**1. Introduction**

202 Neuroimaging for Clinicians – Combining Research and Practice

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Williams & Wilkins, Wolters Kluwer, 1999

Haemolytic-Uraemic Syndrome (HUS) was first described in 1955 by Gasser (Pérez del Campo et al., 2000) and defined as a multi-systemic syndrome, due to the association of microangyopathic haemolytic anemia, thrombopenia and multiorganic aggression. HUS affects mainly kidneys and leads to acute renal failure with high levels of urea and creatinin; it often involves digestive and central nervous systems. Central nervous system (CNS) lesions, typically at the basal ganglia, may also affect cortico-subcortical areas and in so doing determines motor and neurocognitive outcome, and modify the patients' quality of life.

Incidence of HUS varies among continents, highly influenced by migration movements, and it is estimated to be around 18/100,000 in children younger than 5 years old. Some countries, like Argentina and South Africa, are considered "endemic", with a steady and relatively high incidence of HUS during all the seasons of the year; other areas, such as Canada, most of the European countries, and the west coast of the USA, are said to be "epidemic", with sporadic cases and a lower incidence of HUS compared to Latin America and Africa during most of the year, but with self-limited relapses during summertime (Exeni, 2001).

HUS etiology is diverse and physiopathologic mechanisms are not yet well known, but infective microorganisms are frequently involved, especially *Escherichia coli,* serotype O15:H7; this bacteria is able to produce a toxic protein (vero-toxin –VT- or Shiga-toxin –Stx), which "recognizes" the endothelial cells and provokes an endothelial lesion (Scheiring, 2010). Other bacteria seem to be involved in different cases of HUS, like *Salmonella enteritidis*  and *Streptococcus pneumonia*e (De Loos et al., 2002; Prestidge & Wong, 2009). Mutations in genes coding for different components of the complement system seem to be a risk factor for HUS (Skerka et al., 2009). However, the etiologic agent remains unidentified in most patients.

Clinical presentation in the acute phase includes acute renal failure (100% of patients), often high blood pressure (HBP) due to a volume surcharge (35-40% of patients), and neurological

Haemolytic-Uraemic Syndrome:

**3. Results** 


they persisted for more than 1 year after admission.


and neurological symptoms at onset.

present in urine in another patient.

onset Sex M / F#

Patient Age at

Neurologic Symptoms, Neuroimaging and Neurocognitive Outcome 205

Neurologic evaluation was performed by a pediatric neurologist when abnormalities at the

Neurological sequelae were considered "medium-term" when they were present between 4 weeks and 12 months after clinical onset; complications were considered "long-term" when

Neurocognitive evaluation was performed when medium or long term sequelae were identified. In these patients, physiotherapy and neurocognitive intervention were started as

Follow-up was maintained until clinical normalization or at least 2 years after admission.

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

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

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

The most frequent neurologic sign at onset was drowsiness alone (40%) or together with

1 1yr 3mo M D+ Unknown no Accidental traumatic epidural

3 8mo F D+ Salmonella yes Drowsiness. GTCS. Hyponatremia

5 4yr 6mo F D+ Unknown yes GTCS. HBP. Hypoglycemia

9 2yr 2mo M D+ Unknown yes Neurologic depression. Myoclonic

2 2yr 3mo F D+ Unknown yes Drowsiness

6 1yr 2mo M D- Unknown yes GTCS 7 3yr 4mo M D+ Unknown no Drowsiness 8 3yr F D+ Unknown yes HBP. Brain edema.

Agent Dialysis Acute neurologic presentation

hematoma

Drowsiness cardiac arrest myoclonias. Plain EEG within 15 hours

Irritability and drowsiness

seizures

initial neurological examination or complementary tests were identified.

soon as possible after hospital discharge and continued during the school years.

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

without neurologic symptoms was 1:1.2, slightly more frequent in girls.

irritability (16%), while irritability alone was present in 10%.

4 7mo F D+ Unknown yes

Acute Gastro enteritis¹

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

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 medium- and long-term sequelae.

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; Kitamura et al., 2010).

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 with neurological symptoms are also analyzed.
