De Visschere, Pieter

Senepart, Maarten

Seynaeve, Patrick

Vanrietvelde, Frederik

English

Ghent University Academic Bibliography

This article was originally published in a journal published byElsevier, and the attached copy is provided by Elsevier for theauthor’s benefit and for the benefit of the author’s institution, fornon-commercial research and educational use including withoutlimitation use in instruction at your institution, sending it to specificcolleagues that you know, and providing a copy to your institution’sadministrator.All other uses, reproduction and distribution, including withoutlimitation commercial reprints, selling or licensing copies or access,or posting on open internet sites, your personal or institution’swebsite or repository, are prohibited. For exceptions, permissionmay be sought for such use through Elsevier’s permissions site at:http://www.elsevier.com/locate/permissionusematerialAuthor's   personal   copyEuropean Journal of Radiology Extra 62 (2007) 35–38Brain injury due to persistent hyperinsulinemichypoglycemia of infancyPieter Julien Luc De Visschere a,∗, Patrick Seynaeve a,Frederik Vanrietvelde a, Maarten Senepart ba Department of Radiology and MR Imaging, AZ Groeninge Hospital, Loofstraat 43, 8500 Kortrijk, Belgiumb Department of Paediatrics, AZ Groeninge Hospital, Kortrijk, BelgiumReceived 19 July 2006; received in revised form 13 January 2007; accepted 15 January 2007AbstractWe report a case of brain damage in a 6-year old boy with seizures. On admission the patient presented with seizures two to three times a daysince 1 year. Shortly after birth the boy was diagnosed with persistent hyperinsulinemic hypoglycemia of infancy. We describe the magneticresonance imaging findings of brain lesions in our patient and correlate these to the literature. PHHI is a very uncommon disease although itis probably the most frequent cause of persistent neonatal hypoglycaemia. The disease is often associated with brain lesions, showing a rathertypical distribution pattern, affecting most severely the parietal and occipital lobes of the cerebral hemispheres.© 2007 Elsevier Ireland Ltd. All rights reserved.Keywords: Infancy; MRI; Hypoglycemia; Brain1. IntroductionPersistent hyperinsulinemic hypoglycemia of infancy(PHHI) is a rare disorder in which insulin secretion in theneonatal period is excessive and glucose-independent, result-ing in severe bouts of hypoglycaemia. It is a very uncommondisease although it is probably the most frequent cause ofneonatal hypoglycaemia [1–4]. The underlying pathomech-anism is inappropriate oversecretion of insulin, leading tosevere hypoglycaemia. The disease was previously knownas nesidioblastosis, a term first used by Laidlaw in 1938 todescribe neodifferentiation of pancreatic islets, changes seenin hyperfunctional disorders of pancreatic insulin-producingcells [5]. Nowadays this term has been replaced by persis-tent hyperinsulinemic hypoglycemia of infancy or congenitalhyperinsulinism of the newborn. It is a potentially life-threatening condition. The disease is often associated withbrain atrophy and important permanent brain damage, whichhave been attributed to periods of hypoglycaemia. On MRI∗ Corresponding author. Tel.: +32 478790144.E-mail address: pmzgvm@yahoo.com (P.J.L. De Visschere).hypoglycaemic damage has a typical distribution pattern,affecting most severely the parietal and occipital lobes ofthe cerebral hemispheres [3,4,6,7]. The importance of earlydiagnosis and appropriate management cannot be overem-phasized because neuroglycopenia in association with PHHIis a preventable cause of neurological handicap. We presenta case of a child in whom brain lesions are documented atthe age of 6 years after developing episodes of convulsionsat the age of 5.2. Case reportA 6-year-old boy was referred to the department of radi-ology for cranial magnetic resonance imaging investigation.He presents with episodes of convulsions two to three timesa day, developed since 1 year. The seizures manifest as focaljerking of the left leg and sometimes the left arm withoutlosing consciousness.He was born at 37.5 weeks after an uneventful preg-nancy and delivery. There was an initial normal postnatalcourse but shortly after birth the boy had repeated, pro-found hypoglycaemic episodes. Insulin levels were obtained1571-4675/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.ejrex.2007.01.005Author's   personal   copy36 P.J.L. De Visschere et al. / European Journal of Radiology Extra 62 (2007) 35–38and showed marked elevation, establishing the diagnosis ofpersistent hyperinsulinemic hypoglycemia of infancy. Pan-creatic venous sampling was consistent with diffuse formof PHHI. Treatment included intravenous glucagon andoctreotide. Diazoxide did not result effect. Because the hypo-glycaemic episodes had not abated, the infant underwent asubtotal pancreatectomy. Insulin levels at present are satisfy-ing. Octreotide (sandostatin) 3/day SC remains necessary tostabilize serum glucose levels with normal glucose uptake.Because of insufficient feeding pattern a gastrostomy wasinevitable. The convulsions are treated with tegretol sirupin combination with depakine. No initial MR neuroimagingstudies were obtained in the acute phase.Actual physical examination reveals normal growth andweight for his age. Neurological examination shows a poorequilibrium and a weak coordination and locomotor system.Initially there was a normal mental and motor development,but meanwhile he attends special education because of loco-motor difficulties.Electric encephalographic investigation shows regularepileptiformic grapho-elements, in both centroparietal lobesand on the right side in the temporo-occipital lobes.On axial FSE T2-weighted MR-images (Figs. 1–3) areasof abnormal high signal intensity are present in the deep andsubcortical periventricular white matter in the occipital andparietal lobes. The affected areas demonstrate hypointensitieson axial SE T1-weighted MR-images. (Fig. 4) At the samelevel there is marked thinning of the occipital and parietalFig. 1. Axial FSE T2 MRI. Areas of abnormal high signal intensity on T2weighted MR images are seen in the deep and subcortical periventricularwhite matter of the occipital and parietal lobes (arrows). There is markedthinning of the occipital and parietal cortex (arrowheads).Fig. 2. Axial FSE T2 MRI. Areas of abnormal high signal intensity on T2weighted MR images are seen in the deep and subcortical periventricularwhite matter of the occipital and parietal lobes (arrows).Fig. 3. Axial FSE T2 MRI. Areas of abnormal high signal intensity on T2weighted MR images are seen in the deep and subcortical periventricularwhite matter of the occipital and parietal lobes (arrows). There is markedthinning of the occipital and parietal cortex (arrowheads).Author's   personal   copyP.J.L. De Visschere et al. / European Journal of Radiology Extra 62 (2007) 35–38 37Fig. 4. Axial FSE T1 MRI. The affected areas in the deep and subcorticalwhite matter in the occipital and parietal lobes demonstrate hypointensitieson T1 weighted MR images (arrows). The posterior horns of the lateralventricles are dysmorphic and enlarged (arrowheads), due to tissue loss inthe parietal and occipital cortex.cortex resulting in dysmorphic and enlarged posterior hornsof the lateral ventricles, compatible with tissue loss. The basalganglia and cerebellum appear normal. There is no deviationof the midline.3. DiscussionPersistent hyperinsulinemic hypoglycemia of infancy isa clinically, pathologically and genetically diverse syndromereferring to a group of genetic disorders that result in impairedregulation of insulin secretion in the -cells of the pancreas[1]. It is a very rare disease with an estimated annual incidenceof 1/30,000 to 1/50,000 live births. In isolated communitieswith high rates of consanguinity the incidence is much higherand may affect as many as 1 in 2500 live births, especiallyin the Arabian peninsula [2,5]. Although the majority of thecases occur sporadically, several genetic defects have beendescribed [1,5,8]. Two clinically indistinguishable forms ofthe disease have been identified by pathologists: a diffuse anda focal form.Hypoglycemia is not uncommon and episodes of hypo-glycaemia can be seen in up to 8% of low-risk neonates[3,6,9]. Hypoglycemia during the neonatal period can resultfrom a variety of metabolic and endocrine disorders of fastingadaptation [1,2]. Persistent hyperinsulinemic hypoglycemiaof infancy is the most common cause of persistent or recurrenthypoglycaemia [1–4].Patients with PHHI are usually born at term with normalor low birth weight. Most cases present within the first fewdays of life with severe prolonged hypoglycaemia [4], resis-tant to glucagon therapy. Symptoms are often non-specificand include refusal to feed, irritability, hypothermia, sweat-ing, floppiness, lethargy, somnolence, brief myoclonal jerks,respiratory distress, cyanosis, apnea and seizures [1,5,6]. Insevere cases of life-threatening hypoglycaemic attacks, comaand neonatal death may occur [5].Neuroglycopenia in association with PHHI increases therisk of brain atrophy and permanent brain damage [8]. Neu-rological handicap may affect up to 20% of infants who havesuffered from PHHI [2]. Hypoglycemic injury to brain tissuecan cause mental retardation, cerebral palsy, seizure disorder,microcephaly, spasticity and ataxia [1,3,6]. Caraballo et al.describe a series of 15 patients with occipital lobe epilepticsyndromes following neonatal hypoglycemia [10]. Sever-ity of the hypoglycaemia and delayed initial treatment arethought to be a f ctor that increases the risk of developmentaldelay [1].MRI is the neuro-imaging technique of choice to detectbrain damage in PHHI [9]. In numerous cases of persistenthypoglycaemic hypoglycaemia MRI reveals no abnormal-ities. During or immediately after the acute episode ofprolonged hypoglycaemia, diffuse brain edema may be seen[4]. Traill et al. describe two cases of neonatal hypoglycaemiain which MRI shows edema in the parieto-occipital cortexand underlying white matter in the acute phase and profoundatrophy of these regions in the chronic phase [11].The brain lesions on neuroimaging studies in childrenwith prolonged neonatal hypoglycaemia are rather typical,affecting the parietal and occipital lobes of the cerebral hemi-spheres most severely. Alkaly et al. reviewed 23 cases ofneonatal hypoglycaemia and found that in 82% the occipi-tal lobes were involved [12]. The damage consists of diffusebilateral symmetrical lesions exhibiting an atrophic characterand involving both the cortex and underlying white mat-ter [3,4,6]. In most cases the cerebral white matter changesare mild, Mori et al. however present a case in which thisdamage was extensively and severely [13]. The lesions aredetected on MRI images as hyperintensities on T1-weightedimages [9]. In severe cases progressive parenchymal loss isdescribed with predominantly occipital involvement, show-ing hypointense areas resembling infarction and dilatationof the occipital horns of the lateral ventricles [9]. In somepatients the brain damage is more extensive, extending intothe posterior portions of the frontal lobes and involving theglobus pallidus [3]. Occasionally the deep gray matter struc-tures (putamen, caudate nucleus) may be involved as well [4].Brain damage seems to be more severe with longer durationof the hypoglycaemic episode [12].Long-term follow up studies after repeated episodes ofhypoglycaemia show diffuse brain atrophy and areas ofAuthor's   personal   copy38 P.J.L. De Visschere et al. / European Journal of Radiology Extra 62 (2007) 35–38cystic degeneration in the affected parietal and occipitallobes. If focal parenchymal abnormalities were present ini-tially, these may develop into laminar cortical necrosisand/or encephalomalacia-like lesions [3,4]. Spar et al. reportparenchymal loss or hypodensities in the occipital regions inthe late period [7].The differential diagnosis of this pattern of neonatal braindamage detected by neuroimaging studies is not very exten-sive. Severe sagittal sinus thrombosis can cause bilateralparamedian brain injury, however the thrombosed sinus canbe identified by MRI. Bilateral posterior cerebral arterycompression may cause occipital infarction but the patternis different than that seen in hypoglycaemic brain injury[3]. Neonatal hypoxic-ischemic injury sometimes causes thesame pattern of damage as hypoglycaemic damage.The parietal-occipital lobe pattern of brain injury in PHHIis nearly identical to that of several other causes of hypo-glycaemia [3,4]. This suggests that the pattern of damageprincipally reflects injury from hypoglycaemia and not that ofan underlying disorder such as anoxic-ischemic encephalopa-thy. However delineation of hypoglycaemic brain injury as adistinct condition is complicated as hypoxia and/or asphyxiaare frequently coinciding [3,4]. Hypoxia and/or asphyxiapotentiate the deleterious effects of hypoglycaemia on theneonatal brain, and vice versa [4]. Moreover in hypoxic-ischemic injury there is diminished cardiac output, leading toischemia and resultant lack of oxygen and glucose deliveryto the brain. Thus, ischemic and hypoglycaemic injury aresuperimposed [3].The cause of the changes in T1 and T2 signal intensi-ties on MRI arising from the damaged cerebral cortex ismost likely the same as in hypoxic-ischemic injury. Likelypossibilities include calcification, petechial hemorrage andmyelin degradation [3]. Hypoxic/ischemic conditions patho-logically represent reaction of glial cells and macrophages tohypoxia [9]. Neuropathological observations suggest that themost superficial layers of the cortex are primarily involvedin hypoglycaemia-induced cortical injury, whereas predom-inantly the intermediate and deep layers of the cortex areaffected in hypoxemic lesions. Lesions in the ‘watershed’areas are characteristically in hypoxia-ischemia [11]. Unfor-tunately currently available spatial resolution of MRI doesnot allow imaging differentiation of these histopathologicalchanges [4].Differences in the pattern of hypoglycaemic versushypoxic-ischemic injury are probably due to the ability of thebrain to utilize alternative energy sources (f.e. lactate) and themaintenance of cardiac output and cerebral perfusion in thecase of hypoglycaemia. Glucose is the primary energy sourcefor the brain and must be supplied continuously, because thebrain has little or no reserve stores of glycogen. This makesthe brain vulnerable to damage in cases of hypoglycaemia.Hyperinsulinism is especially likely to cause hypoglycaemicbrain damage, because insulin blocks the production of alter-native fuels that might sustain brain metabolism, such asketones [1,14].The reason that the parietal and occipital lobes are pref-erentially affected is not obvious [3,6,12,14]. The pattern ofdamage does not correspond to the regions with the highestglucose metabolism, indicating that it is not a simple mat-ter of demand and supply of glucose as an energy source[3,6]. Some investigators postulated that selective occipitalvulnerability may be related to intense axonal migration andsynaptogenesis, which occurs within the occipital lobes dur-ing the neonatal period [7,9,12,15]. According to Alkaly etal. during the neonatal period the posterior circulation struc-tures of the brain are more metabolically active than thoseof the anterior circulation [12]. It has also been hypothesizedthat high metabolic turnover during early life predisposes thisarea to injury as occurs in mitochondrial diseases [10]. Otherinvestigators suggest that additional contributing factors mayrelate to a regional developmental deficit in expression orfunction of the glucose membrane transporter proteins [14].References[1] Steinkrauss L, Lipman TH, Hendell CD, et al. Effects of hypoglycemiaon developmental outcome in children with congenital hyperinsulinism.J Pediatr Nurs 2005;20(2):109–18.[2] Lindley KJ, Dunne MJ. Contemporary strategies in the diagnosis andmanagement of neonatal hyperinsulinemic hypoglycaemia. J Earl HumDev 2005;81:61–72.[3] Barkovich JA, Ali FA, Rowley HA, Bass N. Imaging patterns of neona-tal hypoglycemia. AJNR 1998;19:523–8.[4] Patay Z. Metabolic disorders. In: Tortori-Donati P, editor. Pediatricneuroradiology brain, vol. 651. Springer; 2005. p. 696–7.[5] Kaczirek K, Niederle B. Nesidioblastosis: an old term and a new under-standing. World J Surg 2004;28:1227–30.[6] Avenarius HA, Versteege CWM, Engelshove HA. Cerebral damage dueto neonatal hypoglycaemia. JBR-BTR 2003;86:136–7.[7] Spar JA, Lewine JD, Orrison WW. Neonatal hypoglycemia: CT andMR findings. AJNR 1994;15:1477–8.[8] Nachum Z, Ben-Shlomo I, Rakover Y, et al. Early brain atrophyin persistent hyperinsulinemic hypoglycaemia of infancy. J Pediatr2002;141(5):706–9.[9] Kinnala A, Rikalainen H, Lapinleimu H, et al. Cerebral magneticresonance imaging and ultrasonography findings after neonatal hypo-glycemia. Pediatrics 1999;103:724–9.[10] Caraballo RH, Sakr D, Mozzi M, et al. Symptomatic occipitallobe epilepsy following neonatal hypoglycaemia. Pediatr Neurol2004;31:24–9.[11] Traill Z, Squier M, Anslow P. Brain imaging in neonatal hypogly-caemia. Arch Dis Child Fetal Neonatal Ed 1998;79:F145–7.[12] Alkaly AL, Flores-Sarnat L, Sarnat HB, et al. Brain imaging findingsin neonatal hypoglycaemia: case report and review of 23 cases. ClinPediatr 2005;44:783–90.[13] Mori F, Nishie M, Houzen H, et al. Hypoglycemic encephalopathywith extensive lesions in the cerebral white matter. Neuropathology2006;26:147–52.[14] Filan PM, Inder TE, Cameron FJ, et al. Neonatal hypoglycaemia andoccipital injury. J Pediatr 2006;148:552–5.[15] Aslan Y, Dinc H. MR findings of neonatal hypoglycemia. AJNR1997;18:994–6.

Brain injury due to persistent hyperinsulinemic hypoglycemia of infancy

De Visschere, PieterGE32UZGent0019974248088020023092420000-0002-4842-787785878622-C7A5-11E5-9231-2975B5D1D7B1

Seynaeve, PatrickUGent802000194642976003760234F955AB34-F0ED-11E1-A9DE-61C894A0A6B4

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https://biblio.ugent.be/publication/908528/file/908535.pdf

Brain injury due to persistent hyperinsulinemic hypoglycemia of infancy

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