Acute Neurological Involvement in Diarrhea-Associated Hemolytic Uremic Syndrome

Sylvie Nathanson,* The re sa Kwon, Monique Elmaleh, Marina Charbit, Emma Allain Launay, Je ro me Harambat, Muriel Brun,** Bruno Ranchin, Flavio Bandin, Sylvie Cloarec, Guylhene Bourdat-Michel, Christine Pie ` trement, Ge rard Champion,*** Tim Ulinski, and Georges Desche nes
*Pediatric Unit, Ho pital Mignot, Le Chesnay, France; Pediatric Nephrology Unit and Pediatric Radiology Unit, Ho pital Robert Debre , Paris, France; Pediatric Nephrology Unit, Ho pital Necker-Enfants Malades, Paris, France; Pediatric Nephrology Unit, Pavillon de la Me re et de lEnfant, Nantes, France; Pediatric Unit and **Pediatric Radiology Unit, Groupe Hospitalier Pellegrin, Bordeaux, France; Pediatric Nephrology Unit, Ho pital Edouard Herriot, Lyon, France; Department of Pediatric Nephrology, Childrens Hospital, Toulouse, Centre de Re fe rence du Sud Ouest des Maladies Re nales Rares, Toulouse, France; Pediatric Nephrology Unit, Centre Hospitailer Universitaire Clocheville, Tours, France; Pediatric Unit, Ho pital de la Tronche, La Tronche, France; Pediatric Unit, Ho pital Maison Blanche, Reims, France; ***Pediatric Unit, Centre Hospitalier Universitaire dAngers, Angers, France; and Pediatric Nephrology Unit, Ho pital Armand-Trousseau, Paris, France
Background and objectives: Neurologic involvement is the most threatening complication of diarrhea-associated hemolytic uremic syndrome (DHUS). Design, setting, participants, & measurements: We report a retrospective multicenter series of 52 patients with severe initial neurologic involvement that occurred in the course of DHUS. Results: Verotoxigenic Escherichia coli infection was documented in 24. All except two patients had acute renal failure that required peritoneal dialysis, hemodialysis, or both techniques. A first group of eight patients remained with normal consciousness; five of them had protracted seizures. A second group of 23 patients had stuporous coma; five of these had protracted severe seizures, and 18 had a neurologic defect including pyramidal syndrome, hemiplegia or hemiparesia, and extrapyramidal syndrome. A third group of 21 patients had severe coma. Plasma exchanges were undertaken in 25 patients, 11 of whom were treated within 24 hours after the first neurologic sign; four died, two survived with severe sequelae, and five were alive without neurologic defect. Magnetic resonance imaging (MRI) for 29 patients showed that (1) every structure of the central nervous system was susceptible to involvement; (2) no correlation seemed to exist between special profile of localization on early MRI and the final prognosis; and (3) MRI did not exhibit any focal lesions in three patients. The overall prognosis of the series was marked by the death of nine patients and severe sequelae in 13. Conclusions: Neurologic involvement is associated with a severe renal disease but does not lead systematically to death or severe disability. Clin J Am Soc Nephrol 5: 1218 1228, 2010. doi: 10.2215/CJN.08921209

iarrhea-associated hemolytic uremic syndrome (DHUS) is the main cause of acute renal failure in children who are younger than 5 years. The disease is mainly due to a gastrointestinal infection with verotoxigenic Escherichia coli and the release of verotoxins in the blood. Verotoxins are able to bind at the cell surface of endothelium, leading to the internalization of the subunit A that belongs to the ricin family of vegetal toxins. These toxins are able to inhibit protein syn-

thesis after their release in the cytosol by removing one adenine from the 28S RNA of the 60S ribosomal subunit (1). Although renal endothelium is the main target of verotoxins in humans, extrarenal damage is frequent in DHUS. In addition, neurologic involvement is the most threatening complication of DHUS. Here, we report a series of 52 patients with severe initial neurologic involvement that occurred in the course of DHUS. Among that series, nine patients died and 13 developed severe sequelae.

Received December 11, 2009. Accepted April 3, 2010. Published online ahead of print. Publication date available at www.cjasn.org. S.N., T.K., and M.E. contributed equally to this work. Correspondence: Dr. Sylvie Nathanson, Pediatric Unit, Ho pital Mignot, 177 rue de Versailles, F-78150 le Chesnay, France. Phone: 331-39639293; Fax 33139639396; E-mail: sylvie.nathanson@gmail.com Copyright 2010 by the American Society of Nephrology

Materials and Methods

This was a retrospective study based on the analysis of clinical reports or complete files when available. Inclusion criteria were based on the severity of coma and seizures or the clinical evidence of neurologic defects. Patients with isolated seizures and without a need for specific therapy or without recurrence were not included in this series.
ISSN: 1555-9041/5071218

Table 1. Main initial clinical characteristics and final outcome of patients

Coma Seizures Neurologic Defects RRT Plasma Duration of RRT (days) Neurologic Sequelae Final Outcome

Patient

Gender

Age (years)

BP (mmHg)

Clin J Am Soc Nephrol 5: 1218 1228, 2010

5.8

115/84

PD

20

No

Hemiparesia, dystonia No Ataxia No No Dysphasia No

Alive

2 3 4 5 6 7 0 Stuporous Stuporous Stuporous Stuporous Stuporous Stuporous Stuporous Stuporous Stuporous Stuporous Stuporous 0 ND 0 1 0 PD HD PD/HD PD/HD HD 1 0 0 PD PD PD 1 PD 8 19 9 8 10 12 21 29 11 1 1 PD PD 30 10 No No No No No Exchange No No No Exchange No 2 PD 12 No

F F F M M F

1.1 5.1 3.0 5.3 0.7 16.9

130/90 120/70 100/60 98/46 130/90 175/95

0 0 0 0 0 0

2 2 2 1 2 0

HD HD/PD PD PD PD

24 ESRF 0 8 11 15

No Infusion Exchange Exchange No Infusion

Alive Alive Alive Alive Alive Alive Alive Alive Alive NA No No NA No No No Dead Alive Alive Dead Alive Alive Alive Alive Alive

0.9

100/60

9 10

M M

1.1 2.2

120/80 80/70

Epilepsy, hemiparesia Tetraparesia No

11

4.2

100/70

12 13 14

M M F

1.4 1.1 2.1

129/83 84/41 140/70

15 16 17

F F M

1.0 1.4 2.8

114/71 129/68 135/90

18 19

M F

11.6 6.9

139/66 98/53

Extrapyramidal, pyramidal, hemiplegia Pyramidal Extrapyramidal No Pyramidal No Diplopia, dysphasia Pyramidal, hemiplegia Pyramidal Extrapyramidal, pyramidal Extrapyramidal, cerebellar Pyramidal Extrapyramidal Extrapyramidal, pyramidal Diplopia Extrapyramidal Extreme agitation, dysphasia Facial palsy No

20 21 22 23 Stuporous Stuporous 2 1

F M F M

3.7 6.1 1.0 0.6

116/69

180/110

Stuporous Stuporous Stuporous Stuporous

2 1 2 2

HD HD No DP HD Pyramidal, hemiparesia PD/HD

21 5 0 6 8 10

Exchange Infusion No No Exchange Exchange

No Claude Bernard Horner No Visual defect No 0 Pyramidal Diplopia No Pyramidal, facial palsy, hemiplegia No

Alive Alive Alive Alive Alive Alive

Acute Neurologic Involvement in DHUS

24

1.0

117/78

25

0.1

140/85

Developmental delay Hemiparesia

1219

1220

Table 1. (Continued)
Coma Seizures Neurologic Defects RRT Plasma Duration of RRT (days) Neurologic Sequelae Final Outcome

Patient

Gender

Age (years)

BP (mmHg)

26

3.2

100/66

Stuporous

HD

15

No

No

Alive

27 28 29

M F M

7.9 0.9 1.1

140/80 113/58 110/70

Stuporous Stuporous Stuporous

1 1 2

PD PD/HD PD/HD

15 17 21

Exchange No Exchange

Epilepsy No No

Alive Alive Alive

30 31 32 Severe Severe Severe Severe Severe Severe Severe 1 1 1 2 HD HD PD PD 1 PD/HD 22 9 4 14 23 1 PD 8 No Exchange Exchange Exchange Exchange No 1 HD 15 Exchange

M M F

7.5 7.1 1.3

100/70 83/64

Stuporous Stuporous Severe

0 1 0

HD PD PD

12 35 23

Exchange No Exchange

Alive Alive Alive Dead No NA No NA No Severe disability Alive Dead Alive Dead Alive Alive

33

5.2

155/95

Pyramidal No Severe disability NA

Clinical Journal of the American Society of Nephrology

34

1.0

118/75

35

0.9

90/60

36 37 38 39

M F M F

1.2 3.5 10.3 1.1

90/62 84/44 NA 100/50

40 41 42 43 44 Severe Severe Severe 2 2 1

F F M F F

2.5 15 4.9 2.3 3.2

115/90 170/120

120/70

Severe Severe Severe Severe Severe

0 1 1 0 0

PD PD/HD HD PD/HD PD PD HD HD

6 49 9 15 4 25 10 12

Exchange Exchange Exchange No Exchange Infusion No Exchange

Dead Alive Dead Dead Alive Alive No Severe disability Alive Alive

45

0.9

130/70

NA No NA NA Severe disability Blindness

46

2.0

160/90

47

1.3

118/66

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48

1.3

Severe

Extrapyramidal, pyramidal, cerebellar Pyramidal, paresia No Extrapyramidal, pyramidal Pyramidal No Extrapyramidal, pyramidal Extrapyramidal, pyramidal Extrapyramidal, pyramidal Extrapyramidal, pyramidal Paresia No No Extrapyramidal, pyramidal, blindness No Paresia Diplopia Extrapyramidal Extrapyramidal, pyramidal Extrapyramidal, pyramidal Extrapyramidal, pyramidal Extrapyramidal, pyramidal, tetraplegia No PD 3 Exchange NA

Dead

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ESRF, end-stage renal failure; HD, hemodialysis; NA, not applicable; ND, not determined; PD, peritoneal dialysis; RRT, renal replacement therapy.

Extrapyramidal, pyramidal, blindness No Extrapyramidal, pyramidal Extrapyramidal, pyramidal

Neurologic Defects

The 26 centers of the French Socie te de Ne phrologie Pe diatrique responded to the survey, and 11 of them had cases to include in the study. Fifty-two patients (28 girls and 24 boys) with HUS and severe acute neurologic involvement that occurred from 1975 to 2008 were included in the series The main demographic and clinical data are presented in Table 1 according to the severity of consciousness troubles: Patients of group 1 had a normal consciousness and a Glasgow score of 14 or 15 (2); patients of group 2 had not a normal consciousness and a Glasgow score between 9 and 13; patients of group 3 presented with severe consciousness troubles and had a Glasgow score of 9. Pyramidal syndrome was defined by a sole reflex in extension (Babinski sign), exaggerated osteotendinal hyperreflectivity, and spastic hypertonia. Extrapyramidal syndrome was defined by axial dystonia and extrapyramidal hypertonia. Patients were aged from 0.1 to 16.9 years (median 2.1 years). All except two patients had acute renal failure (Table 1) that required peritoneal dialysis (n 23), hemodialysis (n 18), or both techniques (n 9) during a median duration of 12 days (range 0 to 49 days). In addition, one patient did not recover any renal function from the acute phase. Gastrointestinal prodrome featured diarrhea in 50 of 52 and only vomiting in two of 52. All patients had at least two hematologic feature of HUS (Table 2): Anemia (49 of 52 had a blood hemoglobin 10 g/dl) that required blood transfusions in 47, thrombopenia (50 of 50; data unavailable for two patients), or schistocytosis (48 of 50; data unavailable for two patients). Verotoxigenic E. coli infection was documented in 24 of 52, including one patient with isolated vomiting. None of the 43 patients who remained alive experienced recurrence of HUS. Magnetic resonance imaging (MRI) was available for 29 patients. All MRIs were performed before and after gadolinium injection. Image interpretation was performed by one radiologist who is specialized in pediatric neuroradiology. MRI findings were compared with clinical and biological data. Data are presented as median and range.

Final Outcome

Alive Alive Exchange No 1 11 HD HD

Neurologic Sequelae

Alive

Duration of RRT (days)

Exchange

RRT

18

HD

HD

21

Exchange

Plasma

No Severe disability No

No

Alive

Results
A global analysis of the series shows that, at last follow-up, nine patients had died (mean age 3 years), 12 patients had severe disabilities and no longer had autonomy of life, five patients had mild sequelae, and 26 patients had fully recovered. Severe hypertension 97th percentile 30 mmHg according to gender, age, and length was observed in seven of 45 patients. Hyperleucocytosis (Table 2) was noted in 48 of 48 patients (median 31,965/mm3; range 15,220 to 83,000/mm3). Hyponatremia (Table 2) 130 mmol/L was observed in 23 patients, but severe hyponatremia 120 mmol/L occurred in only three patients. Other biologic parameters are presented in Table 2 and show increased C-reactive protein (CRP; normal value 12 mg/L) in three of 41 patients, low plasma protides (normal values 55 to 70 g/L) in 44 of 49 patients, low serum albumin (normal values 35 to 45 g/L) in 27 of 28 patients, high plasma aspartate aminotransferase (normal value 45 U/L) in 41 of 44 patients, and high plasma alanine aminotransferase (normal value 45 U/L) in 35 of 44 patients. The most frequent neurologic signs were alteration in consciousness (44 patients), seizures (37 patients), pyramidal syndrome (27 patients), and extrapyramidal syndrome with hypertonia (22 patients). Twelve patients displayed coma and seizures in addition to pyramidal and extrapyramidal syndromes. More limited neurologic defects included diplopia, dysphasia, and facial palsy.

Seizures

Coma

Severe

Severe Severe 129/67 96/52 M M 50 51 1.2 1.3

0 0

BP (mmHg)

Age (years)

Table 1. (Continued)

Gender

2.8

Patient

49

52

2.6

108/53

95/58

Severe

1222

Table 2. Main biological parameters

Schistocytosis Leucocytes (/mm3) Platelets (103/mm3) CRP (mg/L) Serum Sodium (mmol/L) Plasma Protides (g/L) Plasma Albumin (g/L) AST (U/L) ALT (U/L)

Patient

Gender

Stool PCR

Hb (g/dl)

STX1 O26 36 18

54,000 18,100 27,000 21,300 15,900 32,000 202 187

49 12 217 19 23

52 33 54 50 55

21 33 23

232 306 182 196 208

241 210 115 54 67 180

O157H7

17 50 34 64 16 19 21 80 75

O157H7

Clinical Journal of the American Society of Nephrology

O157H7

O157H7

O157 O157

38 164 56 107 28 208 200 145 69 265 279 157 243 6 63

18 15 12 19 13 26 26 20 22 32

294 44 280 17 28 581 183 196 59 78 184 243 57 71 28

191 167 170 16 30 392 227 258 56 179 70 192 22 12

STX O157H7

STX2

23 21

157 104 123 87 89 398 561 127 114 111 200 67 188 46 19 207 333

82 26 131 36 129 501 238 57 172

O26 O157H7 27% 1.8%

Yes Yes 2.0% 3.5% 5.0% 2.0% 3.0% 10.0% Yes 10.0% 0.0% 5.0% 6.5% 11.0% 15.0% 10.0% Yes 16.0% Yes 3.0% 8.0% 4.5% 6.5% 3.2% Yes Yes 2.0% 2.5% 1.2% 2.7% Yes 6.0% 4.5% 49,900 78,900 34,200 37,000 37,200 46,700 36,800 53,000 43,100 30,200 62,000 45,400 19,150 20,300 31,500 15,600 15,220 47,000 23,700 22,000 28,500 18,470 28,000 23,400 32,900 40 87 52 10 20 27 43 10 9 23 12 27 28 35 34 47 49 38 74 66 40 17 45 50,800 51,700 230 97 47 50 51 51 56 39 32 51 36 35 44 36 41 54 39 44 61 50 37 46 49 35 47 41 44 46 53 52 67 25 26 163 343

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 15 19 30

F F F F M M F M M M M M M F F F M M F F M F M F M M M F M M M F M F F M F

120 89

Clin J Am Soc Nephrol 5: 1218 1228, 2010

O111 STX2

7.9 7.0 8.0 8.3 4.7 8.7 6.5 8.1 6.4 7.9 10.0 7.1 6.5 6.4 5.1 5.9 5.8 5.8 6.6 6.7 6.6 5.6 6.0 7.0 6.7 10.4 7.0 4.8 5.9 6.6 5.9 6.6 6.3 8.0 5.2 7.8 7.0

124 138 124 137 140 141 122 142 132 132 124 NA 122 122 130 122 125 129 131 132 125 141 117 138 128 127 128 132 130 122 123 138 134 NA 121 140 131

Clin J Am Soc Nephrol 5: 1218 1228, 2010

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1223

A first group of eight patients (five girls and three boys) remained with normal consciousness, five with subintrant seizures that lasted for 24 hours, including two who secondarily needed mechanical ventilation as a result of a high dosage of antiepileptic drugs. Of the eight patients, six had a neurologic defect including pyramidal syndrome in four with hemiplegia in two and extrapyramidal signs in two. All patients were alive at last follow-up. Significant neurologic sequelae consisted of hemiparesia in two and epilepsy in one. Other extrarenal involvement included transient diabetes (n 1), mild pancreatitis (n 2), and transient myocardial dysfunction (n 1). Of the eight patients, six needed dialysis for a mean duration of 15 days (creatinine at last follow-up 83 mol/L; range 26 to 350 mol/L), and one definitely progressed to end stage renal failure. A second group of 23 patients (eight girls and 15 boys) had stuporous coma. Five patients had protracted severe seizures. Eighteen patients had a neurologic defect including pyramidal syndrome in 11 with hemiplegia or hemiparesia in three and extrapyramidal syndrome in seven. All but two patients were alive at last follow-up. Significant neurologic sequelae consisted of residual paresia in three patients, epilepsy in one, and developmental delay in one. Other extrarenal damages included diabetes (n 1), pancreatitis (n 5), perforating colitis (n 3), and transient myocardial dysfunction (n 1). All but one patient underwent dialysis for a mean duration of 12 days (median of serum creatinine at last follow-up 69 mol/L; range 27 to 203 mol/L). A third group of 21 patients had severe coma that needed mechanical ventilation (median of duration 10 days; range 1 to 34 days). Six patients had severe protracted seizures. Neurologic defects consisted of pyramidal syndrome in 12 and extrapyramidal syndrome in 13. Fourteen patients were alive at last follow-up. Five patients had severe disabilities and needed to be admitted to specialized institutions for severe neurologic disability. Other extrarenal damages included diabetes (n 1), pancreatitis (n 4), angiocholitis (n 1), and transient myocardial dysfunction (n 1). All patients needed dialysis for a mean duration of 15 days, but all recovered renal function (median of serum creatinine at last follow-up 58 mol/L; range 27 to 230 mol/L). Of note, three patients from group 2 (patients 10, 26, and 29) and three from group 3 (patients 34, 46, and 49) with seizures associated with pyramidal and extrapyramidal syndromes fully recovered without neurologic sequelae. Figures 1 and 2 show the diffuse brain damage on the initial MRI of patient 49 and the remaining damage by 6 months. Patient 49 finally had fully recovered normal color vision at last follow-up. Plasma therapy was undertaken for 29 patients (four of eight in group 1, nine of 23 in group 2, and 16 of 21 in group 3). Plasma infusion was administered to four patients, and plasma exchanges were conducted for 25. The mean delay between the onset of neurologic symptoms and plasma exchange was 3.6 days. Of the 25 patients that underwent plasma exchanges, 11 were treated within 24 hours after the first neurologic sign; four died, two survived with severe sequelae, and five were alive without neurologic defect. The outcome of this group of 11

ALT (U/L)

AST (U/L)

Plasma Albumin (g/L)

252 1810 167 114 71 104 260 93 16 16 23 94 32 366 254 6 71 40

Plasma Protides (g/L)

Serum Sodium (mmol/L)

CRP (mg/L)

Platelets (103/mm3)

197 235 68 166

AST, aspartate aminotransferase; ALT, alanine aminotransferase; Hb, hemoglobin.

Leucocytes (/mm3)

Schistocytosis

Hb (g/dl)

O157H7

O103 STX O157H7 O157

Table 2. (Continued)

Gender

Patient

38 39 40 41 42 43 44 45 46 47 48 49 50 51 52

M F F F M F F F F F F F M M F

O157H7

Stool PCR

STX2

O157

VT2

6.0 8.6 8.4 6.6 6.5 6.5 5.4 7.1 8.2 8.9 10.0 6.9 7.8 9.3 6.2

Yes 0.0% 1.0% 2.0% 0.5% 1.9% Yes 2.0% 1.5% 20.0% 0.1% 5.0% 11.5% 10.0% 1.3%

15,500 23,500 39,600 22,500 83,000 31,930 39,100 67,700 26,600 25,100 35,500 47,800 29,950 32,600 18,640

56 40 38 58 90 51 25 37 60 41 45 32 17 77 77

126 124 126 124 132 137 126 135 117 125 126 129 129 110 130

53 53 51 52 44 45 55 31 45 53 56 46 46 49 52

28 32

18 31

164 76 156 302

214

198 21 114 310

252 270 173 10 51 118 150 39

106

1224

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Clin J Am Soc Nephrol 5: 1218 1228, 2010

Figure 1. Patient 49: MRI findings at day 3 in a 3-year-old girl with severe coma, pyramidal and extrapyramidal symptoms, and cortical blindness suspected on day 15 of evolution. (a and b) Fluid-attenuated inversion recovery axial view on the third day after admission shows bilateral and symmetrical high-intensity signal in the lateral geniculate bodies (1), posterior limbs of internal capsule (3), thalamus (4), and medial occipital cortex (5) as well as temporal insulae (2), including external capsule, claustrum, and extreme capsule. (c) Diffusion-weighted imaging shows hypersignal in lateral the geniculate bodies (1) and insulae (2), only areas demonstrating a restricted diffusion as a result of cytotoxic edema. (d) Noncontrast coronal T1-weighted view shows a spontaneous hyperintense signal in the lateral geniculate bodies (1), probably as a result of hemorrhage.

patients (belonging to groups 2 and 3) was significantly different from neither the patients in group 2 or 3 who were not treated with plasma exchange nor the rest (group 2 and 3) of the series (bilateral Fisher exact test). Results from 29 MRIs are detailed in Table 3. Early MRI of the central nervous system (CNS) was performed during the acute phase within 10 days after the first neurologic sign of the disease in 17 patients. As a matter of fact, MRI analysis of this series of 29 showed that (1) every structure of the CNS was susceptible to involvement, (2) damage seemed to be randomly localized according to individuals, and no special profile of localization on early MRI had a particular correlation with the final prognosis in terms of lethality and neurologic sequelae; diffuse damage to several substructures of the CNS frequently led to death (patients 11, 14, 33, 37, and 43) or severe disabilities (patient 51), but complete recovery without any sequelae (see Figures 1 and 2 for patient 49) was also observed in two patients (patients 15 and 49); (3) hemorrhagic lesions were observed in five patients (patients 3, 11, 14, 29, and 36), two of

whom died and two of whom fully recovered without any sequelae; and (4) MRI performed by days 1 (patient 38), 4 (patient 5), and 26 (patient 27) strikingly did not exhibit any focal lesions in three patients despite clinical pyramidal syndrome or severe coma. The use of gadolinium did not lead to nephrogenic systemic fibrosis in survivors.

Discussion

This series of 52 patients with DHUS and severe neurologic involvement is the most important ever reported in the literature. The most frequent clinical features of neurologic damage were coma, seizures, and pyramidal and extrapyramidal syndromes. Neurologic complications of HUS led to death in 17% of patients and to severe sequelae in 23%. Conversely, 50% of patients remained alive and had a complete neurologic recovery. The most frequent cause of HUS in European children is the gastrointestinal infection with verotoxigenic E. coli. Other causes include pneumococcal infections and genetic forms secondary to gene alterations in complement regulators and are far

Clin J Am Soc Nephrol 5: 1218 1228, 2010

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1225

Figure 2. Patient 49: MRI findings at day 15 (a) and 6 months later (b). (a and b) Fluid-attenuated inversion recovery axial view. At day 15 (a), hypersignal persists only in the previous restricted diffusion areas. Six months later (b), slight hypersignal in the left insula and the geniculate bodies is still visible (the child had at that time disturbed color vision).

more infrequent. In our series, verotoxins or verotoxigenic strains of E. coli were identified in approximately 50% of patients. The second half of the patients with DHUS are highly suspected of gastrointestinal infection with verotoxigenic E. coli (1) because of the acute presentation of HUS, (2) because of the lack of recurrence in patients who remained alive, (3) because all patients were living in France and did not have exposure to Shigella dysenteriae type 1, and (4) because of the rarity of genetic forms of HUS. Nevertheless, severe forms of DHUS were associated with mutation of complement regulators in two reports, suggesting that a special genetic background may sensitize children who are infected with veritoxogenic strains of E. coli to acute DHUS, in particular to severe forms and complications (3,4). Severe neurologic involvement is not rare in DHUS. A search for DHUS with neurologic involvement in the literature resulted in retrieval of seven series that totaled approximately 150 patients (511). The French national survey of DHUS numbered 1308 cases between 1993 and 2007, and our patients, who were recruited from the same centers that participate to the French survey, include 39 cases in the same period, suggesting that the frequency of neurologic involvement is approximately 3%. This prevalence is significantly lower than those estimated in the seven series reported in the literature, but one should keep in mind that (1) the figures given by the French national survey are reliable, (2) our series is supposed to be complete because every pediatric nephrology unit has been directly and individually contacted for this series, and (3) isolated seizures were excluded from our series. The prognosis of neurologic involvement in our series was intermediate among the three most important series (6,8,11) and those of Hahn et al.

(10). The age of patients who died or continued to have severe disabilities was not significantly lower compared with patients who fully recovered in our series as well in all series of the literature. As already reported in the literature, most patients of our series had high levels of white blood cell, CRP and, alanine aminotransferase and low levels of sodium and total protein (1214). The mechanisms of damage in the CNS are frequently considered to be due to multiple factors, including local microangiopathy, hypertension, and hyponatremia (6). Recent advances showed that verotoxin receptor Gb3 is not expressed in neurons and glial cells. Subsequently, verotoxins may not directly damage neural cells, whereas neuroinflammation through massive cytokine release may play a critical role in apoptosis of neural cells (15,16). The severity of neuroinflammation may be represented by hyperleucocytosis and increased plasma levels of CRP. In a series of 64 autopsied children with DHUS, the brain was examined in 32 and showed microangiopathy in 11 and hemorrhages in 21, suggesting that the main cause of damage is a parenchymal ischemia that is directly due to the cerebral localization of microangiopathy (7). Our series shows that a threatening level of hypertension at onset of neurologic signs is relatively infrequent and that only three patients had severe hyponatremia susceptible to leading directly to cerebral damage. By contrast, most but not all MRI examinations showed features of parenchymal ischemia or hemorrhages. Thrombotic occlusion that affected either carotids or vertebral arteries as well as territorial infarction, evoking cerebral artery occlusion, was not observed here and has never been described elsewhere. Consistently, the analysis of MRIs of our series showed random localization of parenchymal damage without any systematization. Similar to the cases reported in the literature

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Table 3. MRI: Localization of CNS damage

Patient Day Cortex Subcortical WM Periventricular WM Ventricular Dilation Thalamus Capsules Caudate Nucleus Putamen Pallidum

2 3 5 10 11 13 14 15 20 21 22 26

24 9 4 49 2 18 10 3 22 39 6 33

No No No No Yes No Yes Yes No Yes No No

No No No Yes No No Yes No No No Yes No

Yes No No No No Yes Yes Yes Yes No No Yes

No No No No DIL DIL DIL No No DIL No No

No No No No Yes No Yes Yes No No No No

No Yes No No No No No Yes No No No No

No Yes No Yes No No Yes No No No No No

No Yes No Yes No No Yes Yes Yes No No No

No Yes No No No No Yes No No No Yes No

27 28 29 32 33 34 36 37 43 45 49

26 30 2 8 1 20 2 1 44 37 3

No No No No No No Yes No No No Yes

No No No No Yes No Yes Yes No No Yes

No No Yes Yes Yes Yes No Yes Yes No Yes

No DIL No DIL No No No No No DIL No

No No No No No No No Yes Yes No Yes

No No No No No No No Yes No No Yes

No No No No No No No No Yes No No

No No No No Yes Yes No No Yes Yes Yes

No No No No No No No No Yes No No

50 51 52

1 20 1

No Yes Yes

No Yes No

Yes Yes No

No DIL No

No Yes Yes

No No No

Yes Yes No

Yes Yes Yes

Yes Yes No

DIL, presence of ventricular dilation; ND, not determined; WM, white matter. a 0 no seizures; 1 repeated seizures; 2 subintrant seizures. (5,1721), we were unable to find any specific profile of damage localization that could predict patients outcome. Consequently, the interest of MRI is limited to checking the localization of parenchymal damage in patients and especially in those with stupor and coma, in whom clinical examination lacks of accuracy. It is interesting that three patients in our series had normal or subnormal MRIs despite isolated pyramidal syndrome or stupor with or without pyramidal syndrome. Only one of these patients had severe hypertension, and the other two had normal sodium and normal BP. Sequelae were limited to epilepsy in only one of these three patients. Similar findings have been reported in the literature (5) and remained unexplained. By contrast, of genetic forms of HUS that are due to complement regulators and to thrombocytopathic thrombocytopenic

Clin J Am Soc Nephrol 5: 1218 1228, 2010

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1227

Table 3. (Continued)
Brain Stem Cerebellum Geniculate Body Coma Seizuresa Neurologic Defects Plasma Neurologic Sequelae Final Outcome

No No No No Yes No Yes No No No No No

No No No No Yes No No No No No No No

No No No No No No No No No No No No

0 0 0 Stuporous Stuporous Stuporous Stuporous Stuporous Stuporous Stuporous Stuporous Stuporous

2 2 1 1 1 0 0 0 2 1 2 1

Pyramidal Extrapyramidal Pyramidal Extrapyramidal, pyramidal Extrapyramidal, cerebellar Extrapyramidal Extrapyramidal, pyramidal Diplopia Pyramidal Diplopia No Extrapyramidal, pyramidal, cerebellar Pyramidal, paresia No Extrapyramidal, pyramidal Pyramidal Extrapyramidal, pyramidal Extrapyramidal, pyramidal Paresia ND Extrapyramidal Extrapyramidal, pyramidal Extrapyramidal, pyramidal, blindness No Extrapyramidal, pyramidal Extrapyramidal, pyramidal

No Infusion Exchange No No No Exchange No Exchange Infusion No No

No Ataxia No No NA No NA No No Visual defect No No

Alive Alive Alive Alive Dead Alive Dead Alive Alive Alive Alive Alive

No No No No No No No Yes Yes No Yes

No No No No No No No Yes No No Yes

No No No No No No No No No No Yes

Stuporous Stuporous Stuporous Severe Severe Severe Severe Severe Severe Severe Severe

2 1 2 0 1 1 1 1 0 1 2

Exchange No Exchange Exchange Exchange No Exchange Exchange No Infusion Exchange

Epilepsy No No Severe disability NA No No NA NA Blindness No

Alive Alive Alive Alive Dead Alive Alive Dead Dead Alive Alive

No Yes No

No No Yes

Yes No No

Severe Severe Severe

0 0 2

Exchange No Exchange

No Severe disability No

Alive Alive Alive

purpura as a result of ADAMTS13 deficiency or autoimmunity, data on plasma therapy and plasma exchange in severe forms of DHUS with extrarenal complications are scarce in the literature (22). A multicenter, controlled trial of plasma infusion was completed in France more than 20 years ago and concluded a beneficial effect, especially in the prevention of cortical necrosis (23). Treatment with plasma exchange has been reported

in several single cases and in one series without a clear-cut conclusion (7,24-27). For half of the studied patients, we could not find direct benefits of plasma exchange, even when started a few hours after the onset of neurologic complications; however, this does not exclude clinical benefits of plasma exchange, because complications might have been even worse if plasma exchange had not been performed. This study does not allow

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Clinical Journal of the American Society of Nephrology

Clin J Am Soc Nephrol 5: 1218 1228, 2010

any definite conclusion on the efficacy of plasma exchange for patients who have DHUS with CNS involvement.

Conclusions

The prognosis of neurologic complications of DHUS are not systematically associated with death or severe neurologic disability. The prognosis is not related to a special localization of damage in the CNS but to the general severity of the disease: Nearly all patients with neurologic involvement had severe renal damage and required dialysis.

14.

15.

Acknowledgments
We sincerely thank Odile Boesfplug-Tanguy for useful help in the retrospective analysis of neurologic symptoms and Brigitte Llanas for additional data collection.

16.

Disclosures
None.

17.

References
1. Sandvig K: Shiga toxins. Toxicon 39: 1629 1635, 2001 2. Yager JY, Johnston B, Seshia SS: Coma scales in pediatric practice. Am J Dis Child 144: 1088-1091, 1990 3. Fang C, Fremeaux-Bacchi V, Liszewski MK, Pianetti G, Noris M, Goodship THJ, Atkinson JP: Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 111: 624 632, 2008 4. Edey MM, Mead PA, Saunders RE, Strain L, Perkins SJ, Goodship TH, Kanagasundaram NS: Association of a factor H mutation with hemolytic uremic syndrome following a diarrheal illness. Am J Kidney Dis 51: 487 490, 2008 5. Steinborn M, Leiz S, Rudisser K, Griebel M, Harder T, Hahn H: CT and MRI in haemolytic uraemic syndrome with central nervous system involvement: Distribution of lesions and prognostic value of imaging findings. Pediatr Radiol 34: 805 810, 2004 6. Cimolai N, Morrison BJ, Carter JE: Risk factors for the central nervous system manifestations of gastroenteritisassociated hemolytic uremic syndrome. Pediatrics 90: 616 622, 1992 7. Gallo GE, Gianantonio CA: Extrarenal involvement in dairrhoea-associated haemolytic-uraemic syndrome. Pediatr Nephrol 9: 117119, 1995 8. Eriksson KJ, Boyd SG, Tasker RC: Acute neurology and neurophysiology of haemolytic-uraemic syndrome. Arch Intern Med 84: 434 435, 2001 9. Sheth KJ, Swick HM, Haworth N: Neurological involvement in hemolytic-uremic syndrome. Ann Neurol 19: 9093, 1986 10. Hahn JS, Havens PL, Higgins JJ, ORourke PP, Estroff JA, Strand R: Neurological complications of hemolytic-uremic syndrome. J Child Neurol 4: 108 113, 1989 11. Bale JF, Brasher C, Siegler RL: CNS manifestations of the hemolytic-uremic syndrome. Am J Dis Child 134: 869872, 1980 12. Teramoto T, Fukao T, Hirayama K, Asano T, Aoki Y, Kondo N: Escherichia coli O-157-induced hemolytic uremic syndrome: Usefulness of SCWP score for prediction of neurological complication. Pediatr Int 51: 107109, 2009 13. Kamioka I, Yoshiya K, Satumora K, Kaito H, Fujita T, Iijima K, Nakanishi K, Yoshikawa N, Nozu K, Matsuo M, Japa-

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

nese Society for Pediatric Nephrology: Risk factors for developing severe clinical course in HUS patients: A national survey in Japan. Pediatr Int 50: 441 446, 2008 Garg AX, Suri RS, Barrowman N, Rehman F, Matsell D, Rosas-Arellano M, Salvadori M, Brain Haynes R, Clarck WF: Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: A systematic review, meta-analysis, and meta-regression. JAMA 290: 1360 1370, 2003 Eisenhauer PB, Jacewicz MS, Conn KJ, Koul O, Wells JM, Fine RE, Newburg DS: Escherichia coli shiga toxin 1 and TNF- induce cytokine release by human cerebral microvascular endothelial cells. Microb Pathog 36: 189 196, 2004 Takahashi K, Funata N, Ikuta F, Sato S: Neuronal apoptosis and inflammatory responses in the central nervous system of a rabbit treated with Shiga toxin-2. Neuroinflammation 21: 511, 2008 Theobald I, Kuwertz-Bro king E, Schiborr M, Heindel W: Central nervous system involvement in hemolytic uremic syndrome (HUS): A retrospective analysis of cerebral CT and MRI studies. Clin Nephrol 56: S3S8, 2001 Schmidt S, Gudinchet F, Meagher-Villemure K, Maeder P: Brain involvement in haemolytic-uraemic syndrome: MRI features of coagulative necrosis. Neuroradiology 43: 581585, 2001 Ogura H, Takaoka M, Kishi M, Kimoto M, Shimazu T, Yoshioka T, Sugimoto H: Reversible MR findings of hemolytic uremic syndrome with mild encephalopathy. Am J Neuroradiol 19: 1144 1145, 1998 Nakamura H, Takaba H, Inoue T, Yoshisuke S, Saito F, Ibayashi S, Fujishima M: MRI findings of hemolytic uremic syndrome with encephalopathy: Widespread symmetrical distribution. J Neuroimaging 13: 7578, 2003 Signorini E, Lucchi S, Mastrangelo M, Rapuzzi S, Edefonti A, Fossali E: Central nervous system involvement in a child with hemolytic uremic syndrome. Pediatr Nephrol 14: 990 992, 2000 Michael M, Elliott EJ, Craig JC, Ridley GF, Hodson EM: Interventions for haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura: A systematic review of randomized controlled trials. Am J Kidney Dis 53: 259 272, 2009 Loirat C, Sonsino E, Hinglais N, Jais JP, Landais P, Fermanian J, French Society of Paediatric Nephrology: Treatment of the childhood haemolytic uraemic syndrome with plasma. Pediatr Nephrol 2: 279 285, 1988 Kanno Y, Kobayashi H, Rai T, Kanno K, Watanabe K, Obara K, Sato Y: Hemolytic uremic syndrome associated with Shiga toxin producing Escherichia coli infection in a healthy adult woman. Intern Med 43: 620 623, 2004 Yaginuma M, Sazaki N: A case of hemolytic uremic syndrome caused by verotoxin producing enteropathogenic Escherichia coli (O157:H7) with prolonged cerebrovascular dysfunction [in Japanese]. Rinsho Shinkeigaku 40: 237242, 2000 Valles PG, Pesle S, Piovano L, Davila E, Peralta M, Principi I, Lo Giudice P: Postdiarrheal Shiga toxin-mediated hemolytic uremic syndrome similar to septic shock. Medicina 65: 395 401, 2005 Nakatani T, Tsuchida K, Yoshimura R, Sugimura K, Takemoto Y: Plasma exchange therapy for the treatment of Escherichia coli O-157 associated hemolytic uremic syndrome. Int J Mol Med 10: 585588, 2002