We have identified that the rate of neurological involvement in STEC-HUS is 10.9%. Neurological involvement is associated with predominantly good long-term outcome (90.4%) and a reduced case-fatality rate (4.5%) compared to older reports.
The reported rate of neurological involvement in children with HUS varies between 10.4% and 52% (Supplementary Table 1).[11–16, 18, 20–25, 27–35] We report a rate of 10.9% based on a strict definition of neurological involvement (seizures, encephalopathy or focal neurological deficit). We considered features such as irritability or lethargy to be non-specific. Four patients met the criteria for neurological involvement, but STEC infection was not confirmed, and they were excluded; no alternative etiology was identified. The possibility of failure to identify STEC infection in this small group exists - their inclusion would increase the rate of neurological involvement to 12.3%.
Seizure [16/22 (72.7%)] was the most common presentation of neurological involvement. Neurological involvement was noted early in the disease course, manifesting within 48 hours of admission to hospital in 72.7%. Close monitoring of CNS symptoms and careful clinical assessment is important to identify neurological involvement in children with HUS early in the course of their disease.
Demographic variables did not predict neurological involvement in our cohort and we did not identify a trend for a higher degree of leukocytosis or peak creatinine, as reported previously (Table 1).[14, 18, 46] The E. coli serogroups identified were comparable between the neurological and non-neurological groups. Children in the neurological group had a significantly greater need for dialysis [86.4% vs. 48.9%, (P<.001)], PICU admission [86.4% vs. 16.1%, (p<0.001)] and a longer length of hospital stay [21(13-34) vs. 9 (6-15), (p<0.001)], reflecting a more severe course of illness in this group.
Neuro-radiology in children with HUS is focused on the exclusion of hemorrhage and the identification of cerebral edema and vasculitis.[19] Children in the neurological group underwent CT and/or MRI depending on their individual clinical circumstances. Based on availability, and if patients are sufficiently stable to allow for a longer examination duration, MRI is the imaging modality of choice. We identified the typical DWI abnormalities of both deep white and grey matter in our patients (n=7).[13] All children who had DWI changes had a normal neurological outcome (Table 3). Therefore, observed DWI changes are reversible lesions in children with good neurological recovery and routine follow up neuroimaging is not required, unless abnormal neurological examination.
Evidence supporting the use of supplemental treatments, such as PE or Eculizumab, in STEC-HUS is lacking.[47–50] Extensive cases series and small cohort studies have been published but no randomized control trials have been reported (Supplementary Table 2).[13, 15, 29, 33, 34, 37–43, 51–53] Many specialists, whilst cautiously skeptical of the role of such treatments, tend to use supplemental therapies in severe cases of HUS, particularly in the context of CNS involvement.[47–50] In our cohort, we reserved additional treatments for children with severe disease, treating 20/202 children (9.9%) with PE, 4/202 (1.9%) with Eculizumab and 4/202 (1.9%) with both. Our initial approach is treatment with PE; reserving Eculizumab for use when prompt initiation of PE is not practicable or if overwhelming multi-system involvement. It is important to avoid the simultaneous use of PE and Eculizumab as monoclonal antibodies will be removed by PE. It is difficult, based on our positive experience, to forgo supplemental therapies until the outcomes of randomized controlled trials are available.
Neurological involvement in HUS has been reported to be associated with high mortality and significant long-term neurological morbidity (Supplementary Table 1).[11–16, 18, 20–25, 27–35] Reported outcomes vary depending on the period studied and the case definition employed. Studies based on cohorts of children with HUS and CNS involvement before 2010 had a median mortality rate of 16.9% (IQR: 7.0-44.6%)[11, 12, 19, 21–25, 27, 28, 30] and long-term neurological sequelae of 13.8% (IQR: 11.1–33.2%).[12, 19, 22, 24, 30, 31] More recent studies (cohorts after 2010), have better outcomes with lower mortality [13.9%, (IQR:12.5- 22%)][13, 14, 16, 18, 20, 34] and less long-term neurological sequelae [8.3%, IQR: 5.3-34.6%)].[13, 15, 16, 18, 33–35] Substantial improvements in diagnosis and supportive care have evolved in the intervening period. In our neurological group (n=22), one patient died, and two children had long-term neurological consequences – giving comparative rates of 4.5% case-fatality, 9.5% mild neurological sequelae and no severe neurological sequelae. The rate of kidney sequelae on follow-up is significantly better than that described in other cohorts – 13.5% vs 20-25%. [2, 54] It is likely that advances in supportive care are the primary driver for improved outcomes (renal and neurological) in our cohort compared to older published cohorts. We believe that more optimism should be afforded when counseling parents regarding long-term neurological and renal sequelae.
Making comparisons between cohorts of HUS patients treated using different protocols in different centers is not optimal. Differences in the case definition, case capture, inclusion of aHUS patients, length of follow-up and treatment modalities, along with demographic variables and the genetic background of the population make comparisons complex. Our cohort benefits from a high degree of case capture based on a well-defined geographical area served by a single tertiary center –near complete capture of HUS cases with more mild disease involvement will have an impact on measurement of overall disease severity.
One important limitation of our study is the ability to detect more subtle changes in neurocognitive function and behavior. The PCPC was developed to quantify overall functional morbidity in children after critical illness- application of more sensitive scales may allow for the detection of more subtle changes in neurocognitive outcomes and behavior.[46, 55, 56]