Caterina ZanusPaola CostaGianluca TorneseElena FaleschiniMarco Carrozzi

Institute for Maternal and Child Health - IRCCS “BurloGarofolo”, Trieste, Italy

Corresponding author:Caterina ZanusInstitute for Maternal and Child Health - IRCCS “BurloGarofolo”Via dell’Istria 65/134137 Trieste, ItalyTel.: 0403785214Fax: 0403785544E-mail: caterina.zanus@burlo.trieste.it

Abstract

We describe the case of a 16-month-old girl withcongenital hyperinsulinism diagnosed at the age of11 months, after a history of a single convulsiveseizure at 4 months of age, followed by frequentunexplained paroxysmal events related to sleep. Thediagnosis was made when a second convulsiveseizure occurred and a severe hypoglycemia wasdetected. Since the treatment with diazoxide wasstarted, both seizures and sleep disorder disap -peared. This case support the recommenda tions ofthe literature to consider a congenital hyperinsu -linism even in cases of infantile convulsionsapparently “benign” and/or in the evaluation ofatypical motor or behavioral paroxy smal manife -stations of uncertain origin; in this field, thecorrelation of hypoglycemia with sleep is a currenttopic of discussion and remains to be clarified.

KEY WORDS: hyperinsulinism, seizures, sleep, parox-ysmal awakenings.

Introduction

Congenital hyperinsulinism (CHI) comprises a groupof different genetic disorders with the common findingof recurrent episodes of hyperinsulinemic hypoglyce -mias due to an inappropriate secretion of insulin bythe pancreatic β-cells (1). Despite recent advances, the genetic basis of CHI is

146 Clinical Cases and Reviews in Epilepsy 2016; 1(2):146-148

still unknown in about 50% of patients. To date, themolecular basis of congenital CHI involves defects innine key genes (ABCC8, KCNJ11, GLUD1, GCK,HADH, SLC16A1, HNF4A, HNF1A and UCP2), theproducts of which are involved in regulating insulinsecretion (3-13). CHI is considered to be the mostfrequent cause of persistent recurrent hypoglycemiain newborns and infants (1, 2).Hypoglycaemic seizures during the neonatal periodare the main presentation of CHI and are usuallyrecognized. However, a misdiagnosis of epilepsy canbe made in cases of seizures appearing later sodelaying the recognition and the management ofrecurrent hypoglycemias which can cause com -plications and irreversible secondary brain damage(3-5).

Clinical case

This girl came to our attention at the age of 11 monthsfor the diagnostic interpretation of paroxysmal eventsduring sleep associated with interictal EEG abnorma -lities. She was born from an uneventful pregnancy, theperinatal period was normal, the developmentalmilestones were adequate for age. A first non febrileseizure had occurred during sleep at the age of 4months. A mild (74 mg/dL) hypoglycemia was observedafter episode and attributed to fasting. The neurologicalexamination and MRI were normal. The EEG showedinterictal paroxysmal sequences of bilateral synchro -nous diffuse irregular slow waves. The girl wasdismissed from the hospital with the prescription ofendorectal diazepam to stop seizures. In the following months “strange” paroxysmal episodesappeared, initially occurring every 10-15 days, thenmany times in a week. They occurred only in theafternoon sleep, at a set time (between 11 a.m. and 2p.m.). The episodes began with awakening, the childcried “like for a colicky pain”, with eyes wide open,sometimes looking down; muscle tone didn’t change,sometimes drooling and a flushing face were described.She appeared uncomfortable, therefore her motherstopped episodes lasting more than 3-5 minutes withendorectal diazepam, in the hypothesis of seizures.She was more doubtful in face of other abruptawakenings in which the girl appeared confused,hypotonic, with lolling head, sometimes suckingmovements; the mother never noticed paleness,tremors and cold sweating.Both episodes were recorded with a video EEG (Video1-2). The differential diagnosis between seizures andpara somnias was initially kept due to the atypical pre -

Brief reports/Clinical cases

Paroxysmal awakenings and seizures in congenital hyperinsulinism: a late diagnosis

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sentation of the episodes and the lack of a clearcorrelation with the EEG paroxysmal activity.During a second video EEG, the girl had a seizure withfocal motor signs which rapidly generalized (Video 3).The first-level metabolic investigation showed a severehypoglycemia (28 mg/dl). Subsequent investigationslead to the diagnosis of congenital hyperinsulinism(absence of urinary ketones, normal ammonia, profileof acylcarnitines, plasma amino acids and lactic acid,high insulin level). The genetic investigation was normal(the main genes were analyzed: ABCC8, KCNJ11,GLUD1, HNF4A, GCK, HADH).A treatment with diazoxide was started, with bloodglucose normalization, seizure control and normaliza -tion of EEG; the episodes during sleep disappeared.At the control of 16 months of age the psychomotordevelopment progressed normally and the EEG wasnormal.

Discussion

Typical presentation of CHI are neonatal seizures oc-curring during hypoglycemia and this usually leads toprompt diagnosis. When treatment resolves both hy-poglycemia and seizures, CHI has a favorable evolutionbut in other conditions the disorder can evolve towardmore complex situations. In infancy, seizures can evenshow specific electro-clinical features fitting with epilep-tic syndromes such as West syndrome and infantilespasms not always associated with neuroradiologicalevidence of brain damage (6).Atypical presentations of CHI are neurologic and psy-chiatric symptoms appearing with varying latency duringlife. When paroxysmal episodes appear in a child witha regular psychomotor development, a diagnosis of anidiopathic form of epilepsy can be erroneously made.Yoshikawa et al. reported the case of a persistent hy-

Paroxysmal awakenings and seizures in congenital hyperinsulinism: a late diagnosis

Clinical Cases and Reviews in Epilepsy 2016; 1(2):146-148 147

perinsulinemic hypoglycemia interpreted as benign in-fantile convulsion. The Author described an 18-month-old boy with a normal psychomotor development anda normal EEG who developed seizures at 3 months ofage. At that time, the exams showed a normal bloodsugar level and the diagnosis of benign infantile con-vulsion was made. When seizures reappeared at 7months of age hypoglycemia associated with hyperin-sulinism was disclosed (7).The possibility of misdiagnosis of critical events duringhypoglycemia is well known and described in cases ofinsulinoma, a pathology of adults rarely described inchildren. One study documented that 64% of patientswith insulinomas were diagnosed as having neurologicdisorders, with 12% being treated with anticonvulsantdrugs (8). Less than 30 cases of insulinoma at youngage have been published, and this rarity makes a timelyand accurate diagnosis even more difficult (9). Vagueand insidious symptoms like faintness, myalgias,paraesthesias, unexplained irritability, decrease inschool performance, the combination of seizures andepisodic confusional states, seizures unresponsive toanticonvulsant treatment are described. The literatureunderlines the importance of fatigue and fasting. Inparticular, early morning behavioural changes are em-phasized (10). The juvenile age and the time lockedappearance of symptoms, in particular of early morningseizures, can be elements relevant for the diagnosticclassification of a specific well known epileptic syn-drome. In the two cases described in the literature,myoclonic and generalized seizures occurring early inthe morning were diagnosed as juvenile myoclonicepilepsy; the refractoriness of the seizures and othersigns of neuroglycopenia lead to discover severe hy-poglicemias and an insulinoma (11, 12).Suzuki et al. describe abnormal nocturnal and earlymorning behavior interpreted as Rapid Eye MovementSleep Behavior Disorder in three adult cases (13).

Figure 1 - EEG recording of drowsiness and sleep showing interictal abnormalities: sequences of bilateral synchronousdiffuse irregular slow waves, lasting maximum 5 seconds (EEG, EKG, PNG, EMG 1 = left deltoid muscle).

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C. Zanus et al.

148 Clinical Cases and Reviews in Epilepsy 2016; 1(2):146-148

Complex mechanisms by which sleep may affect glucoseregulation and hypoglycemia may interfere with sleepare interesting topics still debated in the literature (14).In our case, episodes appeared only during a paroxys-mal awakening, particularly during postprandial naps.It can be hypothesized that after a particularly highcarbohydrate containing lunch, a hyperinsulinemic re-sponse occurred provoking paroxysmal non epilepticepisodes and rare epileptic seizures. EEG interictalchanges are consistent with the diagnosis, consideringthat hypoglycemia can activate both slow activities andepileptiform abnormalities (15).The diagnosis was initially difficult due to the atypicalpresentation of the episodes, the absence of signsusually associated with hypoglycemia (paleness,tremors, sweating) and the lack of a clear correlationwith the EEG paroxysmal activity.In conclusion, the literature recommends to considerhyperinsulinism in all patients with vague and insidioussymptoms, ‘‘funny turns’’, atypical neurological signs,complex behavioral manifestation, seizures associatedwith deterioration of school performances and behaviornot responding to standard anticonvulsant treatment.A red flag is considered a low/normal blood glucoselevels at the time of event. Taking a full history andclinical attention are essential to recognize a treatabledisorder and prevent neurological sequelae.

References

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2. Simsek E, Binay C, Flanagan SE, Ellard S, Hussain K,Kabukçuoglu S. Congenital hyperinsulinism presenting withdifferent clinical, biochemical and molecular genetic spectra.Turk J Pediatr. 2013;55(6):584-90.

3. Steinkrauss L, Lipman TH, Hendell CD, Gerdes M, ThorntonPS, Stanley CA. Effects of Hypoglycemia on DevelopmentalOutcome in Children With Congenital Hyperinsulinism. JPediatr Nurs. 2005;20(2):109-18.

4. Mazor-Aronovitch K, Gillis D, Lobel D, Hirsch HJ, Pinhas-Hamiel O, Modan-Moses D, B Glaser B Landau H. Long-term neurodevelopmental outcome in conservatively treatedcongenital hyperinsulinism. Eur J Endocrinol. 2007;157(4):491-7.

5. Menni F, Lonlay P, Sevin C, et al. Neurologic outcomes of90 neonates and infants with persistent hyperinsulinemichypoglycemia. Pediatrics. 2001;107(3):476-479.

6. Kumaran A, Kar S, Kapoor RR, Hussain K. The clinicalproblem of hyperinsulinemic hypoglycemia and resultantinfantile spasms. Pediatrics. 2010;126(5):1231-6.

7. Yoshikawa H, Honma T, Abe T. Persistent hyperinsulinemichypoglycaemia followed as benign infantile convulsionSeizure. 2003;12(3):186-187.

8. Dizon AM, Kowalyk S, Hoogwerf BJ. Neuroglycopenic andother symptoms in patients with insulinomas. Am J Med.1999;106(3):307-310.

9. Gozzi Graf T, Brändle M, Clerici T, l’Allemand D. Insulinoma:only in adults?-case reports and literature review. Eur JPediatr. 2014;173(5):567-74. doi: 10.1007/s00431-013-2005-8

10. Kao K, Simm PJ, Brown J. Childhood insulinoma mas-querading as seizure disorder. J Paediatr Child Health.2014;50(4):319-22. doi: 10.1111/jpc.12399

11. Jaladyan V, Darbinyan V. Insulinoma misdiagnosed as ju-venile myoclonic epilepsy. Eur J Pediatr. 2007;166(5):485-487.

12. Horváth E, Gozar H, Chira L, Dunca I, Kiss E, Pávai Z In-sulinoma diagnosed as drug-refractory epilepsy in an ado-lescent boy: a case report. Rom J Morphol Embryol. 2013;54(4):1147-1151.

13. Suzuki K, Kawasaki A, Miyamoto M, MD, Miyamoto T, Kan-bayashi T, Sato M, Shimizu T, Hirata K. Insulinoma Mas-querading as Rapid Eye Movement Sleep Behavior Disor-der. Medicine. 2015;94(25)e1065. doi: 10.1097/MD.0000000000001065.

14. Jauch-Chara K, MD, Schultes B Sleep and the response tohypoglycaemia Best Pract Res Clin Endocrinol Metab.2010;24(5):801-15. doi: 10.1016/j.beem.2010.07.006.

15. Niedermeyer E. Metabolic central nervous system disorders.In: Niedermeyer E, Lopes Da Silva F. Electroencephalog-raphy. Basic principles, clinical applications, and relatedfields. Lippincott Williams & Wilkins, Philadelphia. 1999:416-431.

Video 1-2 - Video EEG sequences of paroxysmal eventsoccurring during sleep in a 11-month girl with normal psy-chomotor development and a previous convulsive seizureat 4 month of age. The episodes occurred only in the after-noon sleep, at a set time (between 11 a.m. and 2 p.m.),initially every 10-15 days, then many times a week. In thetwo videos the episodes begin with awakening, the childcrying and appearing uncomfortable; the child is seated,presenting several episodes of lolling or dropping head. TheEEG is rich of movement artifacts and shows diffuse slowactivities, sometimes presenting in sequences of diffuse slowwaves not specifically correlated with head movements. The record was considered insufficient for a definite diagnosisand another video EEG recording was requested.(EEG, ECG = EKG, EMG 1 = left deltoid muscle, EMG 2 =right deltoid muscle).

Video 3 - Video EEG recorded the day after showed aseizure with focal motor signs and rapid diffusion. Thedisclosing of a severe hypoglycemia lead to the diagnosis ofcongenital hyperinsulinism (EEG, EKG, PNG, EMG 1 = leftdeltoid muscle, EMG 2 = right deltoid muscle).

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