BRIEF REPORT

Neurologic involvement in atypical hemolytic uremicsyndrome and successful treatment with eculizumab

Kaan Gulleroglu & Kibriya Fidan & Veysel S. Hançer &

Umut Bayrakci & Esra Baskin & Oguz Soylemezoglu

Received: 15 November 2012 /Revised: 8 January 2013 /Accepted: 11 January 2013 /Published online: 7 February 2013# IPNA 2013

AbstractBackground Atypical hemolytic uremic syndrome (aHUS)is associated with defective regulation of the complementpathway. Neurological involvement is the most commonextrarenal complication and represents a major cause ofmortality and morbidity.Case-diagnosis/treatment Two girls aged 11 and 6 years,respectively, developed aHUS and were treated immediatelywith plasma exchange (PE) and fresh frozen plasma infusion(PI). Although initial improvement in renal function wasseen in both cases, the first patient showed progressingthrombotic microangiopathy (TMA) despite daily PE, andneurological manifestations (seizures, vision loss, loss ofbalance, and confusion) developed after 1 month. The sec-ond patient developed cerebral TMA (seizures, vision loss,and nystagmus) 6 days after initial presentation andremained unresponsive to PE/PI. Neurological symptomswere similar in both patients, even though they had differentcomplement protein mutations. Treatment with eculizumabachieved complete control of neurological symptoms within24 h and gradually normalized hematological and renalparameters in both children.

Conclusions Based on our two cases, we conclude thateculizumab is a rapid-acting, effective, and life-saving treat-ment for pediatric patients with aHUS and severe neurolog-ical involvement, which works by inhibiting complement-mediated TMA in the kidney and other organs, such as thebrain.

Introduction

Hemolytic uremic syndrome (HUS) is characterized bymicroangiopathic hemolytic anemia, thrombocytopenia andacute kidney injury [1]. Typical or Shiga toxin-producingEscherichia coli (STEC) HUS accounts for over 90 % ofcases [1, 2]. Atypical HUS (aHUS) accounts for 5–10 % ofcases, carries a poor prognosis, and is characterized by over-activation of the alternative complement pathway, causinginflammation, platelet activation. and thrombotic microan-giopathy (TMA) [2].

Extrarenal complications of systemic TMA in HUS in-clude neurological, pancreatic, and cardiac involvement [3,4]. Although frequency estimations do not always distin-guish between typical and atypical HUS, neurological com-plications affect 10–48 % of aHUS cases [3–5] and thusrepresent a major cause of morbidity and mortality.

Plasma exchange (PE) and plasma infusion (PI) havetraditionally served as first-line therapies for aHUS [1, 6].However, while some patients appear to improve followingPE/PI therapy [1], others fail to respond [7]: 65 % of patientsdie, require dialysis, or develop permanent renal damagewithin the first year of diagnosis, despite treatment withPE/PI [1, 7–9]. A targeted treatment option is eculizumab,a humanized monoclonal antibody that blocks terminalcomplement activity by binding to complement protein C5

K. Gulleroglu :U. Bayrakci : E. BaskinDepartment of Pediatric Nephrology, Baskent University,Ankara, Turkey

K. Fidan (*) :O. SoylemezogluDepartment of Pediatric Nephrology, Gazi University MedicalHospital, O6500, Beşevler, Ankara, Turkeye-mail: kibriyafidan@yahoo.co.uk

V. S. HançerDepartment of Medical Biology and Genetics,Faculty of Medicine, Istanbul Bilim University, Istanbul, Turkey

Pediatr Nephrol (2013) 28:827–830DOI 10.1007/s00467-013-2416-9

and thus preventing the generation of proinflammatory C5aand the lytic C5b-9 complex. Approved in the USA andEurope for the treatment of aHUS, eculizumab has demon-strated efficacy in aHUS patients both with and withoutidentified complement mutations [6, 10–12]. Here, we de-scribe successful eculizumab treatment for neurological in-volvement in two children with aHUS.

Case reports

Case 1

An 11-year-old girl presented with anuria, pallor, and vomit-ing without diarrhea. Her blood pressure was 118/78 mmHg,and physical examination was remarkable only for peripheraledema. Laboratory tests revealed microangiopathic hemolyticanemia (hemoglobin 9.61 g/dl with schistocytes on the pe-ripheral blood smear), thrombocytopenia (platelets56,000/μl), and severe acute kidney injury (serum creatinine4.72 mg/dl). She also had albumin levels of 2.4 g/dl; highserum lactate dehydrogenase (LDH; 2681 U/l; normal range110–285 U/l); elevated ferritin (1,249 ng/ml; normal range4.63–204 ng/ml); undetectable haptoglobin (<6 mg/dl; normalrange 11–220 mg/dl); low complement C3 (54 mg/dl; normalrange 79–152 mg/dl). The patient exhibited severe protein-uria, severe hypoalbuminemia resistant to albumin infusion,and a 24-h urinary protein excretion of 558 mg/m2/h. Stoolspecimens were negative for STEC and Shigelladysenteriaetype 1. Atypical HUS was diagnosed.

Hemodialysis, PI, and PE were initiated. After six PI andsix PE sessions, urine output gradually increased and plasmacreatinine levels progressively decreased to 1.31 mg/dl. Ge-netic analysis showed polymorphisms in the complementfactor H (CFH) gene A307A (rs1061147) in exon 7 andH402Y (rs1061170) in exon 9. She had also compoundheterozygote mutations in complement factor I (E26K andP83T). These mutations are not defined in the Exome Se-quencing Project (ESP), and the sequence graphics andamino acid changes are shown in Fig. 1a, b.

One week after PE/PI were discontinued, serum creatinineincreased, leading once again to initiation of PE sessions;renal function subsequently improved, but hematologicalparameters worsened (hemoglobin 7.61 g/dl; platelets38,000/μl), demonstrating ongoing TMA.

One month after initial presentation, the patient had mul-tiple tonic–clonic seizures despite PE treatments. Her bloodpressure was normal (110/70 mmHg). Two days after sei-zure onset, she developed loss of vision and severe confu-sion. Her funduscopy was normal. Fluid attenuatedinversion recovery (FLAIR) and T2-weighted magnetic res-onance imaging (MRI) scans revealed bilateral, symmetricalhyperintensities on the occipital and posterior parietal lobes,

and edema in these areas was observed on diffusion-weighted MRI scans and apparent diffusion coefficientmaps. These findings indicated progressive TMA in thecerebral vasculature. At this time, the laboratory findingswere: hemoglobin 7.89 g/dl; platelets 48,000/μl; serum cre-atinine 1.78 mg/dl; LDH 2356 U/l. Levetiracetam treatmentwas administered for seizure control and after the meningo-coccal immunization status had been confirmed, we imme-diately started the patient on intravenous eculizumabtherapy at eculizumab 900 mg, twice weekly, with subse-quent improvements in vision, renal function, and hemato-logical parameters. Eculizumab therapy was continued(600 mg, twice weeks). Four days after the seizure, anelectroencephalogram (EEG) was performed and found tobe normal. Complete neurological recovery was achievedafter 1 month, and a MRI scan at 2 months showed noabnormalities. Levetiracetam treatment was discontinued,and PE was stopped during the second month of eculizumabtreatment. Proteinuria (38 mg/m2/h) began to decrease5 weeks after the first dose of eculizumab and fell to min-imal levels within 5 months (3.4 mg/m2/h). At the time ofwriting, the patient has been receiving eculizumab 600 mgevery 2 weeks for the last 15 months. Neurological, renal(creatinine 0.78 mg/dl), and hematological parameters (he-moglobin 12.56 g/dl; platelets 178,000/μl; albumin 4.1 g/dl;LDH 68 U/l; ferritin 24 ng/ml) were normal at the last visit.

Case 2

A 6-year-old girl initially presented with vomiting andstomach ache, and a urinary tract infection was suspected.Symptoms did not improve despite treatment with antibiot-ics, and she was referred to our hospital with anuria, pallor,weakness, and vomiting without diarrhea. Physical exami-nation revealed peripheral edema and a blood pressure of110/70 mmHg. Laboratory tests indicated hematuria, hemo-lytic anemia (hemoglobin 10.3 g/dl with schistocytes),thrombocytopenia (platelets 51,000/μl), severe acute renalfailure (creatinine 4.67 mg/dl), and oliguria (urine output100 cc/day). Other laboratory findings included elevatedserum LDH (1590 U/l), low haptoglobin (6 mg/dl), andlow complement C3 (5 mg/dl; normal range 79–152 mg/dl).Stool specimens were negative for STEC and Shigella dys-enteriae type 1.

Daily hemodialysis and plasmapheresis were started im-mediately. After 5 days, urine output gradually improved,macroscopic hematuria disappeared, LDH levels slowly de-creased to 900 mg/dl, and platelet count increased to110,000/μl. She was diagnosed with aHUS, and geneticanalysis later revealed a heterozygous mutation (L262P) inthe membrane cofactor protein (MCP) gene (Fig. 1c).

Six days after admission, the patient developed a tonic–clonic epileptic seizure accompanied by stable normal blood

828 Pediatr Nephrol (2013) 28:827–830

pressure; this was followed by vision loss and nystagmus.Macroscopic hematuria recurred, hemoglobin levels andplatelet counts decreased (6.7 mg/dl and 85,000/μl, respec-tively), and serum LDH increased (1740 U/l). Her fundu-scopy was normal. The EEG revealed diffuse low waves andirregularity at all leads, consistent with cerebral dysfunction.T2-weighted FLAIR revealed bilateral hyperintense whitematter lesions in the occipital and posterior parietal regions.

A single dose of meningococcal vaccine was followed bythe administration of eculizumab 600 mg after PE. Prophy-lactic antibiotic was started for the meningococcal infec-tions. Within 24 h the patient’s vision had returned tonormal. By day 3, hematological and renal parametersshowed improvement, and macroscopic hematuria had dis-appeared. PE/PI was discontinued 1 week after the initiationof eculizumab treatment. Three doses of eculizumab 600 mgwere administered weekly, followed by maintenance thera-py with 600 mg every 2 weeks. Five weeks after the initi-ation of eculizumab therapy, the patient’s neurological,renal, and hematological parameters were normal: LDH170 mg/dl; proteinuria 260 mg/day. During the follow-upperiod her C3 levels have remained in normal limits. Sincethe level of C3 normalized within a short time period,complement gene mutations were not analysed. Eculizumabtherapy was stopped after five doses and the patient hasremained in a good condition with no proteinuria, as wellas normal hematological parameters and normal neurologi-cal examination, during her last 9 months of follow-up.

Discussion

Neurological involvement is the most frequent extrarenalcomplication in HUS [2–4, 8] and displays multifactorialpathophysiology, which may involve multifocal TMA,

metabolic insults (uremia, hyponatremia, hypocalcemia),uncontrolled blood pressure or focal toxin-mediated mech-anisms [5]. Improper complement activation and regulationprobably contribute towards systemic TMA and centralnervous system disease progression [11, 13]. Treatmentstrategies include PI, PE, and complement inhibition withmonoclonal antibodies, such as eculizumab.

Mutations have been identified in approximately 50–70 %of aHUS patients, affecting genes encoding complement reg-ulators [CFH, complement factor I (CFI), complement factorH-related proteins and MCP] and complement activators[complement factor B (CFB) and C3] [1, 8, 10]. Our patientsexhibited compound heterozygous CFI and CFH mutations(Patient 1) and a heterozygous MCP mutation (Patient 2).Many different complement mutations have been reported,but the downstream consequence of them all is over-activation of the alternative complement pathway [2, 7, 8],excessive liberation of different cleavage fragments from C3and C5, and formation of the lytic C5b-9 complex. Althoughwe found mutations in CFI and MCP genes, these werepreviously undescribed in the ESP, and as such we cannotspeculate that these are disease-causing mutations withoutfurther functional studies, which was beyond the scope ofour study. Thus, we report only the amino acid sequences.

In aHUS, the major pathological event is TMA, the mainunderlying cause of which is endothelial injury. TMAoccurs systematically in the body and, therefore, neurolog-ical involvement is a part of this systemic involvement [8].Posterior reversible encephalopathy syndrome (PRES)-re-lated lesions, believed to be caused by vasogenic edema,are associated with posterior white matter hyperintensity [5].TMA and PRES can produce similar clinical manifestations,including vision loss, and may be interrelated in aHUS: theedema in PRES can be caused by TMA, and uncontrolledcomplement activation and excessive C5a would increase

Fig. 1 a Case 1: factor I, E26Kmutation. b Case 1: Factor I,P83T mutation. c Case 2:membrane cofactor protein,L262P mutation

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vascular permeability to further exacerbate edema [13]. Asour patients experienced vision loss, it is also noteworthythat a relationship exists between CFH polymorphisms andage-related macular degeneration. CFH is the major inhibi-tor of the alternative complement pathway, and uncontrolledactivation of the alternative complement pathway oftenresults in ocular drusen in the macula. This is particularlysignificant with the H402Y mutation [14].

A combination of complement defects and risk haplo-types clearly underlies disease manifestation in aHUS [2, 3].Consequently, aHUS management is not a simple matter ofreplacing and removing/restoring a single deficient factorthrough PI and PE [7]—our patients deteriorated despiteintensive PE/PI. Instead, targeting the complement systemmay modify disease progression and thus treat aHUS moreeffectively [7, 8, 10]. In contrast to PE/PI, eculizumabappears to be effective in aHUS regardless of the underlyingcomplement mutation [6, 10–12] and has been approved forits treatment (clinicaltrials.gov identifiers: NCT00844545,NCT00844844, NCT00844428, NCT00838513) [10]. Ourcases showed that eculizumab effectively inhibits progres-sive TMA in aHUS, thus supporting the results from theseprevious trials [6, 8, 10–12]. With regard to our second case,our plan is initiate long-term eculizumab therapy if thepatient has a new neurological crisis [15].

Although eculizumab has recently been used to reverseneurological impairment in an adult with aHUS [11], webelieve that our cases represent the first published use ofeculizumab for vision loss and neurological involvement inpediatric patients.

Acknowledgments Assistance with writing this manuscript was pro-vided by Bioscript Stirling Ltd, UK, and funded by Alexion Pharma-ceuticals. We give special thanks to Dr. Reyhan Diz Kucukkaya in theDepartment of Internal Medicine, Division of Hematology at IstanbulBilim University, Istanbul, Turkey.

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