Neurological Complications of
Hemolytic-Uremic Syndrome
Jin S. Hahn, MD; Peter L. Havens, MD, MS; Joseph J. Higgins, MD;
P. Pearl O’Rourke, MD; Judy A. Estroff, MD; Roy Strand, MD

Abstract
Of 78 children identified with hemolytic-uremic syndrome at the Children’s Hospital, Boston, from 1976 to 1986, 16 patients
(20.5%) had neurological manifestations during their hospitalization. The most common manifestations were significant
alterations in consciousness (coma, stupor) in 12 patients, and either generalized or partial seizures in ten patients. Others
included hemiplegia (4 patients), decerebrate posturing (3), cortical blindness (2), hallucinations (1), and dystonic posturing
(1). Cranial computed tomographic scans were abnormal in eight of 11 patients scanned. The abnormalities included diffuse
cerebral edema (4 patients), large vessel infarctions (3), diffuse multiple small infarcts (4), and multiple hemorrhages (1).
Five patients died as a result of their central nervous system complications, and six had neurological sequelae at discharge.
Five patients recovered and at discharge had no evidence of neurological dysfunction. (
1989;4:108-113).
JChild Neurol

is defined

by
syndrome
~jemolytic-uremicmicroangiopathic
hemolytic
JL

the presence of

thrombocytopenia, and acute oligoanuric
Hemolytic-uremic syndrome occurs
most frequently in children younger than 5 years old,
although the syndrome has been reported at all ages.
Often there is a prodrome of gastroenteritis or virallike illness. Hemolytic-uremic syndrome has been
anemia,

renal failure.

seen in association with different infections, illnesses,
and medications. It is a multisystemic disorder in
which deposition of fibrin in the microvasculature

leads to intravascular thrombosis. Although improvements in general patient care and dialysis have reduced the mortality rate from about 21 % before 19741
to 4% to 7% by the mid-1980s,2-4 significant longterm morbidity still occurs in 10% to 20% of patientS4’5
in the form of neurological sequelae, chronic renal failure, of hypertension. Several authors have emphasized the importance of neurological complications of

hemolytic-uremic syndrome, which occur in approximately 30% to 50% of patients.4-6 The present study
examines the spectrum of neurological manifestations
in patients with hemolytic-uremic syndrome. In a
previous report, the relationship between laboratory
in hemolytic-uremic synparameters and outcome
7
drome was detailed. ~

Methods
Medical records of 78 children seen at the Children’s Hospital, Boston, between 1976 and 1986 with the diagnosis of
hemolytic-uremic syndrome were reviewed retrospectively.
The age of these children ranged from 6 months to 16.5
years, with a mean of 4.8 years. Sixty-one of the 78 patients
(78%) were 5 years of age or younger. Data were collected
on presenting history, acute phase of illness, and outcome
at hospital discharge. Cranial computed tomographic (CT)
scans were reviewed by the authors (J.A.E. and R.S.) Laboratory values and urinary outputs were recorded and sub7

sequently analyzed as previously described.’

Case Reports
From the Departments of Neurology, Pediatrics, and Anesthesia, Children’s Hospital and Harvard Medical School, Boston,
MA.
This paper was presented in part at the Child Neurology
Society Meeting, October 24, 1987.
Address correspondence to Dr Jin S. Hahn, Department of
Neurology C-338, Stanford University Medical Center, Stanford,
CA 94305.

Case 1
A previously healthy 11-month-old boy was admitted to a

local hospital because of vomiting and diarrhea for four
days. On admission, the hematocrit was 32%, platelet count
150,000/u.L blood urea nitrogen 54 mg/dL, and creatinine
3.0 mg/dL. He was hydrated with intravenous fluids. He de-

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veloped bloody diarrhea and anuria. The child had generalized tonic-clonic seizures, which lasted approximatelv 20
minutes, prompting a transfer to the Children’s Hospital.
Upon arrival to the Children’s Hospital, he was noted to be
stuporous and had opisthotonic posturing, left abducens
palsy, hypertonia, and bilateral Babinski reflexes. He continued to have frequent generalized tonic-clonic seizures
with intermittent left-body partial motor seizures. He developed status epilepticus, requiring intubation and induction of pentobarbital coma. Other than a mild hyperkalemia
(potassium, 5.5 mmol/L), the electrolytes were unremarkable. An initial cranial CT scan on the day of admission was
considered to be normal. He was also treated with fresh
frozen plasma and dialysis. On the second day, he remained
comatose, although pentobarbital had been discontinued.
On the third day, he became hypotensive and developed
further brain stem dysfunction. Another CT scan revealed
multiple areas of infarcts, particularly in the white matter.
Multiple infarcts were seen also in the frontal and temporal
cortical regions and the basal ganglia (Figure 1). An EEG at
this time revealed diffuse slowing, right greater than left.
Plasmapheresis was instituted, but shortly thereafter, he
lost all brain stem reflexes. Fundoscopy revealed multiple
retinal hemorrhages. Brain stem auditory evoked potentials
were absent and an EEG showed no cerebral activity. Supportive care was withdrawn and the patient died.

Case 6
A 4-year-old girl was admitted to a local hospital with an
8-hour history of vomiting, bloody diarrhea, abdominal
cramping, and diffuse abdominal pains. She had a lowgrade fever of 101°F. At the other hospital, she was hydrated
with normal saline. Her blood urea nitrogen was 154 mg/dL,
creatinine 8.2 mg/dL, hematocrit 19%, and platelet 54,000/
pL. The peripheral blood smear showed hemolysis (red
blood cell fragments, helmets, and schistocytes). Her urine

FIGURE 1
Cranial CT in case 1 showing multiple areas of low attenuation consistent with multiple infarcts, located in the white
matter, frontal and temporal gray matter, and the basal

ganglia.

output decreased gradually over a week, and she became
anuric. She

was transferred to the Children’s Hospital,
where peritoneal dialysis was started. After 3 days of uneventful dialysis, she was transferred back to the local hospital for further peritoneal dialysis. At transfer, the patient
was edematous but had no neurological abnormalities. Her
blood urea nitrogen was 33 mg/dL, and creatinine 4.2 mg/dL.
Three days later the patient developed a fever, and her mental status declined. A lumbar puncture was performed and
found to be normal. Blood cultures grew Staphylococcus epidenuidis, and vancomvcin was started. Over the ensuring 24
hours she developed a left hemiplegia, left facial weakness,
and blindness. She was readmitted to the Children’s Hospital, where she was noted to be irritable. Although her pupils
were 4 to 5 mm in diameter and reacted to light bilaterally,
she appeared to be blind. She had a left facial weakness and
left hemiplegia with hyperreflexia and an extensor plantar
response on the left side. ECG revealed left lateral wall ischemia, and echocardiogram confirmed left ventricular dysfunction. On the second hospital day, she became stuporous
and developed papilledema and a dilated right pupil. She
had a brief left-sided focal motor seizure. A CT scan revealed
multiple areas of low attenuation, including a large right
posterior frontal and left parieto-occipital lesions, consistent
with multiple infarcts (Figure 2). Because of signs of increased intracranial pressure, she received dexamethasone
and was intubated, paralyzed (with pancuronium), and
hyperventilated. She received both peritoneal dialysis and
plasmapheresis and had a gradual resolution of the anuria.
On hospital day 15, she was successfully extubated but had
a residual left
hemiparesis and cortical blindness.

Case 9
An 11-year-old boy was admitted to a local hospital after a
three-day history of abdominal pain, vomiting, and diar-

rhea. The diarrhea eventually became bloody. He was
treated with promethazine and intravenous hydration.
He developed microangiopathic changes on the peripheral
blood smear and thrombocytopenia (platelet 49,000/~L).
After three days of hospitalization, there was a decrease
in urine output and transient alteration in mental status,
prompting a transfer to the Children’s Hospital.
On admission to the Children’s Hospital, he was confused, frightened, and disoriented with poor short-term
memory. There was a suggestion of bilateral abducens palsies. Deep tendon reflexes were increased and Babinski
responses were present bilaterally. There was marked dysmetria and tremor. Laboratory studies revealed a hematocrit
of 41%, a platelet count of 41,000/~L, blood urea nitrogen
53 mg/dL, and creatinine 3.2 mg/dL. His maximum blood
pressure was 144 mm Hg systolic and 84 mm Hg diastolic.
Hemodialysis was started, since previous appendectomy
precluded peritoneal dialysis. An initial cranial CT scan was
considered to be normal. Hemodialysis and plasmapheresis
were initiated. On the second hospital day, he became comatose and had decerebrate posturing to painful stimuli. A
repeat CT scan revealed a large left basal ganglia hemorrhagic
infarct, right temporoparietal infarcts, and other multifocal
areas of infarctions (Figure 3). Shortly thereafter the patient
became acutely hypotensive and lost all brain stem reflexes.
Despite supportive measures, he did not improve, and
eventually brain death criteria were met and supportive
measures were discontinued.

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FIGURE 2
Cranial CT in case 6 showing multiple areas of low attenuation, large right posterior frontal and left parieto-occipital infarcts.

Results

Neurological Manifestations
Of the 78 patients with hemolytic-uremic syndrome,
16 (20.5%) had neurological manifestations during
their hospitalization. Significant alteration in consciousness, ie, coma or stupor, was present in 12 patients. Seizures were also frequent and occurred in 10
patients (generalized in 5, partial in 3, and secondarily
generalized in 2). Other manifestations included
hemiplegia or hemiparesis (in 4 patients), decerebrate

posturing (3), cortical blindness (2), hallucinations
(1), and dystonic posturing (1).
Of the 16 patients with neurological manifestations, 11 (14.1 % of all patients) had serious neurologi-

cal sequelae (Table 1). There were five deaths, and all
occurred in children who had developed neurological
complications. The remaining six children had persistent neurological signs at discharge, consisting of
hemiparesis, altered level of consciousness, blindness, or

dystonic posturing.

Five patients had transient neurological dysfunction (seizures, hallucinations, stupor, and hypotonia)
but recovered completely, and at discharge had no
evidence of neurological sequelae (Table 2).
Cranial CT was abnormal in eight of the 11 patients scanned. Findings are summarized in Tables 1
and 2. These abnormalities included: diffuse cerebral
edema (in 4 patients), large vessel infarctions (3),
multiple small infarcts (4), and parenchymal hemor-

rhages (1).
Electroencephalograms obtained in 8 cases were
abnormal (see Tables 1 and 2).

Neuropathological Manifestations
Neuropathological examination of the brain was available in three of the five patients who died. In all three
cases, there was evidence of extensive cerebral edema

FIGURE 3
Cranial CT in case 9 revealing a large left basal ganglia
hemorrhagic infarct, right temporoparietal infarct (at other
levels), and multiple small areas of infarctions.

and cerebellar tonsillar and tentorial herniations.
Microthrombi or large vessel thrombi were not found
in any of the cases. In case 9 there was a large confluent area of hemorrhagic infarction and necrosis
involving the left basal ganglia, internal capsule, anterior thalamus, amygdala, hippocampus, and insular cortex (Figure 4). Left lateral ventricular hemorrhage was present with extension of the hemorrhage
into the fourth ventricle. Another large (3 x 3 cm) cortical and subcortical hemorrhage was found in the

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TABLE 1
HUS Patients With Significant Neurological Sequelae

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TABLE 1 (continued)

HUS

=

hemolytic uremic syndrome; LP

=

lumbar puncture.

TABLE 2
HUS Patients With Neurological Manifestation But Good Outcome

HUS

=

hemolytic uremic syndrome.

right parieto-occipital area. In addition, a small right
occipital cortical hemorrhage and cervical and thoracic
spinal cord petechial hemorrhage were noted. Thrombosis of the cerebral vasculature was not found. In
case 1, there were multiple areas of irregular cortical
softenings, particularly in the forebrain. Microscopic
examination revealed widespread neuronal necrosis,
consistent with anoxic encephalopathy. Case 11
revealed multiple areas of cortical necrosis predominantly in border-zone areas, right parieto-occipital
hemorrhagic infarct, and pontine necrosis.

Discussion
In this study, we found a wide spectrum of neurological complications in patients with hemolytic-uremic

syndrome, varying from generalized disturbances,
such as stupor, coma, and seizures, to more focal

signs, including hemiplegia, hemiparesis, cortical
blindness, and extrapyramidal signs. The incidence
of neurological manifestations was 20.5% and the
incidence of serious neurological sequelae was 14%.
The incidence of serious neurological complications
in other series varied from 30% to 50%.4-6 These differences may reflect either the improvement of intensive care in recent years or a bias in patient acquisition
in our series.
Several mechanisms have been proposed to explain the neurological complications in hemolyticuremic syndrome. Nonspecific metabolic derangements, hypertension, and renal failure, may in part
account for the relatively high incidence of seizures
and alterations in consciousness. Although intravascular coagulation and microthrombi are the hallmarks
of this syndrome in the renal system, these have not
been consistently found in the central nervous system.

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vasculature, while microthrombi were limited to the
kidneys. Thus, in a few cases, the neurological complications may be caused by large vessel thrombosis,
a process different from that responsible for the renal,

hematological, and gastrointestinal manifestations.
There were five deaths in our series, all occurring
in children who had neurological complications. It
appears that the presence of neurological complications is a mortality risk factor. The mortality rate in
hemolytic-uremic syndrome in our study (6.4%) is
similar to those of more recent series. 4,5
In the past, the clinical usefulness of admission
laboratory values to predict subsequent neurological
dysfunction have been limited.3-5 As we reported
previously, in this series the combination of serum
calcium <
7.6 mg/dL and urine output < 0.4 mL/kg/
hr was able to predict serious morbidity or death with
82% sensitivity, 99% specificity, and 90% positive
7

predictive value.7
FIGURE 4
Gross pathology of the brain in case 9 with bilateral hemorrhagic infarctions and necrosis. Scattered fixation artifacts
are present and have the appearance of multiple focal cystic
lesions.

Acknowledgment
Neuropathological material was kindly provided by Dr
William Kupske.

References
The three patients in our study who had neuropathological examination had evidence of focal ischemia in
their brains. However, microthrombi and large vessel
thrombi were not found. Rooney et al6 examined
brains of seven patients who had neurological complications and died of hemolytic-uremic syndrome. In
these cases, no microthrombi or distinctive pathological processes were found in the brains. In contrast,
Upadhyaya et al8 studied the brains of three patients
with hemolytic-uremic syndrome and severe neurological symptoms and found microthrombi in the
brains of two cases. Evidence of ischemia with focal
areas of infarction were noted in all three. Our series
is somewhat unusual in that there were three patients
who had large bland or hemorrhagic infarcts. Trevathan et al9 recently reported three cases of hemolyticuremic syndrome with large-vessel infarctions in the
distribution of middle and anterior cerebral arteries
as demonstrated by CT. Autopsy, available in one of
the cases, revealed large-vessel thrombi in the cerebral

1. Proesmans W, Eeckels R: Has heparin changed the prognosis

of the hemolytic-uremic syndrome? Clin Nephrol 1974;2:169173.
2. Trompeter RS, Schwartz R, Chantler C, et al: Haemolyticuraemic syndrome: An analysis of prognostic features. Arch
Dis Child 1983;58:101-105.
3. Loirat C, Sonsino E, Varga-Moreno A, et al: Hemolytic-uremic
syndrome: An analysis of the natural history and prognostic
features. Acta Paediatr Scand 1984;73:505-514.
4. Sheth KJ, Swick HM, Haworth N: Neurological involvement in
hemolytic-uremic syndrome. Ann Neurol 1986;19:90-93.
5. Bale JF, Brasher C, Siegler RL: CNS manifestations of the
hemolytic-uremic syndrome: Relationship to metabolic alterations and prognosis. AmJ Dis Child 1980;134:869-872.
6. Rooney JC, Anderson RM, Hopkins IJ: Clinical and pathological aspects of central nervous system involvement in the
1971;7:28-33.
haemolytic uraemic syndrome. Aust PaediatrJ
7. Hahn JS, Havens PL, Higgins, JJ, et al: Predictors of outcome in
hemolytic-uremic syndrome. Ann Neurol 1987;22:451-452.
8. Upadhyaya K, Barwick K, Fishaut M, et al: The importance of
nonrenal involvement in hemolytic-uremic syndrome. Pediatrics

1980;65:115-120.
9. Trevathan E, Dooling EC: Large thrombotic strokes in hemolyticuremic syndrome. J Pediatr 1987;111:863-866.

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