demonstrated efficacy and safety in
the management of atypical HUS with severe systemic
alterations21. The results of this treatment in children
with severe neurological compromise due to D+HUS
are still uncertain, so it is necessary to critically evaluate the results of the studies that are currently carried
out before recommending their use7 – 10, 22.
In our patients, there was no history of unsafe dietary intakes or affected family in the preceding period
or concomitant with the clinical picture. However, in
patient 1, diarrhea began while he was out of his region
of origin during the summer, without access to drinking water and patient 2, lived in a rural place and they
consumed water from streams of water.
We do not know the electrolyte status of children
before referral to our hospital. It is possible that cerebrovascular symptoms have been superimposed
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on those caused by moderate to severe hyponatremia
(cerebral edema, intracranial hypertension). Similarly,
although no lesions resembling central pontine myelinolysis, bilateral periventricular lesions may suggest a
central extrapontine myelinolysis, by rapid correction
of natremia. Therefore, it is necessary to bear in mind
the initial hydroelectrolytic state at the time of treating
a child with D+HUS21.
Antibiotic prescription and late recollection of
stool samples for analyses, likely explain the absence of
detection for the etiological agent. Clinical and laboratory characteristics also discarded atypical HUS.

Conclusions
Although the neurological involvement in D+HUS
is frequent, it is usually due to reversible conditions.
Cerebrovascular diseases are a cause of permanent
CNS damage, which must be detected early to optimize
treatment and thereby improve long-term prognosis.
The severity of the underlying systemic alterations predicts the level of permanent neurological compromise.
Therefore, the treatment of arterial hypertension, hydroelectrolytic alterations, and renal failure continue
to be the fundamental pillar in the prevention of neurological damage. Even so, in severe cases, the use of
specific therapies could be beneficial.

Ethical Responsibilities
Human Beings and animals protection: Disclosure
the authors state that the procedures were followed according to the Declaration of Helsinki and the World
Medical Association regarding human experimentation developed for the medical community.
Data confidentiality: The authors state that they have
followed the protocols of their Center and Local regulations on the publication of patient data.
Rights to privacy and informed consent: The authors
have obtained the informed consent of the patients
and/or subjects referred to in the article. This document is in the possession of the correspondence author.

Financial Disclosure
Authors state that no economic support has been associated with the present study.

Conflicts of Interest
Authors declare no conflict of interest regarding the
present study.

Clinical Case
Hemolytic uremic syndrome - M. López et al

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