Pediatric Diabetes 2011: 12: 513–517 © 2011 John Wiley & Sons A/S

doi: 10.1111/j.1399-5448.2010.00732.x
All rights reserved Pediatric Diabetes

Case Report

Acute cerebral infarction and extra pontine

myelinolysis in children with new onset type 1
diabetes mellitus

Petzold S, Kapellen T, Siekmeyer M, Hirsch W, Bartelt H, Siekmeyer W, Stefanie Petzolda ,

Kiess W. Acute cerebral infarction and extra pontine myelinolysis in children Thomas Kapellena ,
with new onset type 1 diabetes mellitus. Manuela Siekmeyera ,
Pediatric Diabetes 2011: 12: 513–517. Wolfgang Hirschb ,
Neurological complications of diabetic ketoacidosis (DKA) are still associated Heike Bartelta ,
with significant mortality and morbidity. We report on two children who Werner Siekmeyera and
suffered from acute cerebral infarction (CI) and extra pontine myelinolysis Wieland Kiessa
(EPM) at onset of type 1 diabetes. Initially, clinical management had not been a Department of Women and Child
performed according to generally accepted guidelines. Putative risk factors Health, Hospital for Children and
that may have predisposed for the development of acute cerebrovascular Adolescents, University of Leipzig,
complications are discussed. Not only cerebral edema (CE) but also other Leipzig, Germany; and b Department of
severe neurological complications such as CI should be suspected when Imaging and Radiotherapy, Section
neurological deterioration occurs during DKA. We conclude that not only an Paediatric Radiology, University of
exceeded rehydration therapy but also a rapidly reduced serum osmolality due Leipzig, Leipzig, Germany
to an unbalanced rapid blood sugar decrease and serum sodium increase may
have lead to the neurological disease. We propose that a reserved and Key words: ASS – CE – CI – CPM –
well-defined rehydration strategy in the first 6 (−12) h of therapy is crucial for DKA – EPM – MRI – type 1 diabetes
recovery and can reduce neurological complications of patients with DKA. Corresponding author:
Wieland Kiess, MD,
University Hospital for Children and
Adolescents, University of Leipzig,
Liebigstrasse 20a,
D – 04103, Leipzig,
Germany.
Tel: 49-341-9726000;
fax: 49-341-9726009;
e-mail: wieland.kiess@medizin.
uni-leipzig.de

Submitted 5 July 2010, Accepted for

publication 4 October 2010

Diabetic ketoacidosis (DKA), the metabolic conse-
quence of very low levels of effective insulin action, is
a frequent presentation of type 1 diabetes in children.
The worldwide incidence is reported to be 15–70%,
depending on the availability of health care and fre-
quency of diabetes (1–5). DKA can be associated
with life-threatening complications, first and foremost
cerebral events like cerebral edema (CE) and also cere-
bral infarction (CI), thrombosis or central pontine
and extra pontine myelinolysis (CPM/EPM) (6–9).
Clinically apparent CE is a rare but devastating com-
plication in pediatric type 1 diabetes, occurring in
<1% of cases. It results in significant neurological
morbidity in 35–40% of survivors and represents the
leading cause of acute mortalities of diabetes in chil-
dren (1,3,10–14). Furthermore, there have only been
few case reports (around 30) in children with regard
to the occurrence of CPM or EPM (15–17), mostly
without DKA. Myelinolysis seems to be rare in DKA
despite the well-known osmotic shifts accompanied
513
Petzold et al.
by changing blood sugar levels and sodium imbal-
ance. There is controversy about the association and
the underlying pathophysiologic mechanism of DKA
and CE. The major risk factors seem to be young
age, severity of acidosis, degree of hypocapnia, high
initial serum urea nitrogen concentration, and sever-
ity of dehydration (3,5,13,18–21). Children with these
clinical or biochemical features should be monitored
extensively for signs of neurologic deterioration. We
report on two patients with severe acute neurological
complications at the onset of diabetes.
Case 1
A previously healthy 2-yr-old girl presented to the
emergency room with a 1-wk history of polydipsia,
polyuria, weight loss, and vomiting. Past medical
history was unremarkable. On examination, the child
appeared lethargic and Glasgow Coma Scale was
determined 8. The girl was extremely dehydrated,
Kussmaul breathing was present. She was immediately
admitted to the intensive care unit. Laboratory
investigations showed a glucose level of 36 mmol/L
(650 mg/dL), acidosis [pH 7.07, base excess -25,
bicarbonate 4.3 mmol/L, pCO2 15.2 mmHg (2 kPa)]
and a HbA1c level of 10.8% (normal range
4.8–6.0%). Urea nitrogen was 7.7 mmol/L (normal
range 2.2–7.0 mmol/L), osmolality was 342 mosm/L,
sodium (138 mmol/L) and potassium (3.9 mmol/L)
levels were normal. Rehydration with 0.9% saline
was started (20 mL/kg/h over the first 4 h). Insulin
infusion was started immediately with 0.05 U/kg/h.
Sodium levels remained unchanged during therapy
and glucose levels dropped by 4 mmol/L (75 mg/dL)
per hour. Eleven hours after presentation vomiting, an
acute rise of blood pressure (peak with 192/107 mmHg,
initial abrupt pulse rise of 153 bpm – than pulse drop
55 bpm), stupor, and dilated, poorly reacting pupils
were noted. Immediate intubation and mechanical
ventilation became necessary due to apnoea. Because
CE was suspected, 1.0 g/kg mannitol was administered
immediately. Thirty minutes later, a cranial CT scan
was performed which did not show any signs of
CE or other cerebral abnormalities. During recovery
over the next week, a mild right hemiparesis was
observed. The cranial magnetic resonance imaging
(MRI) scan showed infarction of the left posterior
cerebral artery (Fig. 1). Ophthalmological examination
revealed a homonymic hemianopsia on the right
side. Treatment with acetylsalicylic acid (ASS) was
started. Laboratory analysis for factor V Leiden,
antiphospolipid antibodies, anticardiolipin antibodies,
anti-B2 glycoprotein, protein C and S activities,
plasminogen activator inhibitor, antithrombin III,
factor VIII activity levels, and lipoprotein (a) showed
normal values. The girl was discharged to a
514
A B
Fig. 1. Cranial magnetic resonance imaging (16 d after the therapy
started) showing hyperintense lesions in the occipital area (A and B,
solid arrow) consistent with infarction in the distribution of the left
posterior cerebral artery in a 2-yr-old girl with new onset of type 1
diabetes mellitus.
rehabilitation hospital on ASS and subcutaneous
insulin twice a day. Four months later, the cranial
MRI scan showed that the previously described area
of infarction had receded. Laboratory thrombophilia
testing was repeated after 3 and 12 months and showed
normal results again. Therapy with ASS was stopped.
One year after diagnosis of type 1 diabetes, the girl is
visiting the kindergarden, her verbal skills are excellent
and no hemiparesis is present. She has mild equilibrium
problems and the homonymic hemianopsia is still
present. Metabolic control of her diabetes is satisfying
and HbA1c is currently 7.0% (normal range 4.8–6.0%).
She attends primary school without difficulties and
has a normal visual performance and motor skill
development.
Case 2
A previously healthy 14-yr-old boy presented to
a district hospital with acute abdominal pain and
weight loss of 2 kg over the last 2 wk. Past medical
history was unremarkable. On examination the boy
was dehydrated, showed Kussmaul breathing and
cold extremities, weakness, and a cloudy speech.
Laboratory investigations showed a glucose level
of 34 mmol/L (612 mg/dL), acidosis [pH 6.913,
bicarbonate 4.3 mmol/L, pCO2 17.8 mmHg (2.3 kPa)],
and HbA1c level of 11.2% (normal range 4.8–6.0%).
Unfortunately, urea nitrogen and osmolality were
not measured upon delivery to the hospital, serum
sodium levels were decreased by 124 mmol/L, and
serum potassium (4.8 mmol/L) levels were normal.
Despite severe acidosis the boy stayed in the district
hospital and rehydration with 0.9% saline was started
(12.5 mL/kg/h over the first 2 h). Insulin infusion was
immediately started at 0.1 U/kg/h. Sodium levels went
up to 131 mmol/L during the first 3 h of infusion, while
Pediatric Diabetes 2011: 12: 513–517

glucose levels dropped by 18.5 mmol/L over this time.
After 4 h of therapy, the boy was getting increasingly
somnolent and was consequently transferred to our
hospital and admitted to the intensive care unit.
Laboratory investigations showed a glucose level
of 21.4 mmol/L (386 mg/dL), persisting acidosis [pH
7.124, bicarbonate 4.0 mmol/L, pCO2 19.2 mmHg (2.6
kPa)], urea nitrogen of 8.3 mmol/L (normal range
2.2–7.0 mmol/L), and osmolality 335 mosm/L. Sodium
(132 mmol/L) and potassium (4.5 mmol/L) levels were
normal. Rehydration was continued with isotonic 5%
glucose solution (3.5 mL/kg/h) and insulin infusion
at 0.1 U/kg/h. Sodium levels remained unchanged
during the therapy and glucose levels dropped by
1 mmol/L (18 mg/dL) per hour. After 24 h of therapy,
the boy had slowly recovered with normalized blood
glucose levels. Forty-eight hours after the initial
presentation, the boy was conspicuous of right
hemiparesis and left ptosis. Neurological examination
revealed a considerable disturbance of equilibrium and
coordination, loss of strength, positive Babinski reflex
on the right side, and speech disorder. MRI (Fig. 2)
revealed multifocal hyperdense lesions in the left and
temporomesial areas of the thalamus with affections
of the paraterminal gyrus of the frontal lobe and in
the precuneus. Considering the underlying clinical
picture, diagnosis of EPM was most likely. Upon
steroid therapy (dexamethason 0.2 mg/kg) over 3 d,
neurological symptoms receded except for muscular
weakness and paraesthesia. Additional therapy with
mannitol to induce osmotic diuresis was not indicated;
hence, the patient only showed signs of focal CE.
Three days later, the MRI showed unchanged lesions
without progression. Laboratory analysis for factor
V Leiden, antiphospolipid antibodies, anticardiolipin
antibodies, anti-B2 glycoprotein, protein C and S
activities, antithrombin III, and lipoprotein (a) showed
normal results.
The boy was transferred to a rehabilitation centre.
Today he is in good general condition without major
neurological sequelae and in stable metabolic control.
Discussion
Morbidity and mortality rates for DKA are estimated
between 0.15 and 0.31%. In countries with low levels of
medical facilities and high degree of poverty, morbidity
and mortality of DKA are even greater. CE is the
most serious complication of DKA (1–3,10–14,20).
However, over the last decades other neurological
complications at new onset of type 1 diabetes
have been identified. CI, sinous venous thrombosis,
and hemorrhages are other causes of neurological
deterioration during the treatment of DKA (6–9).
These complications are critical and important for the
outcome.
Pediatric Diabetes 2011: 12: 513–517
Cerebral complications in type 1 diabetes
A B
Fig. 2. Cranial magnetic resonance imaging of a 14-yr-old boy with
new onset of type 1 diabetes mellitus (3 d after the therapy started)
showing multifocal hyperintense lesions in the left thalamus (A,
solid arrows) and temporomesial on both sides of the thalamus
with affections of the paraterminal gyrus of the frontal lobe (B,
solid arrows), also bilateral in the precuneus (A, discontinued
arrows) without contrast medium enhancement – compatible with
extra pontine myelinolysis.
We report on two children with cerebral compli-
cations at new onset of type 1 diabetes. In both
cases, several major risk factors for CE were present:
greater severity of acidosis, higher degree of hypocap-
nia, high initial serum urea nitrogen concentration,
elevated serum osmolality and severe dehydration. In
both cases, no bicarbonate had been administered.
The first patient had received excessive rehydration
therapy above the recommended amounts: more
than 50 mL/kg over the first 4 h are considered as
a risk factor for CE. The cause of CI could be
a combination of diffused cerebral swelling with
transtentorial brain herniation and compression of
vessels against the adjacent edge of the tentorium. The
most vulnerable arteries are the posterior cerebral and
anterior choroidal arteries, both of which cross the
free edge of the tentorium. Notably, asymptomatic
or mildly symptomatic cell swelling may not be
uncommon during and even before the start of
the treatment of DKA (8,10,14,22). Following Case
1, we changed our hospital treatment guideline:
rehydration with 0.9% saline, 20 mL/kg/h in the first
hour (no more than 500 mL/h), 10 mL/kg/h in the
second hour (no more than 500 mL/h), 6 mL/kg/h
in the third hour, 4 mL/kg/h in the fourth hour,
afterwards 2–4 mL/kg/h. A maximum infusion rate
of 40–50 mL/kg/h in 4 h should not be exceeded.
If blood sugar is less than 20 mmol/L (360 mg/dL)
under insulin therapy or decreases more than
4 mmoL/kg/h (70 mg/dL/h), isotonic 5–10% glucose
solution should be given. Neurological monitoring
is recommended, especially in the first 24 h. Our
guideline is in accordance with the current treatment
recommendation (2). However, we have defined an
upper limit of fluid administration for the first 2 h
to avoid intracellular fluid imbalance. Considering all
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aspects, the aetiology of DKA-related CE is likely
multifactorial and needs to be seen as a result of
an interplay of complex pathophysiological processes
including ischemia, hypoxia, inflammation, metabolic
derangement, or oxidative stress (3,14,20–23).
Our second patient developed extensive asymmetric
extra pontine lesions following an unbalanced serum
glucose reduction compared to serum sodium increase
in combination with excessive rehydration therapy
(more than 50 mL/kg over the first 4 h). The pro-
posed underlying pathogenesis of myelinolysis is an
aggressive correction of hyponatremia (15–17). It is
more likely to occur if the electrolyte imbalance is long
standing before correction (i.e., more than 48 h). There
are reports of EPM in adults following rapid correction
of hyperglycemia and hypernatremia (16). A search of
the pediatric literature revealed that there are only few
reports on cases of EPM. Clinical settings varied with
craniopharyngioma resection, post-pituitary surgery,
adrenal insufficiency, post-orthotopic liver transplant,
ornithine transcarbomylase (OTC) deficiency, syn-
drome of inappropriate antidiuretic hormone secretion
(SIADH), head injury, Wilson’s disease, leukaemia,
and dehydration secondary to enteritis (15,16). There
are only two reports, very similar to our case, where
an EPM in a pediatric patient with DKA has been
described (15,16). The exact mechanism of demyeliza-
tion is still unknown. It is proposed that in regions
of compact interdigitation of white and grey matter,
cellular edema, which is caused by fluctuating osmotic
forces, results in compression of fiber tracts and induces
demyelination (16,17). Physical damage of oligoden-
droglial cells (mechanical shearing and shrinking) may
also play a role (16).
The generally accepted rate of hyponatremia
correction is 12 mmol/d or 0.5 mmol/h (15,24). The
recommended rate of correction of blood glucose is
2.7–3.8 mmol/L/h (50–70 mg/dL/h). In our patient,
both criteria were ignored. First, serum sodium
levels rose more than 2 mmol/L/h during the first
3 h of infusion, while glucose levels dropped by
6 mmol/L/h over this time. We propose that this rapid
osmotic shift was the major underlying reason for the
development of EPM. Furthermore, the patient was
also at increased risk due to his elevated serum urea
nitrogen concentration and his reduced blood flow due
to dehydration aggravated by low PaCO2 . All these
factors may lead to vasoconstriction which results in
cerebral ischemia, hypoxia, and an increased capillary
permeability (3,14–17).
In conclusion, the two patients presented with
new onset of type 1 diabetes with DKA and
developed cerebral complications. Not only an
exceeded rehydration therapy but also a rapidly
reduced serum osmolality due to an unbalanced rapid
blood sugar decrease and serum sodium increase may
516
have lead to the neurological disease. We propose that
a reserved and well-defined rehydration in the first
6 (−12) hours of therapy is the most critical point
and can reduce neurological complications. An upper
limit of fluid administration for the first 2 h (500 mL/h)
should generally be considered to avoid intracellular
fluid imbalance.
Considering the increasing incidence of type
1 diabetes, especially in very young age, every
pediatrician in pediatric intensive care should be
aware of the signs of CE and, in addition, other
neurological causes for neurologic deterioration during
the treatment of DKA.
Acknowledgements
We thank the nurses and physicians who help to care for these
children and thank the families for their cooperation and help.
References
1. Dunger DB, Sperling MA, Acerini CL et al. ESPE/
LWPES consensus statement on diabetic ketoacidosis
in children and adolescents. Arch Dis Child 2004: 89:
188–194.
2. Wolfsdorf J, Craig ME, Daneman D et al. Diabetic
ketoacidosis in children and adolescents with diabetes.
Pediatr Diabetes 2009: 12: 118–133.
3. Vavilala MS, Richards TL, Roberts JS et al. Change
in blood-brain barrier permeability during pediatric
diabetic ketoacidosis treatment. Pediatr Crit Care Med
2010: 3: 332–338.
4. Rewers A, Klingensmith G, Davis C et al. Presence of
diabetic ketoacidosis at diagnosis of diabetes mellitus
in youth: the Search for Diabetes in Youth Study.
Pediatrics 2008: 5: e1258–e1266.
5. Rosenbloom AL. Hyperglycemic crises and their
complications in children. J Pediatr Endocrinol Metab
2007: 1: 5–18.
6. Ho J, Mah JK, Hill MD, Pacaud D. Pediatric stroke
associated with new onset type 1 diabetes mellitus: case
reports and review of the literature. Pediatr Diabetes
2006: 7: 116–121.
7. Shrier DA, Shibata DK, Wang HZ, Numaguchi Y,
Powers JM. Central brain herniation secondary to
juvenile diabetic ketoacidosis. Am J Neuroradiol 1999:
20: 1885–1888.
8. Roe TF, Crawford TO, Huff KR, Costin G, Kauf-
man FR, Nelson MD Jr. Brain infarction in children
with diabetes ketoacidosis. J Diabetes Complicat 1996:
10: 100–108.
9. Keane S, Gallagher A, Ackroyd S, McShane MA,
Edge JA. Cerebral venous thrombosis during diabetic
ketoacidosis. Arch Dis Child 2002: 86: 204–205.
10. Glaser NS, Wootton-Gorges SL, Buonocore MH
et al. Frequency of sub-clinical cerebral edema in
children with diabetic ketoacidosis. Pediatr Diabetes
2006: 7: 75–80.
11. Roberts MD, Slover RH, Chase HP. Diabetic ketoaci-
dosis with intracerebral complications. Pediatr Diabetes
2001: 2: 109–114.
Pediatric Diabetes 2011: 12: 513–517

12. Roche EF, Menon A, Gill D, Hoey H. Clinical
presentation of type 1 diabetes. Pediatr Diabetes 2005:
2: 75–78.
13. Carlotti AP, St George-Hyslop C, Guerguerian
AM, Bohn D, Kamel KS, Halperin M. Occult risk
factor for the development of cerebral edema in children
with diabetic ketoacidosis: possible role for stomach
emptying. Pediatr Diabetes 2009: 8: 522–533.
14. Levin DL. Cerebral edema in diabetic ketoacidosis.
Pediatr Crit Care Med 2008: 3: 320–329.
15. Sivaswamy L, Karia S. Extrapontine myelinolysis in a
4 year old with diabetic ketoacidosis. Eur J Paediatr
Neurol 2007: 6: 389–393.
16. Bonkowsky JL, Filloux FM. Extrapontine myelinol-
ysis in a pediatric case of diabetic ketoacidosis and
cerebral edema. J Child Neurol 2003: 2: 144–147.
17. Singh DK, Rastogi M, Husain M. Central pontine
myelinolysis in a pediatric head injury patient. Pediatr
Neurosurg 2010: 46: 51–53.
18. Mallare JT, Cordice CC, Ryan BA, Carey DE,
Kreitzer PM, Frank GR. Identifying risk factors
for the development of diabetic ketoacidosis in new
onset type 1 diabetes mellitus. Clin Pediatr 2003: 42:
591–597.
Pediatric Diabetes 2011: 12: 513–517
Cerebral complications in type 1 diabetes
19. Glaser N, Barnett P, McCaslin I et al. Risk factors
for cerebral edema in children with diabetic ketoacido-
sis. N Engl J Med 2001: 4: 264–269.
20. Glaser NS, Wootton-Gorges SL, Marcin JP et al.
Mechanism of cerebral edema in children with diabetic
ketoacidosis. J Pediatr 2004: 2: 164–171.
21. Glaser N, Yuen N, Anderson SE, Tancredi DJ,
O’Donnell ME. Cerebral metabolic alterations in rats
with diabetic ketoacidosis: effects of treatment with
insulin and intravenous fluids and effects of bumetanide.
Diabetes 2010: 59: 702–709.
22. Glaser N. Cerebral injury and cerebral edema in
children with diabetic ketoacidosis: could cerebral
ischemia and reperfusion injury be involved?. Pediatr
Diabetes 2009: 10: 534–541.
23. Roberts JS, Vavilala MS, Schenkman KA, Shaw D,
Martin LD, Lam AM. Cerebral hyperemia and
impaired cerebral autoregulation associated with
diabetic ketoacidosis in critically ill children. Crit Care
Med 2006: 8: 2217–2223.
24. Soupart A, Decaux G. Therapeutic recommendations
for management of severe hyponatremia: current
concepts on pathogenesis and prevention of neurologic
complications. Clin Nephrol 1996: 46: 149–169.
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