This document describes 5 patients who developed infantile spasms after experiencing neonatal-onset hyperinsulinemic hypoglycemia (HH). All 5 patients initially presented with HH in the neonatal period, which was treated with diazoxide. After a variable latent period, all 5 patients then developed infantile spasms between 5 months and 1.2 years of age. The spasms responded variably to treatment with antiepileptic drugs. All patients showed developmental delays, and brain imaging found abnormalities in only 1 of the 4 patients who received MRIs. The authors conclude that hypoglycemic brain injury from neonatal HH, even if treated, can later manifest as infantile spasms after a latent period.

1. The Clinical Problem of Hyperinsulinemic Hypoglycemia and Resultant Infantile
Spasms
Anitha Kumaran, Sri Kar, Ritika R. Kapoor and Khalid Hussain
Pediatrics 2010;126;e1231-e1236; originally published online Oct 18, 2010;
DOI: 10.1542/peds.2009-2775
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://www.pediatrics.org/cgi/content/full/126/5/e1231
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2. CASE REPORTS
The Clinical Problem of Hyperinsulinemic
Hypoglycemia and Resultant Infantile Spasms
AUTHORS: Anitha Kumaran, MRCPCH, Sri Kar, MRCPCH,
Ritika R. Kapoor, MRCPCH, and Khalid Hussain, MD abstract
London Center for Pediatric Endocrinology and Diabetes, Great Hyperinsulinemic hypoglycemia (HH) is a cause of severe hypoglyce-
Ormond Street Hospital for Children, Clinical and Molecular
Genetics Unit, Institute of Child Health, University College mia in the newborn and infancy period and is associated with a high
London, London, United Kingdom risk of neurologic handicap and epilepsy. Infantile spasms after expo-
KEY WORDS sure to HH is rare and has been described in only 1 previous report. We
persistent hyperinsulinemia hypoglycemia of infancy, infantile report the clinical, biochemical, and neurodevelopmental characteris-
spasms
tics of 5 patients with neonatal-onset HH who subsequently developed
ABBREVIATIONS infantile spasms. All 5 patients had neonatal-onset HH of varying sever-
HH—hyperinsulinemic hypoglycemia
EEG—electroencephalogram ity and duration. These patients presented with the characteristic ictal
AED—antiepileptic drug pattern of spasms in clusters at a mean age of 6.6 months. Character-
www.pediatrics.org/cgi/doi/10.1542/peds.2009-2775 istic hypsarrhythmia was noted in only 3 of 5 patients. Structural ab-
doi:10.1542/peds.2009-2775 normality was found in only 1 of 4 patients who underwent MRI of the
Accepted for publication Jun 24, 2010 brain. Infantile spasms responded to medical treatment in 3 patients,
Address correspondence to Khalid Hussain, MD, Developmental
spasms in 1 patient were refractory to antiepileptic drugs, and treat-
Endocrinology Research Group, Clinical and Molecular Genetics ment duration was insufficient for us to comment on the response in 1
Unit, Institute of Child Health, University College London, 30 patient. Developmental delay was evident in all of them. In conclusion
Guilford St, London WC1N 1EH, United Kingdom. E-mail:
neonatal HH of varying severity is associated with later (after a latent
k.hussain@ich.ucl.ac.uk
period) development of infantile spasms. The latent period before the
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
onset of the spasms can be variable; hence, long-term neurodevelop-
Copyright © 2010 by the American Academy of Pediatrics
mental follow-up (until 1 year of age) is necessary. Pediatrics 2010;126:
FINANCIAL DISCLOSURE: The authors have indicated they have
no financial relationships relevant to this article to disclose.
e1231–e1236
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3. Hyperinsulinemic hypoglycemia (HH) Hypoglycemic brain injury is a recog- day, which was suggestive of infantile
is a cause of persistent hypoglycemia nized insult that triggers infantile spasms. She had achieved normal
and occurs because of dysregulated spasms. However, the mechanism of developmental milestones that re-
insulin secretion.1 This unregulated se- hypoglycemic brain injury resulting in gressed after the onset of these sei-
cretion of insulin suppresses glucose infantile spasms is unclear. There has zures. Results of an MRI scan of her
production by inhibiting glycogenolysis, only been 1 previous case report of a brain were normal at 6 weeks and 1
gluconeogenesis, lipolysis and ketogene- patient with infantile spasms and HH.13 year of life. An EEG showed encepha-
sis, which leads to a lack of alternative In this report, we describe the cases of lopathy with a right posterior tempo-
fuels available for brain function. Hence, 5 infants with neonatal-onset HH (with ral focus and no evidence of hypsar-
the brain is highly susceptible to hypo- and without seizures) who, after a la- rhythmia. Her seizures were clinically
glycemic damage with a high risk of neu- tent period, subsequently developed felt to be infantile spasms and were
rologic handicap, cerebral palsy, and ep- infantile spasms. Our case series sug- difficult to manage. Her seizures were
ilepsy.2– 4 Hypoglycemic brain injury is gests that brain injury caused by neo- unresponsive to sodium valproate,
typically associated with generalized natal HH (diazoxide-responsive and adrenocorticotrophic hormone, and
epilepsy, although focal epilepsy might -unresponsive) may lead to the devel- prednisolone, but the seizures re-
also occur.5 Generalized epilepsy in as- opment of infantile spasms later in the sponded to a combination of vigaba-
sociation with HH is recognized in hy- infancy period. trin and lamotrigine. A repeat EEG at 15
perinsulinism/hyperammonemia syn- months showed better background or-
drome, a form of HH associated with CASE REPORTS ganization and reduction in epilepti-
hyperammonemia.6– 8 Patient 1 form activity but persistent slow activ-
Infantile spasms are a rare form of ep- ity in the left temporal area.
Patient 1 was born via normal vaginal
ilepsy and have a characteristic ictal delivery at 40 weeks’ gestation with a A developmental assessment at 4
pattern of spasms that occur in clus- birth weight of 3.9 kg. She presented years of age showed mild generalized
ters.9 The onset is typically in infancy with generalized seizures at 3 days of hypotonia and receptive language de-
(peak incidence at 6 months), and as- age (Table 1). Investigations included a lay with significant speech and expres-
sociated interictal electroencephalo- full septic screen, the results of which sive language delay. She continues
grams (EEGs) show a chaotic high- were negative, and serum calcium, with lamotrigine for ongoing seizures.
voltage pattern called hypsarrhythmia, magnesium, lactate, ammonia, and Her head circumference, which was at
although this can be variable.10 Out- blood gas measurements and liver the 75th centile at birth, is currently at
come is often poor with severe neuro- function tests, the results of which the 50th centile (Table 1). Her HH is well
cognitive impairment and evolution were all normal. However, the patient controlled on minimal doses of diazox-
into other types of seizures.11 Approxi- was found to be hypoglycemic and re- ide (5 mg/kg per day).
mately 9% to 15% of the cases are quired 12.5 mg/kg per minute (normal:
cryptogenic, and the rest are symp- 4 – 6 mg/kg per minute) of intravenous Patient 2
tomatic. The symptomatic cases are glucose to maintain normoglycemia. Patient 2 was born via normal vaginal
typically associated with several pre- Further investigations revealed HH (Ta- delivery at 40 weeks’ gestation with a
natal, perinatal, and postnatal fac- ble 2). The diagnostic criteria for HH birth weight of 3.2 kg. He presented on
tors (including hypoglycemia), tu- are listed in Table 3.14 The HH re- day 2 when he was found to be floppy
berous sclerosis, structural brain sponded to diazoxide (13 mg/kg per and in respiratory distress. The re-
lesions (such as lissencephaly, hemi- day); the seizures did not respond to sults of routine hematology, microbiol-
megalencephaly, focal cortical dys- phenobarbitone or phenytoin and ogy, and biochemical investigations
plasia, septal dysplasia, and callosal were eventually controlled with clonaz- were normal. However, his blood glu-
agenesis), chromosomal abnormali- epam. Over the next 6 weeks the pa- cose concentration was 0.4 mmol/L
ties (such as Down syndrome and tient was weaned off antiepileptic when he was floppy. He required up to
del1p36), or single gene defects (mu- drugs (AEDs) and discharged from the 12 mg/kg per minute of an intravenous
tations of the ARX or CDKL5 gene).12 In hospital only on diazoxide. glucose infusion to maintain normo-
the vast majority of cases there is a At 9 months the patient developed clus- glycemia. Investigation results con-
temporal latency between an en- ters of head nods and jerking of her firmed HH (Table 2), which responded
cephalopathic event and the onset of upper body without lower-limb involve- to diazoxide. Despite resolution of hy-
infantile spasms. ment at a frequency of nearly 200 per poglycemia he continued to have gen-
e1232 KUMARAN et al
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4. CASE REPORTS
eralized seizures, and an EEG revealed
Near-total pancreatectomy
Motor and visual delay
a burst-suppression pattern. Pheno-
Case 5 barbitone was used to control the sei-
Hypsarrhythmia
zures, and the patient was gradually
Vigabatrin
weaned off of it at 4 weeks.
Normal
Normal
Female
5 mo
50th
At 6 weeks of age he presented with
4.5
10
9
tonic clonic seizures that lasted 2 min-
Subtotal pancreatectomy
utes and were not associated with hy-
poglycemia. The seizures responded
Adrenocorticotropic
Gross motor delay
hormone 2 wk
partially to phenobarbitone and phe-
Hypsarrhythmia
Case 4
nytoin. An EEG showed bursts of sharp
Awaited
left-sided activity, and results of an MRI
Normal
Male
1.2 y
75th
scan of his brain were normal. He con-
10
9
8
tinued to have right-sided partial sei-
Right parieto-occipital cyst
Prednisolone; currently on
zures and generalized tonic clonic con-
Bilateral sharp and slow
Coordination difficulties,
speech and language
Diazoxide, chlorthiazide
vulsions almost daily for 3 months
carbamazepine
Case 3
despite an optimal dosage of AEDs. At 3
discharges
months of age, the seizure pattern
changed to 8 to 10 clusters with 5 to 6
delay
Normal
Male
2.5 y
50th
flexor spasms within each cluster. An
9
9
9
EEG showed hypsarrhythmia. After a
Vigabatrin and prednisolone previously;
failed trial of vigabatrin and pred-
currently on valproate, topiramate,
nisolone, he was commenced on val-
Hypsarrhythmia; previous burst
proate and topiramate, which resulted
Gross motor and visual delay
Diazoxide, weaned by 9 mo
in some reduction of seizures.
Case 2
At 9 months of age he was successfully
and levetiracetam
weaned off of diazoxide. At 2.5 years of
suppression
age, he has significant motor and vi-
sual development delay with an abnor-
Normal
Normal
Male
2.5 y
25th
mal sleep pattern and feeding difficul-
10
9
3
ties that require gastrostomy. He can
and vigabatrin previously; currently on
Valproate, adrenocorticotropic hormone,
sit with support for short periods but
does not fix or follow well. Attempts to
control his spasms have been difficult.
Language and speech delay
He still continues to have seizures (6 to
Bilateral epileptic activity
Case 1
Diazoxide, chlorthiazide
10 clusters of flexor spasms) and has
just been commenced on levetirac-
etam with gradual withdrawal of the
lamotrigine
topiramate for better seizure control
Normal
Normal
Female
and to facilitate a ketogenic diet. His
75th
4y
seizures now are tonic seizures and
8
9
9
occur singly or in clusters every few
Age at onset of infantile spasms, mo
Head circumference before spasms
ammonia, urate, and carnitine
analysis, cutaneous slit-lamp
organic acid, serum lactate,
profiles, cerebrospinal fluid
weeks, and he has myoclonic jerks
Results of plasma amino acid,
daily. His head circumference was ini-
serum pyruvate, serum
ophthalmology screen
TABLE 1 Demographics
tially at the 25th centile, but it is cur-
Treatment for seizures
examination, and
rently at the 0.4th centile (Table 1).
Brain MRI results
Treatment for HH
Development
Apgar score
Patient 3
Current age
EEG results
1 min
5 min
Gender
Patient 3 was born at 39 weeks’ gesta-
tion with a birth weight of 3.2 kg. He
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5. TABLE 2 Results of Biochemical Investigations 1.2 years of age, he remains seizure-
Case 1 Case 2 Case3 Case 4 Case 5 free with moderate global develop-
Glucose, mmol/L 1.4 2.7 0.7 2.1 2.3 mental delay. Results of an MRI scan of
Insulin, pmol/l 78.9 63.8 100.4 258.3 103.3 his brain are awaited. His head cir-
NEFA, mmol/L 0.180 0.110 0.008 0.008 0.160
BOHB, mmol/L 0.005 0.005 0.005 0.005 0.050 cumference has remained at the 75th
Day of screen 7 7 10 2 3 percentile.
NEFA indicates nonesterified fatty acids; BOHB, 3- -hydroxybutyrate.
Patient 5
TABLE 3 Diagnostic Biochemical Features of HH was introduced. A repeat MRI scan of Patient 5 was born at 40 weeks’ gesta-
Glucose infusion rate 8 mg/kg per min the brain showed persistence of right tion with a birth weight of 3.7 kg. She
Laboratory blood glucose level of 3 mmol/L with presented on day 2 with poor feeding,
parieto-occipital cystic damage involv-
detectable serum insulin/C-peptide
suppressed/low serum ketone bodies ing the cortex and white matter. At 2.5 hypotonia, and generalized seizures.
suppressed/low serum fatty acids years’ follow-up, he has coordination Her blood glucose concentration was
difficulties and sleep and language de- 0.6 mmol/L at the time of presentation.
lay. He continues on carbamazepine She was commenced on intravenous
presented at day 2 with poor feeding, for ongoing generalized seizures that dextrose and required 24 mg/kg per
irritability, and generalized seizures. tend to wax and wane and require es- minute of dextrose to maintain normo-
The only biochemical abnormality de- calation of the AED dose. His head cir- glycemia. Results of investigations
tected was a low blood glucose level at cumference has remained stable at confirmed HH (Table 2). At 2 weeks, she
the time of the symptoms (blood glu- the 50th percentile. developed tonic clonic and partial sei-
cose: 0.7 mmol/L). The intravenous glu- zures. These seizures were predomi-
cose infusion rate required to main- Patient 4 nantly focal, involved the right or left
tain normoglycemia was 14 mg/kg per Patient 4 was born via cesarean deliv- upper and lower limbs, and lasted 5
minute. Results of further investiga- ery (for polyhydramnios and reversal seconds to 2 minutes, although some
tions confirmed HH (Table 2), which re- of end diastolic flow) at 33 weeks’ ges- involved her whole body. The fre-
sponded to diazoxide (15 mg/kg per tation with a birth weight of 3.1 kg. He quency of the seizures was 4 to 5
day). He required phenobarbitone, developed mild respiratory distress at times per week and partially re-
phenytoin, and midazolam infusion for birth and required continuous positive sponded to phenobarbitone. At 8
2 days to control the seizures, and he airway pressure for 5 hours. He was weeks concomitant myoclonic jerks
was discharged from the hospital at 6 noted to have symptomatic (lethargy developed, and an EEG revealed parox-
weeks of life with no AEDs. and floppy) hypoglycemia (1.9 mmol/L) ysmal bursts of generalized epilepti-
on day 1 and required 15 mg/kg per form activity that were associated with
He presented a week later with right- clinically apparent myoclonic jerks.
sided partial seizures (4 –5 episodes) minute of intravenous dextrose infu-
that were not associated with hypogly- sion to maintain normoglycemia. Re- The HH was refractory to medical
cemia and responded to phenobarbi- sults of investigations confirmed HH treatment with diazoxide and oct-
tone. Results of an MRI scan of his (Table 2). His HH failed to respond to reotide, and she also required a near-
brain at 7 weeks showed a right diazoxide and octreotide; eventually, at total pancreatectomy at 2.5 months of
parieto-occipital cyst, and EEG results 3 months of age, he required a near- age. After pancreatectomy she devel-
were reported as normal. He was total pancreatectomy for diffuse con- oped diabetes mellitus and required
weaned off AEDs by 6 months of age. genital hyperinsulinism. After the pan- subcutaneous insulin therapy. She
At 9 months of age he developed createctomy he developed diabetes was discharged to her local hospital at
extensor-type infantile spasms, 15 in a mellitus and required subcutaneous 3 months of age on phenobarbitone,
span of 2 to 3 minutes, with additional insulin injections. which was gradually weaned off over a
absence seizures. An EEG revealed At 8 months of age he developed infan- period of 4 weeks.
high-amplitude sharp and slow waves tile spasms (1–2 clusters per day) with At 4.5 months of age she developed
on both hemispheres (left right) developmental regression. An EEG was clusters of trunk flexion suggestive of
with a temporal and posterior empha- abnormal with poor background ac- infantile spasms. Results of an MRI
sis. The seizures responded to high- tivity and hypsarrhythmia. Seizures scan of the brain at 5 months were
dose prednisolone, which was gradu- ceased after a 2-week course of adre- structurally normal. Her EEG pattern
ally weaned off, and carbamazepine nocorticotropic hormone. Currently, at revealed typical hypsarrhythmia. She
e1234 KUMARAN et al
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6. CASE REPORTS
was commenced on vigabatrin with a uted to the early neonatal seizures. Tu- spasms as a result of immaturity of the
plan to wean off of phenobarbitone. She berous sclerosis was excluded by lack myelination process, and it is possible
had attained normal development until of any signs on neuroimaging, cutane- that repeat MRI in our patients at an
the onset of spasms, at which time her ous slit-lamp examination, and oph- older age ( 2 years) might be more
development regressed (poor head con- thalmologic evaluation. Despite exten- informative.22 Although neuroimaging
trol and visual fixation). Her head cir- sive biochemical investigations (see results were normal, a decrease in
cumference was at the 50th centile at Table 1), no other cause of the infantile head circumference percentiles after
birth and is currently at the 2nd centile. spasms was found. the onset of spasms was noted in 3 of
Infantile spasms typically begin weeks the 5 patients (Table 1), which quite
DISCUSSION to months after an initiating injury; likely reflects the extent of brain injury
The pathophysiological mechanisms during this latent period, neural cir- and compromise in brain growth.
underlying infantile spasms are not cuits become epileptogenic. The onset Rener-Primec et al23 reported an in-
known, although various etiologies (in- of infantile spasms varied from 3 to 9 creased proportion of head circumfer-
cluding hypoglycemic brain injury) months in our case series. The tempo- ences below the 10th percentile in the
have been proposed.15,16 Hypoglycemia ral latency between the onset of insult infantile spasm group compared with
is a recognized cause of infantile and development of infantile spasms is controls, and significantly poor neuro-
spasms, but the mechanism(s) of how well documented to be variable.9,19 This developmental outcome was associ-
hypoglycemic brain injury triggers in- temporal latency can probably be ex- ated if the head circumference per-
fantile spasms is unclear. In a recent plained by the developmental desyn- sisted below the 10th percentile in the
study that examined the etiology of re- chronization hypothesis, whereby an fourth and fifth month after the onset
mote symptomatic epilepsy with onset insult results in desynchronization of of infantile spasms.
in the first 3 years of life, it was noted development of 2 central nervous Infantile spasms may also result from
that neonatal hypoglycemia (not spe- system processes, which causes dis- abnormalities of structure or function
cifically HH) was the most common eti- ruption of normal functional interac- of cortical and subcortical structures
ology and that infantile spasms was tions. This desynchronization becomes or their communicating pathways.24 A
the most common seizure type.17 HH is significant as the brain matures and recent multiple-hit model based on
a form of hypoglycemia that is associ- results in functional deficit that mani- this concept was developed by Scant-
ated with a high risk of developmental fests as infantile spasms.15 Although elbury et al.25 By introducing lipopoly-
delay, mental retardation, and epilepsy.3 rare, seizures before the onset of saccharide and doxorubicin intracere-
The unique biochemical profile (with spasms have been reported and asso- brally at postnatal day 3 and
insulin-inhibiting glycogenolysis, glu- ciated with unfavorable outcome and p-chlorophenylalanine intraperitone-
coneogenesis, lipolysis, and ketogene- resistance to steroid treatment.20 ally at postnatal day 5, they were able
sis) observed in patients with HH ren- In our series of patients, EEGs were ab- to create a rat model that replicates
ders the brain more susceptible to injury normal in all 5 patients, but typical hyp- most of the features of human infantile
in comparison with other hypoglycemic sarrhythmia was seen in only 3 of spasms and would be helpful in the un-
states. Our clinical observations suggest them. In a recent report by Karvelas et derstanding and development of new
that significant brain insult that results al,21 hypsarrhythmia EEG on diagnosis or improved treatment modalities for
in infantile spasms and poor neurodevel- was noted in only 64% of patients in the refractory infantile spasms.
opmental outcome can occur despite the symptomatic group; 22% of their pa-
early diagnosis of HH. tients also experienced other seizures CONCLUSIONS
In our case series, all 5 patients pre- before the onset of infantile spasms. Neonatal-onset HH with the resulting
sented with neonatal-onset HH; 4 of the Arrest or regression of development brain insult may lead to the later devel-
5 patients presented with generalized/ with the onset of spasms and develop- opment of infantile spasms. The latent
partial seizures, including 1 patient mental delay are hallmarks of infantile period before the onset of the spasms
with a burst-suppression pattern in spasms and were noted in all our pa- can be variable; hence, long-term neu-
the neonatal period that was indicative tients (motor, speech, and language rodevelopmental follow-up (until 1
of significant underlying brain injury and visual impairment). year of age) is necessary. Further stud-
and associated with poor outcome.18 Results of MRI scanning of the brain ies are required to understand how HH
None of these patients had any perina- were abnormal for only 1 patient. MRI causes brain damage, which then
tal asphyxia that might have contrib- results can be normal at the onset of leads to infantile spasms.
PEDIATRICS Volume 126, Number 5, November 2010 e1235
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e1236 KUMARAN et al
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8. The Clinical Problem of Hyperinsulinemic Hypoglycemia and Resultant Infantile
Spasms
Anitha Kumaran, Sri Kar, Ritika R. Kapoor and Khalid Hussain
Pediatrics 2010;126;e1231-e1236; originally published online Oct 18, 2010;
DOI: 10.1542/peds.2009-2775
Updated Information including high-resolution figures, can be found at:
& Services http://www.pediatrics.org/cgi/content/full/126/5/e1231
References This article cites 24 articles, 4 of which you can access for free
at:
http://www.pediatrics.org/cgi/content/full/126/5/e1231#BIBL
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following collection(s):
Nutrition & Metabolism
http://www.pediatrics.org/cgi/collection/nutrition_and_metabolis
m
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