DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY CASE REPORT

Hemimegalencephaly: what happens when children get older?

NICKY WU1 | FELIPPE BORLOT1 | ANFAL ALI1 | TIMO KRINGS2 | DANIELLE M ANDRADE1

1 Division of Neurology, Epilepsy Genetics Program, Toronto Western Hospital, Krembil Neuroscience Centre, University of Toronto, Toronto, ON;2 Division of Neuroradiology, Department of Medical Imaging, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada.

Correspondence to Danielle M Andrade, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada. E-mail: danielle.andrade@uhn.ca

PUBLICATION DATA

Accepted for publication 16th December

2013.

Published online 5th February 2014.

ABBREVIATION

HME Hemimegalencephaly

AIMS Hemimegalencephaly (HME) is a rare congenital malformation of cortical development,

usually associated with developmental delay and severe epilepsy. This condition has rarely

been reported in adults. The aim of this study was to examine and compare neurological

findings in adult patients with HME.

METHOD We retrospectively examined adult patients with HME by evaluating the presence of

neurocutaneous disorders, current cognitive development, seizure control, and

documentation of therapies for seizure management and outcomes.

RESULTS Five patients were included in the study (three males, two females; mean age 23y

9mo [SD 6y 1mo], range 18–34y). Four patients had HME that was associated with

neurocutaneous syndromes and the remaining patient had isolated HME. Two patients

required surgical treatment for seizures in childhood. One patient had no intellectual

disability, while one had mild, and three severe intellectual disability. All patients presented

motor deficits ranging from mild hemiparesis in two patients to non-ambulation in one

patient. Patients in whom seizure onset occurred after the 7 years of age had better seizure

control and psychomotor development in adulthood than patients in whom seizure onset

occurred in the first year of life.

INTERPRETATION In our small sample of adults with HME, age at seizure onset, cognitive

disability, and seizure control were found to be associated.

Hemimegalencephaly (HME) is an uncommon congenitalmalformation of the brain characterized by the over-growth of one hemisphere. The enlarged hemisphereexhibits hamartomatous characteristics with dysplastic anddisorganized cell arrangements and atypical cell morpho-logy.1

The clinical picture varies depending on the severity ofthe malformation; however, HME patients typically exhibitrefractory epilepsy.2 Other clinical manifestations includemacrocephaly, colpocephaly, global developmental delay,intellectual disability, hemibody hypertrophy, and hemipa-resis.3 HME may present alone or in association with neu-rocutaneous syndromes, such as epidermal naevus and itssubtypes (i.e. linear naevus sebaceous syndrome and pro-teus syndrome), Klippel–Tr�enaunay–Weber syndrome,neurofibromatosis, or hypomelanosis of Ito.1–4

The pathogenesis of HME is probably related to errone-ous cell signalling during fetal development,1–3,5 possiblydue to genetic chimerism leading to discrepancy betweenthe affected and the unaffected hemispheres.6–8 Chimerismis a possible pathogeic model for isolated HME and neuro-cutaneous syndromes, given the similarities in clinical, neu-roradiological, and histopathological presentation of bothconditions. If two cell lineages arise from the neuralcrest progenitor cell line, one exhibiting normal cellular

physiology and the other abnormal cellular physiology,then different migration patterns could be observed. Thisexplains how skin lesions appear in neurocutaneoussyndromes and an enlarged hemisphere in patients withHME. Additionally, overgrowth of a hemisphere and epile-ptogenesis might be present if the affected cell line exhibitsmutations in the pathways regulating cell proliferation,such as the Wnt/b-catenin9 or phosphoinositide 3-kinase-AKT3-mTOR signalling pathway,8,10 or modified expres-sion of phospho-S67 ribosomal protein, interleukin 1b, andneuropeptide Y.10

While HME is well described clinically in infants andchildren, little has been reported on the long-term evolu-tion of this disorder into adulthood. The aim of this caseseries was to examine and compare neurological findings inadult patients with HME.

METHODSParticipantsAll patients with HME were seen at the Adult TertiaryEpilepsy Centre at the Toronto Western Hospital, Univer-sity of Toronto. Participants were selected based on thefollowing inclusion criteria: (1) age over 18 years; and(2) HME diagnosis confirmed by magnetic resonance imag-ing (MRI) showing diffuse enlargement of one hemisphere.

© 2014 Mac Keith Press DOI: 10.1111/dmcn.12390 905

Patients were excluded if (1) they had not been assessed inthe last 12 months; or (2) there was no clear documenta-tion of seizure frequencies since onset, antiepileptic drugs,or neurosurgeries.

Data collectionWe conducted a retrospective chart review collectingdemographic data, associated conditions, current seizurefrequency, treatments, cognitive evolution, magnetic reso-nance reports and imaging, and neuropathology reports ofpatients who had undergone surgery. Cognitive evolutionwas determined by examining the patients’ history forattention deficits, learning disabilities, or cognitive delay(according to neuropsychologist reports), and if they werefollowing a modified academic curriculum, such as lifeskills or special education programmes. Positive cognitiveevolution was defined as the absence of neurobehaviouraldisorders during adulthood or transition into a regular aca-demic curriculum. This study was approved by theresearch ethics board of the University Health Network.

RESULTSOut of 1750 patients in the Epilepsy Clinic Database, fivequalified for the study (three males, two females, mean age23y 9mo [SD 6y 1mo], range 18–34y). All but one patientpresented global developmental delay in childhood. Threestarted having seizures within the first year of life, and twoafter 7 years of age. HME-associated conditions were hyp-omelanosis of Ito in three patients and linear naevus seba-ceous syndrome in one patient. The diagnosis of HMEwas made after epilepsy onset through neuroimaging (com-puted tomography, MRI, and angiography), confirming thepresence of an enlarged hemisphere with associated dilatedventricles to varying degrees. Other imaging findingsincluded loss of grey matter–white matter differentiation,heterotopias, and cortical enlargement (Fig. 1). Neuro-pathological examination of resected sections from patients3 and 4 revealed gross disorganization or loss of corticallamination with immature balloon cells and disorganizeddendrites (Table I).

Treatment with antiepileptic drugs did not result incomplete seizure control, except in patient 2, who experi-enced a seizure-free period of 14 years before her seizuresresumed at 22 years of age. At present, all patients are onantiepileptic drugs (mean number of drugs 2.2). Patientswith syndromic HME required polytherapy to managetheir seizures. Patients 3 and 4, with childhood seizure fre-quencies in excess of 15 seizures daily, underwent hemi-spherectomy at 9 and 2 years of age respectively. Althoughthese patients continue to experience seizures, seizure con-trol has significantly improved since surgical intervention.

Cognitive impairment in adulthood ranged from lowernormal cognition to severe impairments (Table I). Patient1 has completed high school, albeit following a modifiedcurriculum and is currently a volunteer; patient 2 was ableto complete secondary school on a regular curriculum andis currently attending college. Patients 3, 4, and 5 require

constant supervision for daily living activities; they under-stand only a few simple commands, and use few words tocommunicate.

Our sample of adult patients demonstrated that theremight be an association between age at seizure onset,seizure control, and cognitive disability. Patients with lessextensive brain abnormalities and seizure onset after7 years of age (patients 1 and 2) had better cognitive devel-opment and seizure control during adulthood than patientswith a seizure onset within the first year of life and exten-sive brain abnormalities (patients 3 and 4).

Patients 1 and 2 are able to perform simple work orvolunteer duties, while those with early-onset epilepsy aretotally dependent for activities of daily living. In addition,the patient who presented isolated HME (patient 2) exhib-ited the best prognosis in our sample, being the only oneto experience a long seizure-free period.

On examination, all patients exhibited some form ofmotor defect. Patients 1, 2, 4, and 5 exhibited hemiparesis.Patient 3 was the only non-ambulatory patient in ourcohort. This patient had a fractured left femur at 4 yearsof age, and subsequently experienced several orthopaediccomplications, which may have contributed to his non-ambulatory state.

DISCUSSIONHME is a malformation of cortical development with path-ological findings strongly suggestive of errors affecting allthree phases of neuronal development: cell differentiation/proliferation, neuronal migration, and organization. Theaffected hemisphere usually demonstrates cytomegalic/bal-loon cells, disoriented axons and dendrites, heterotopicneurons, and indistinct/absent cortical lamination.1,11,12

Interestingly, the contralateral, supposedly ‘normal’, hemi-sphere may also be atypical, and this fact may explainthe lack of complete seizure control in our two patientswho underwent hemispherectomy (Patient 3: Engelclass IVA; Patient 4: Engel class IIIA). For instance,non-affected hemispheres were found to present cerebralhypoperfusion and hypometabolism, indicating that theymight also have developed abnormalities in early develop-ment.13 Structurally, the supposedly ‘normal’ hemispherecan demonstrate atypical columnar cortical arrangement,3

possibly contributing to the persistence of seizures afterhemispherectomy.

Long-term outcome in hemimegalencephalyEarly seizure activity may be indicative of the severity ofthe brain overgrowth/dysplastic nature. In turn, the sever-ity of the structural abnormalities could explain the poorer

What this paper adds• This is the first study of the progression of hemimegalencephaly into adult-

hood.

• Patients with late-onset epilepsy may exhibit better seizure control duringadulthood.

• Non-syndromic and/or less extensive hemimegalencephaly is associated withbetter outcomes.

906 Developmental Medicine & Child Neurology 2014, 56: 905–909

outcome (regarding cognition and seizure control) ofpatients in whom seizure onset occurred in the first year oflife, compared with those with seizure onset after 7 yearsof age, in our series. Undoubtedly, neuronal developmentdefects are strongly associated with poor cognition andrefractory epilepsy, as seen in patients with polymicrogyriaand lissencephaly.11,14 Thus, maintaining proper neuronalmigration and cortical lamination to some degree may bebeneficial in facilitating cognitive development and attenu-ating seizure frequency. The effects of continuous seizureson a developing brain, however, may also contribute tocognitive problems in adulthood.

For instance, it has been found that, among childrenwith temporal lobe epilepsy, neuropsychological function is

poorer in those in whom onset occurred early than inthose in whom onset was later, a finding attributed to pro-longed exposure to seizures.15 Moreover, prolonged expo-sure to pharmacoresistant epilepsy can impair cognition. Ina cohort study of 198 children, pharmacoresistant epilepsywas associated with lower performance on cognitive tests.16

Review of the literature demonstrates that in the major-ity of patients with HME, seizure onset occurred betweenthe first days of life and 2 years 6 months.2,5,10,17–20 In rareinstances, however, individuals with HME have experi-enced seizure onset during adulthood. In such cases, sei-zures are usually mild and intelligence is normal.21,22

Indeed, one of our patients was able to complete highschool on a regular curriculum, obtain a college-level

a b c

d e f

g h i

Figure 1: Patient 1 – MRI with (a and b) axial T1-weighted scans and (c) coronal fluid attenuated inversion recovery (FLAIR)-weighted image. The greymatter–white matter transition within the right posterior lobe is ill defined on the FLAIR-weighted sequences. This is confirmed on the T1-weightedsequences where the grey matter–white matter interface is less defined and the white matter is more hypointense compared with the left side overthe entire right occipital lobe extending toward the parietal operculum. Patient 2 – MRI with (d, e, f) axial FLAIR-weighted scans. There is evidence foran ill-defined grey matter–white matter junction, slight hyperintensity of the white matter of the right parietal, frontal, and temporal lobes with sparingof the occipital lobe. Patient 4 – MRI with (g, h, i) T1-weighted scans showing prominent sulcus in the left parietal lobe extending to the periventricularregion; prominent sylvian fissure with coarsening of gyral pattern and mild dilation of the left lateral ventricle.

Case Report 907

TableI:

Dem

ographic

statistics,clinical

data,a

ndmag

netic

resona

nceimagingan

dne

uropatho

logy

repo

rtsin

aserie

sof

adultpa

tientswith

hemimeg

alencephaly

Patients

12

34

5

Age(y)/se

x23/m

ale

24/female

34/female

18/m

ale

20/m

ale

Ageatse

izure

onse

t7y

8y

2d

3mo

11mo

Psy

chomotor

development

Mildlanguagedelayed

Mildgloballydelayed

Severe

globallydelayed

Severe

globallydelayed

Severe

globallydelayed

Hemisphere

affected

Right

Right

Right

Left

Right

Associatedco

nditions

HypomelanosisofIto,

righthemibody

hypertrophy

None

HypomelanosisofIto,

severe

scoliosis

HypomelanosisofIto

Linearnaevusse

bace

ous

syndrome

Intellectualdisabilitya

Mild

None

Severe

Severe

Severe

Currentmedications

Carbamazepine,

topiramate,lamotrigine

Carbamazepine

Carbamazepine,so

dium

divalproex

Clonazepam,phenytoin

Sodium

divalproex,lamotrigine,

nitrazepam

Currentse

izure

status;

typesofse

izures

Threese

izurespermonth;

foca

lonse

tse

izures+foca

lonse

tse

izureswithse

condary

generalization

Seizure

free;previous

foca

lonse

tse

izures+foca

lonse

tse

izureswithse

condary

generalization

40–5

0se

izurespermonth;

foca

lonse

tse

izures

+foca

lonse

tse

izures

withse

condary

generalization

30–6

0se

izurespermonth;foca

lonse

tse

izures

Clusters

ofthreeorfourse

izures

every

6mo;foca

lonse

tse

izures+foca

lonse

tse

izures

withse

condary

generalization

Motorneurological

deficits

Left

mildhemiparesiswith

norm

altoneanddeep

tendonreflexes

Leftmildhemiparesiswith

norm

altoneanddeep

tendonreflexes

Non-ambulatory,bilateral

pyramidalsigns,

global

hyperreflexia,andankle

clonus

Righthemiparesiswith

pyramidalsigns

Left

hemiparesiswithpyramidal

signs.

Left-handdystonic

posture

Neurosu

rgical

interventionsperform

ed

None

None

Rightfunctional

hemispherectomy;

ventricle

peritonealsh

unt

Left

functionalhemispherectomy

andsu

bduralperitonealsh

unt

inch

ildhood;rece

ntly,

anatomicalleft

hemispherectomyand

calloso

tomy

None

Neuroim

agingand/or

neuropathologyreports

MRI:mildpach

ygyria

overrightparietaland

occipitalco

rtexandill-

definedgreymatter–

whitematterjunction

overtherighttemporal,

parietal,andoccipital

lobesb

MRI:theright-sidesh

ows

ill-definedgreymatter–

whitematterjunctionin

theparietal,frontal,and

temporallobes.

The

threedescribedlobes

exhibitedhyperintensity

ofthewhitematter

signalb

Neuropathologyreport:

rese

ctedse

ctions

showedhistological

findingsco

nsistentwith

hemim

egalence

phaly;

cerebralco

rtex

containinglargenumber

ofabnorm

allylarge

neurons;

chaotica

lly

neuronalorganization

withdendritespointing

invariousdirectionsand

noco

rticallaminationc

MRI:left-sided

hemim

egalence

phaly

with

extensiveinvolvementofleft

hemisphere

andrelativesp

aring

oftheoccipitallobe.

Neuropathologyreport:

rese

ctedse

ctionssh

owed

histologicalfindingsco

nsistent

withhemim

egalence

phaly;

disorderedco

rticallamination

andneuronalorientation,

balloonce

lls,

giantneurons,

abnorm

alitiesofneuronal

shapeandNissl

patterns,

poor

greymatter–whitematter

junction,gliosis,

andneuronal

heterotopia

inthewhitematter

MRI:prominentsu

lcusin

the

rightparietallobeextending

deeply

totheperiventricular

region,co

arseningofthegyral

pattern,andaprominent

primitivesy

lvianfissure;mild

dilatationoftherightlateral

ventricle

withheterotopic

grey

matteraroundtheanterior

horn;asy

mmetricaldeepwhite

matterin

rightce

rebral

hemisphere,greymatter–white

matterdifferentiationis

well

maintainedb

aCognitiveevolutionwasdeterm

inedbyexaminingthepatients’history

forevidence

oflearningdisabilitiesorco

gnitivedelay(accordingto

neuropsy

chologistreports),and/ormodified

aca

demic

curriculum,su

chaslife

skills

orsp

ecialeduca

tionprogrammes.

Mildintellectualdisability:patients

havetheabilityto

profiteduca

tionallywithin

aregularclass

withtheaid

of

considerable

curriculum

modifica

tionandsu

pportivese

rvices.

Moderate

intellectualdisability:patients

needco

nsiderable

support

inschool,athome,andin

theco

mmunityin

orderto

participate

fully.Theyca

nlearn

simple

healthandsa

fety

skills,andtheymaywork

inash

elteredworksh

op.Severe

intellectualdisability:patients

needmore

intensivesu

pport

andsu

pervi-

sionthroughouttheir

entire

life.Theymaylearn

someactivitiesofdailylivingandtheirIQ

isbelow

35.bNopathologyreportsare

available

since

these

patients

havenotundergoneany

rese

ctivesu

rgery.cNopre-surgicalMRIavailable.

908 Developmental Medicine & Child Neurology 2014, 56: 905–909

degree, and achieve seizure control for 14 years withmonotherapy. We believe her late seizure onset, isolatedHME presentation, and less extensive brain abnormalityresulted in her experiencing a better clinical outcome thanour other patients.

Isolated versus syndromic hemimegalencephalyHME may result from genetic chimerism tying neurocuta-neous syndrome into the clinical picture of HME.6–8 How-ever, while chimerism and mutations regulating cellproliferation would explain the association between HMEand neurocutaneous syndromes,8–10 the differences in theclinical severity of isolated HME compared with syndro-mic HME have not been widely addressed. Flores-Sarnat1,3

found the same clinical neurological, neuroimaging, andneuropathological features in isolated and syndromicHME.

In our sample of adult patients, of the two patients withlate-onset epilepsy, the one with isolated HME exhibited

a better clinical outcome. Obviously, larger cohorts ofadult patients must be studied to make any statistical asso-ciation.

CONCLUSIONHME progression into adulthood has rarely beendescribed. In our evaluation of five adult patients, a lessfavourable outcome was seen in those in whom seizureonset was earlier, probably reflecting the severity of thestructural malformations. Of the two patients with late-onset epilepsy, the one with isolated HME exhibited abetter clinical outcome than the patient with syndromicHME. In addition, despite a reduction in seizure fre-quency, hemispherectomy did not provide complete seizurecontrol. This may be related to abnormalities on the sup-posedly ‘normal’ contralateral hemisphere. We recognizethat our sample of patients is small, and further studies onadults with HME are necessary to better characterize thelong-term evolution of this condition.

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Case Report 909