**3. Results**

204 Neuroimaging for Clinicians – Combining Research and Practice

symptoms such as irritability, drowsiness, seizures, cortical blindness, hemiparesis or coma, in up to 35-50% of patients (Montoliu, 1989). These symptoms may be a consequence of different disturbances: metabolic distress (hyponatremia, hyperglycemia, acidosis, fluid imbalance), HBP itself, or CNS microangyopathy. Pancreatic failure and heart involvement

HUS treatment is based on hydro-electrolytic management: peripheral and central venous pressure must be monitored and cardiac function must be closely controlled; renal function control is especially important, as well as caloric intake adjustment. Neurologic evaluation at the acute phase and during follow-up is crucial to diagnose CNS damage and prevent

No complementary tests have yet been developed to help the clinician in establishing a medium- or long-term prognosis in patients with HUS presenting with neurologic symptoms. Although during the 1980s some authors observed a good clinical outcome in patients with microangyopathic lesions (Steinborn et al., 2004), few references have reported long-term follow-up in these patients. Over the last 20 years, some cases of posterior reversible leuko-encephalopathy syndrome of subacute onset (presenting with drowsiness, lethargy, visual disturbance or seizures) have been described in the context of HUS, sometimes not even associated with HBP (Bennett et al., 2003; Gómez-Lado et al., 2007;

Prognosis factors previously described in different series of patients (Cimolai et al., 1992 ; Roche et al. 2008), including patient age, acute gastroenteritis symptoms, etiologic agent, seizures at onset, CNS images at the acute phase and neurofunctional tests performance, are reviewed below; clinical course during follow-up and long-term outcome of HUS patients

Over the last 30 years (1981-2011), a series of 64 patients (29 boys and 35 girls) have presented with HUS in our hospital. Clinical charts of children with neurological symptoms







are less frequent during the acute phase of HUS (2% of patients).

medium- and long-term sequelae.

with neurological symptoms are also analyzed.

during the acute phase were reviewed, including:

acute phase and along follow-up.

if acute gastrointestinal infection history was not present. - Laboratory tests (data not shown but available upon request).


Kitamura et al., 2010).

**2. Material and methods** 

paresia.

The following tables summarize the patients' characteristics (sex, age at onset), causative agent, clinical presentation, diagnostic tests and clinical course of the 25 patients with HUS and neurological symptoms at onset.

Median age at presentation was 2 years 8 months (range 7 months-7 years old).

As shown in Table 1, sex distribution in HUS patients with neurologic symptoms reveals a higher proportion of girls (64%), with a boy/girl rate of 1:1.7; the rate among patients without neurologic symptoms was 1:1.2, slightly more frequent in girls.

Recent history of acute gastroenteritis (D+) was present in 24/25 patients with HUS and neurological symptoms at onset, although etiologic agent was only found in blood in 4/25 (two *Salmonella enteritidis* and two *E. coli*). One of these patients presented *E coli* both in blood and urine, and another had *Salmonella* in blood and *E. coli* in urine; *E. coli* was also present in urine in another patient.

The most frequent neurologic sign at onset was drowsiness alone (40%) or together with irritability (16%), while irritability alone was present in 10%.


Haemolytic-Uraemic Syndrome:

4

6

11

15

17

Patient EEG Brain

Plain EEG 15 hours after onset

Bilateral hemispheric abnormalities

Combination θ,α and β waves, without paroxysmal activity

Diffuse slow background. Left temporal paroxysms

Paradoxal reactivity with slow background and slow high voltage waves in both hemispheres, no paroxysms

21 Not performed

22 Not performed

acute phase and MRI control.

Neurologic Symptoms, Neuroimaging and Neurocognitive Outcome 207

Not performed Not performed

Normal at the acute phase. Absence of supra-tentorial pulse 15h after onset

Bilateral hemispheric abnormalities, of left predominance

Normal brain medium artery Doppler ultrasound

ultrasound Brain CT Brain MRI acute

phase

Not performed Not performed Not performed

Corticosubcortical atrophy. Putamen necrosis

Normal Normal Not performed Not performed

Prominent sulci Not performed Not performed Not performed

Not performed Not performed Not performed Not performed

Not performed Normal diffusion

Basal ganglia necrosis and corticosubcortical atrophy, consistent with vasculitis

Multiple corticosubcortical hypointense images, consistent with brain edema

24 Not performed Not performed Not performed Normal Not performed 25 Not performed Not performed Normal Not performed Not performed

Table 2. Results of the pathologic tests in patients with HUS and neurologic symptoms at the

Brain MRI control

Putamen necrosis

Basal ganglia necrosis and corticosubcortical atrophy also affecting cerebellum

brain MRI Not performed


GTCS: generalized tonic-clonic seizure; HBP: high blood pressure;#M:male /F:female;\* Trip to Argentina a few days before acute gastroenteritis

Table 1. Acute neurologic presentation on HUS context.

Nine patients suffered seizures at onset (generalized tonic-clonic, tonic or myoclonic seizures), which stands for 14% of all HUS patients and 36% of neurologic HUS patients. All nine patients survived without important long term sequelae. However, patients presenting seizure recurrence (patient 6) or myoclonic seizures during the acute phase (patient 9) developed medium term sequelae.

One patient presented orolingual dystonia shortly after clinical onset with irritability and drowsiness; no other patients showed abnormal movements at the acute phase or during follow up.

Eleven children had some neurological complementary test performed: eye funduscopy showed fovea erythrosis in patient 4 (exitus), and patient 21 presented delayed and disorganized VEP with normal BEAR. Video EEG was abnormal for all the patients who underwent it (5/9), with slow background activity; transfontanellar US, BMA Doppler US brain CT and MRI (both in the acute phase and during follow-up) findings are summarized in Table 2.

Brain MRI findings of patients 6 (Figures 1 and 2) and 21 (Figures 3 and 4) are consistent with vasculitic lesions due to diffuse hypoxic-ischemic aggression, with cortico-subcortical and basal ganglia distribution. Despite these findings, which were persistent along followup, both patients presented a favorable course without important long-term sequelae.

11 1yr 10mo F D+ Unknown yes Consciousness decrease.

12 1yr 6mo F D+ Unknown yes Drowsiness, pyramidal signs 13 2yr 2mo M D+ Unknown no Irritability-drowsiness

15 1yr 2mo M D+ Unknown yes GTCS

16 3yr 8mo F D+ Unknown yes Drowsiness, irritability

18 2yr 2mo F D+ Unknown yes GTCS. Anisocoria

19 3yr 1mo F D+ *E.Coli* (urine) yes Drowsiness 20 7yr 4mo F D+ Unknown yes Drowsiness

23 4 yr F D+ Unknown yes Drowsiness 24 12 mo F D+ Unknown yes GTCS 25 12 mo M D+ Unknown yes GTCS

GTCS: generalized tonic-clonic seizure; HBP: high blood pressure;#M:male /F:female;\*

acute phase and during follow-up) findings are summarized in Table 2.

17 1yr 8mo F D+ Unknown yes Drowsiness. Loss of consciousness

21\* 3yr F D+ E.Coli yes Stupor. Consciousness decrease.

22 3yr 11mo M D+ Unknown yes Irritability, agitation, drowsiness,

Nine patients suffered seizures at onset (generalized tonic-clonic, tonic or myoclonic seizures), which stands for 14% of all HUS patients and 36% of neurologic HUS patients. All nine patients survived without important long term sequelae. However, patients presenting seizure recurrence (patient 6) or myoclonic seizures during the acute phase (patient 9)

One patient presented orolingual dystonia shortly after clinical onset with irritability and drowsiness; no other patients showed abnormal movements at the acute phase or during

Eleven children had some neurological complementary test performed: eye funduscopy showed fovea erythrosis in patient 4 (exitus), and patient 21 presented delayed and disorganized VEP with normal BEAR. Video EEG was abnormal for all the patients who underwent it (5/9), with slow background activity; transfontanellar US, BMA Doppler US brain CT and MRI (both in the

Brain MRI findings of patients 6 (Figures 1 and 2) and 21 (Figures 3 and 4) are consistent with vasculitic lesions due to diffuse hypoxic-ischemic aggression, with cortico-subcortical and basal ganglia distribution. Despite these findings, which were persistent along followup, both patients presented a favorable course without important long-term sequelae.

*E.coli* (urine) yes Consciousness decrease. Irritability

and blood) yes Drowsiness

Myosis. Pyramidal signs

Slow ocular movements

orolingual dystonia.

Trip to Argentina

10 4yr 6mo M D+ Salmonella

14 6yr F D+ *E.Coli* (urine

a few days before acute gastroenteritis

developed medium term sequelae.

follow up.

Table 1. Acute neurologic presentation on HUS context.


Table 2. Results of the pathologic tests in patients with HUS and neurologic symptoms at the acute phase and MRI control.

Haemolytic-Uraemic Syndrome:

Neurologic Symptoms, Neuroimaging and Neurocognitive Outcome 209

Figure 2.A Figure 2.B

Figure 2.C

Fig. 2. Brain MRI of patient n. 6, fifteen years after clinical presentation. Axial T1 (A) and FLAIR (B), and coronal T2 (C) sequences. The bilateral putamen necrotic areas remain

unchanged compared to the previous study.

A

B

Fig. 1. Brain MRI of patient n. 6, six days after clinical onset.

T1 (A) and T2 (B) axial sequences, consistent with cortico-subcortical atrophy. Symmetrical areas of putamen necrosis.

A

B

T1 (A) and T2 (B) axial sequences, consistent with cortico-subcortical atrophy. Symmetrical

Fig. 1. Brain MRI of patient n. 6, six days after clinical onset.

areas of putamen necrosis.

Figure 2.C

Fig. 2. Brain MRI of patient n. 6, fifteen years after clinical presentation. Axial T1 (A) and FLAIR (B), and coronal T2 (C) sequences. The bilateral putamen necrotic areas remain unchanged compared to the previous study.

Haemolytic-Uraemic Syndrome:

of ischemic lesions.

Neurologic Symptoms, Neuroimaging and Neurocognitive Outcome 211

Figure 3.E Figure 3.F

Figure 3.G Fig. 3. Brain MRI of patient n. 21, six days after clinical onset. Axial T2 FS (E, F) and T1 (G) sequences. Prominence of the convexity sulci and increased ventricular size, consistent with cortico-subcortical atrophy. Bilateral hyperintense areas at the basal ganglia. Multiple cortico-subcortical supratentorial hyperintensities, milder at the cerebellar lobes, suggestive

Figure 3.A Figure 3.B

Figure 3.C Figure 3.D

Fig. 3. Brain MRI of patient n. 21, six days after clinical onset. Coronal FLAIR (A, B, C and D) sequences. Prominence of the convexity sulci and increased ventricular size, consistent with cortico-subcortical atrophy. Bilateral hyperintense areas at the basal ganglia. Multiple cortico-subcortical supratentorial hyperintensities, more subtle at the cerebellar lobes, suggestive of ischemic lesions.

Figure 3.A Figure 3.B

Figure 3.C Figure 3.D

suggestive of ischemic lesions.

Fig. 3. Brain MRI of patient n. 21, six days after clinical onset. Coronal FLAIR (A, B, C and D) sequences. Prominence of the convexity sulci and increased ventricular size, consistent with cortico-subcortical atrophy. Bilateral hyperintense areas at the basal ganglia. Multiple cortico-subcortical supratentorial hyperintensities, more subtle at the cerebellar lobes,

Figure 3.E Figure 3.F

Figure 3.G

Fig. 3. Brain MRI of patient n. 21, six days after clinical onset. Axial T2 FS (E, F) and T1 (G) sequences. Prominence of the convexity sulci and increased ventricular size, consistent with cortico-subcortical atrophy. Bilateral hyperintense areas at the basal ganglia. Multiple cortico-subcortical supratentorial hyperintensities, milder at the cerebellar lobes, suggestive of ischemic lesions.

Haemolytic-Uraemic Syndrome:

Transfontanellar ultrasound\* Pathology

EEG\* Brain MRI\* Renal biopsy. Heart Doppler and EKG

Brain MRI\*. SPECT\*

<sup>15</sup>Transfontanellar ultrasound

<sup>21</sup>Brain CT\*. Brain MRI\*

EEG\*. VEP\*. PEAT

Diffusion MRI\*. EEG Lumbar puncture Brain medium artery Doppler ultrasound

symptoms at the acute phase; (\*) abnormal test.

<sup>9</sup>VEP. ERG. EEG\*

<sup>11</sup>EEG\*

4

6

22

Neurologic Symptoms, Neuroimaging and Neurocognitive Outcome 213

Patient Diagnostic Test Medium-term outcome Long-term outcome 1 No Normal Normal 2 No Normal Normal 3 No Normal Normal

5 No Normal Normal

7 No Normal Normal 8 Eye funduscopy Normal Normal

10 No Normal Normal

12 No Normal Normal 13 No Normal Normal 14 No Normal Normal

16 No Normal Normal 17 EEG\* Normal Normal 18 No Normal Normal 19 No Acute pancreatitis Normal 20 No Normal Normal

23 No normal normal 24 Brain MRI normal normal 25 Brain CT normal normal Table 3. Diagnostic tests, medium- and long-term outcome of patients with neurologic

Left hemiplegia Hypertensive retinopathy Renal function worsening Hypertrophic myocardiopathy

Cognitive and language delay and epilepsy due to cortical dysplasia.

Brain CT Slight cognitive delay Outside follow-up,

EEG\* Learning disability Normal

Visual impairment

Exitus in the acute phase Exitus in the acute

Visual impairment Slight visual

Cognitive impairment Normal

phase

Asymptomatic

Consistent with his base line neurodevelopment

described as normal

impairment Slightly unstructured EEG

Figure 4.A Figure 4.B

Figure 4.C

Fig. 4. Brain MRI of patient n. 21, 6 months after clinical onset. Coronal FLAIR sequences (Figures A and B). Increased ventricular size, bilateral hyperintense areas at the basal ganglia and multiple cortico-subcortical supratentorial hyperintense images, milder at cerebellar lobes, suggestive of subacute ischemic lesions, with laminar cortical necrosis. Axial T1 sequence (C) showing basal ganglia necrosis (arrows) and cortico-subcortical atrophy.

Figure 4.A Figure 4.B

Figure 4.C

atrophy.

Fig. 4. Brain MRI of patient n. 21, 6 months after clinical onset. Coronal FLAIR sequences (Figures A and B). Increased ventricular size, bilateral hyperintense areas at the basal ganglia and multiple cortico-subcortical supratentorial hyperintense images, milder at cerebellar lobes, suggestive of subacute ischemic lesions, with laminar cortical necrosis. Axial T1 sequence (C) showing basal ganglia necrosis (arrows) and cortico-subcortical


Table 3. Diagnostic tests, medium- and long-term outcome of patients with neurologic symptoms at the acute phase; (\*) abnormal test.

Haemolytic-Uraemic Syndrome:

and mild cognitive disabilities.

presented focal seizures).

**5. Conclusions** 

perhaps related to specific auto-immune characteristics.

their school performance and day-to-day life.

Neurologic Symptoms, Neuroimaging and Neurocognitive Outcome 215

1986). The nine patients who presented seizures at onset survived without long-term sequelae, whereas the only exitus presented initial drowsiness and rapidly progressive neurologic deterioration, without seizures (myoclonias happened after resuscitation maneuvers). This was the only patient with neurologic symptoms, acute pancreatitis, endocarditis and RIL pneumonia; *Streptococcus pneumoniae* was not detected (De Loos et al., 2002; Prestidge & Wong, 2009). Neurologic evaluation and follow-up of patients with CNS symptoms allowed early detection of subtle vision dysfunction, visual perception deficit,

Incidence of neurologic symptoms in acute phase of HUS in this group (39%) was similar to former descriptive studies (Sheth et al., 1986; Hahn et al., 1989; Garel et al., 2004; Steinborn et al., 2004); orolingual dystonia was previously observed, but cortical blindness, hallucinations (Cimolai et al., 1896) and cerebellar mutism/anarthria (Mewasingh et al., 2003) were not observed in our group. A slightly higher prevalence in girls was identified (boy/girl rate 1:1.2), as reported by other authors (Cimolai et al., 1986; Rivero et al., 2004; Zambrano et al., 2005); this rate is increased to 1:1,7 when regarding the neurologic patients,

It was previously reported that HUS patients with partial seizures tend to present epilepsy or abnormal movements after HUS recovery (Dhuna et al., 1992; Hue et al., 1992; Koehl et al., 2010). However, none of our patients developed abnormal movements during mediumand long-term follow-up, and seizures or EEG abnormalities at the acute phase did not determine a poor outcome (only the patient with previously diagnosed cortical dysplasia

SHU mortality has decreased in recent years, from 25% in the 1980s to 2% in more recent publications (Rivero et al., 2004). Despite this low mortality rate, a small percentage of patients with neurological symptoms at the acute stage subsequently present neurological sequelae. In our series of 25 children with neurological symptoms, one patient died and 5 had medium-term neurological complications (hemiparesia, cognitive delay or visual perception deficit). The rates of medium-term neurologic morbidity (20%) and mortality (4%) were similar to those of other authors (Hahn et al., 1989; Erikson et al., 2001). Only in one patient after 3 years of follow-up were there persistent minor neurological sequelae (slight cognitive, visual perception and visual construction impairments), with gradual improvement despite the absence of significant changes on MRI and visual evoked potentials monitoring. Although neurocognitive impairment is not frequently reported in HUS (Roche et al., 2008), neuropsychological evaluation and follow-up of these children, especially when basal ganglia (mainly putamen) and cortico-subcortical regions are damaged at the initial brain MRI, helps to identify neurocognitive disabilities. Even if they are not severe, a good neurofunctional diagnosis and rehabilitation can help patients with

In summary, HUS is not yet completely understood from a physiological point of view. The most common neurological manifestations in the acute phase are drowsiness, stupor, irritability and convulsions. Neurological morbidity is important: it affects 20% of children with acute neurological presentation (8% of all patients with HUS). Seizures at presentation were not a risk factor for poor outcome in our series. Electrophysiological abnormalities at the acute phase tend to normalize; when they persist, clinical expression

Five of the 25 patients with neurologic symptoms at the acute phase showed one or more medium-term neurological deficits (Table 3): 1/5 hemiparesia, 4/5 mild cognitive dysfunction and 2/5 visuo-perception and construction deficits, which almost normalized during long-term follow up. Nineteen of the 25 presented normal neurological examination at hospital discharge, and one year later.

Patient 4 died within the first 15 hours after admission, after a rapidly progressive neurologic deterioration and respiratory arrest. He presented lower limb myoclonias after life rescue. Thorax x-ray revealed right inferior lobe (RIL) pneumonia. Abdomen and transfontanellar US were normal. Pathology studies confirmed RIL pneumonia, severe segmentary glomerular and tubular nephropathy, acute pancreatitis, lung and heart interstitial inflammation, diffuse alveolar damage, intracapillary thrombi in lungs and kidneys, brain cortical necrosis with edema and cerebellar granular necrosis. *Steptococcus pneumoniae* was not identified. This represents a mortality of 1.5% of the HUS patients and 4% of the patients with HUS and neurologic symptoms at onset.
