Case report

Progressive hemispheric
shrinking in
hemimegalencephaly: a
possible role for seizurerelated neuronal loss
Francesca Becherini MD, Pathological Anatomy Section,
Surgery Department, Azienda Ospedaliera Universitaria
Pisana, University of Pisa;
Tiziana Pisano MD, Department of Child Neurology and
Psychiatry, IRCCS Fondazione Stella Maris, Pisa;
Maura Castagna MD, Pathological Anatomy Section, Surgery
Department;
Aldo Iannelli MD, Neuroscience Department, Azienda
Ospedaliera Universitaria Pisana, University of Pisa, Pisa;
Renzo Guerrini* MD, Pediatric Neurology Unit and
Laboratories, Children’s Hospital A. Meyer and University of
Florence, Florence, Italy.
*Correspondence to last author at Pediatric Neurology Unit
and Laboratories, Children’s Hospital A. Meyer and University
of Florence, viale Pieraccini 24, 50139 Florence, Italy.
E-mail: r.guerrini@meyer.it
DOI: 10.1111/j.1469-8749.2008.03003.x
Hemimegalencephaly (HME) is a developmental brain lesion
consisting of a unilateral enlarged, dysplastic, and often
highly epileptogenic cerebral hemisphere. Most patients
exhibit early onset intractable seizures, status epilepticus,
hemiplegia, hemianopsia, and developmental delay. Major
surgical procedures are advocated for limiting the devastating
consequences of epilepsy. We studied a female with HME,
early onset intractable seizures and recurrent status
epilepticus, in whom progressive hemiatrophy of the enlarged
hemisphere and normal growth of the contralateral
hemisphere, exceeding the size of the dysplastic hemisphere,
was demonstrated by magnetic resonance imaging.
Histopathology, following functional hemispherectomy at the
age of 7 years, demonstrated severe neuronal loss with an
elevated number of cells exhibiting the morphological and
biochemical features of apoptosis. Eighteen months after
surgery the patient was seizure-free (Engel class I) and
exhibited improved motor and language skills, alertness and
social behaviour. We hypothesize that nearly continuous
seizure activity might sustain seizure-induced brain injury in
the dysplastic hemisphere but causal heterogeneity and
associated anatomical factors may influence differently the
individual predisposition to atrophic changes.

Hemimegalencephaly (HME) consists of a unilateral enlarged
dysplastic cerebral hemisphere. Most patients exhibit early
onset intractable seizures, hemiplegia, hemianopsia, and
moderate to severe developmental delay.1
Through repeat magnetic resonance imaging (MRI) we
demonstrated progressive hemiatrophy of the enlarged
hemisphere in a female with HME and intractable, nearly
continuous seizure activity, and episodes of status epilepticus. Histopathology, following functional hemispherectomy,
performed at the age of 7 years, demonstrated severe neuronal loss. We hypothesize that severe and protracted seizure
activity might underlie atrophic changes in the dysplastic
hemisphere.
Method
CASE REPORT

The patient, an 8-year-old female, had refractory seizures that
started on her first day of life. At 2 days of age, MRI of the
brain revealed HME of the right hemisphere (Fig. 1). Facial
asymmetry, with the right side larger than the left, was
noticed after birth. Left hemiparesis became apparent at 3
months of age and severe developmental delay was noticed
in the first months of life. The patient could hold up her head
at 12 months, sit up at 18 months, shuffle at 3 years, and walk
with help at 4 years. Right gaze preference and left homonymous hemianopsia were evident. No language development
occurred.

See end of paper for list of abbreviations.

Developmental Medicine & Child Neurology 2008, 50: 553–557 553

Seizures exhibited different characteristics through age.
Early seizures were hypomotor, with pallor and staring
and appeared in series or in status from the first day of
life. Treatment with multiple drugs brought seizures down
to four to five episodes per day. From the age of 10
months, however, asymmetric spasms appeared, which
were not improved by drugs and were accompanied, from
the age of 18 months, by asymmetric tonic posturing
with hypermotor activity, screaming, and an expression of
fear, occurring while awake and asleep. Such hypermotor
seizures occurred in clusters on several occasions and,
from the age of 18 months to 22 months, in status epilepticus on three occasions. Seizure clusters and episodes of
status were followed by periods of reduced vigilance and
worsening of motor skills, lasting days or weeks. The origin of these was difficult to attribute with certainty to the
sedative effect of acute administrations of drugs, statusinduced cognitive regression, or both. Several antiepileptic
drug trials proved ineffective. Numerous electroencephalogram (EEG) recordings were obtained from the neonatal

period through childhood, showing severe slowing of
background activity on the left, with recurrent multifocal
seizure activity in the right hemisphere, intermingled with
bilateral, right predominant decremental events, followed
by low voltage activity of increasing voltage and decreasing frequency. We proposed hemispherectomy after first
seeing the patient at age 4 years but her parents were
initially reluctant.
Repeat MRI, performed at the age of 5 years, revealed that
the right dysplastic hemisphere had become smaller than the
contralateral, probably due to a combination of arrested
growth and atrophic changes. The right cerebellar hemisphere was mildly atrophic (Fig. 1). Cognitive assessment
(Behavior Assessment Battery2 [BAB] and Vineland Adaptive
Behaviour Scales3) was consistent with severe impairment.
Language production was limited to a few words. Visual
field assessment, by clinical examination, revealed right
hemianopsia. At 7 years of age, functional hemispherectomy was performed, with section of corpus callosum and
partial removal of the temporal and parietal lobe. Cognitive

a

a´

b

b´

c

c´

Figure 1: Magnetic resonance imaging of the brain at day 2 (a, b, c: 1T, a and b are T2-weighted axial section; c is a T1-weighted
coronal section) and at age 5 years (a¢, b¢,c¢: 1.5T, IR images; a’ and b’ are axial sections and c’ is a coronal section). In a, b, and
c, the right hemisphere (on the left-hand side) is larger than the right hemisphere and exhibits a simplified gyral pattern, with
thickened cortex and dilated ventricular horns. In b and c a dilated calvarium and midline shifting towards the right are also
obvious. In a¢, b¢, c¢ the right hemisphere is clearly smaller than the contralateral, the subarachnoid space is much enlarged on
the right; increased cortical thickening and an irregular, simplified gyral pattern are also apparent, especially in the posterior
quadrant. Some increase in width of cortical sulci is visible in the right cerebellar hemisphere, just beneath the tentorium, possibly due to reduced pressure from the overlaying cerebral hemisphere which is now raised.

554 Developmental Medicine & Child Neurology 2008, 50: 553–557

evaluation 6 months after surgery (BAB2 and Griffiths scales4)
revealed severe to moderate impairment, with verbal skills
being better preserved than visuo-perceptual skills. The
patient was able to point to several alphabetical letters,
to repeat sounds of animals, and to use about 20 words.
Eighteen months after surgery the patient was seizure-free
(Engel class I), was able to move a few steps without support,
no longer neglected her left hand during bilateral movements, had increased her vocabulary to around 30 words,
and exhibited improved alertness and social behaviour.
Postoperative EEG showed normal activity on the left and
residual epileptiform discharges limited to the right occipital
region.
Informed consent for anonymous publication of this
patient’s case was obtained from the parents.

PATHOLOGY

After gross examination, the available portions of the temporal lobe and parietal lobe showed firm brain parenchyma,
with enriched meningeal vascularization and simplified gyral
pattern. The cortex was thickened and the cortical white matter boundaries were ill-defined. Formalin-fixed and paraffinembedded samples were obtained for light microscope
assessment and sections were cut for hematoxylin-eosin, and
luxol fast-blue staining techniques. Immunohistochemistry
(IHC) was performed using neurofilament (NF; 1:400), glial
fibrillary acidic protein (GFAP; 1:1000), synaptophysin
(1:500; Ventana Medical System Inc., Tucson, AZ, USA).
Microscopically, the brain tissue showed areas of agyria,
polymicrogyria, leptomeningeal, and periventricular heterotopia (Figs. 2a, 2b). At low-power magnification, widespread

a

b

c

d

e

f

g

h

i

Figure 2: Histological features of dysplastic cortex: (a) polymicrogyric cortex with fused molecular layers (Hematoxiline & Eosin
[H&E]), magnification 2.5x); (b) leptomeningeal heterotopia (H&E, 2.5x); (c) heterotopic glio-neuronal clusters in the deep white
matter (Luxol fast blu, 20x); (d) cyto-architectural dysplasia with ill-oriented, dysmorphic, giant neurons (Luxol fast blue, 40x);
(e) gliosis (glial fibrillary acidic protein, 20x); (f) anomalous dendritic processes and neurofilament accumulation in the cellular
body of dysmorphic neurons (NF, 40x); (g) immunohistochemistry (IHC) with caspase-3 in neurons and in glial cells in the deep
cortical layers, with a nuclear and cytoplasmic staining pattern (caspase-3, 10x); (h) same as in (g) but at higher magnification
(20x); (i) IHC with caspase-3 in the most superficial cortical layers, including the molecular layer (20x).

Case Report 555

cyto-architectural dysplasia was apparent: the horizontal lamination of the cortex had disappeared and heterotopic glioneuronal clusters were observed on the pial surface and in
the deep white matter (Fig. 2c). At high-power magnification,
ill-oriented, dysmorphic, giant neurons were scattered
throughout the cortex and intermingled with myelinated
fibres. Most neurons were pyramidal in shape, with the larger
elements lying in the deeper part of the cortex. Anomalous
dendritic processes or neurofilament accumulation were evident in the cellular body of dysmorphic neurons (Fig. 2d, 2e,
2f). Morphological signs of hypoxic–ischemic (HI) neuronal
damage were also present. In the cortex, gliosis and microcalcifications were associated with shrunken neurons with
cytoplasmic hypereosinophilia, nuclear pyknosis, and microglial satellitosis. Several oligodendrocytes with pyknotic
nuclei and some axonal spheroids were encountered in the
underlying white matter. To investigate further the nature of
HI damage, IHC was performed using a monoclonal antibody against cleaved caspase-3 (1:200) (#9661- Cell Signaling Technologies Inc., Danvers, MA, USA), as previously
described,5 and compared with non-epileptic autoptic brain
tissue. IHC with caspase-3 showed a high number of positive
cells in the patient’s brain with respect to control tissue, with
a mean of 60 positive cells per 20x magnification power field.
The immunereactivity was conspicuous in the dysplastic cortex, both in neurons and in glial cells. The staining pattern
was mostly cytoplasmic, but also involved dentritic branches
and glial fibres around capillaries (Fig. 2g, 2h, 2i).
Discussion
In this report we identified imaging and pathological findings
indicating that the dysplastic epileptogenic tissue of the
hemimegalencephalic hemisphere can undergo atrophic
changes and lose its highly characteristic enlarged size and
shape. Brain MRI performed at birth revealed HME but a
repeated brain imaging at 5 years of age demonstrated
remarkable shrinking of the dysplastic hemisphere. No further shrinking was detected on repeating MRI at 7 years of
age. Episodes of seizures in clusters and status epilepticus
had occurred in the first 2 years of life, between the first and
second scan, but not between the second and third.
It is difficult to establish whether hemispheric shrinkage
had any detectable clinical consequence in our patient. It
was not possible to determine when it had occurred exactly
and over how long it developed. In addition, the patient had
severe developmental delay, which would have made it difficult to detect mild clinical changes. We do not expect shrinkage of the dysplastic and dysfunctional hemisphere to
generate patent clinical changes, although one might argue
that cessation of episodes of status epilepticus after 3 years of
age might have been correlated to reduced intrinsic epileptogenicity, secondary to reduced ‘critical mass’. Yet, the deleterious consequences of ‘transmitted’ epileptic activity on
the healthy hemisphere were still operating after shrinking
had occurred, as can be inferred from the clinical benefits
observed after hemispherectomy.
Although no systematic follow-up imaging studies of HME
are available, we found reports of three cases in which either
atrophic changes or arrested growth of the hemimegalencephalic hemisphere were documented by repeated MRI.
Wolpert et al.6 observed a child in whom the hemimegalencephalic hemisphere, first seen in the fifth day of life, had

556 Developmental Medicine & Child Neurology 2008, 50: 553–557

become atrophic upon repeated brain MRI at 10 months of
age. Sakuma et al.7 documented HME in the second day of
life in a child with tuberous sclerosis, with subsequent progressive atrophy of a portion of the malformed hemisphere
on repeated imaging at age 6 months and 3 years 2 months.
In both patients the malformed hemisphere had become
smaller than the contralateral. An additional observation of
HME in a patient with tuberous sclerosis was reported by Parmar et al.8 These authors documented, between age 6 month
and 2 years 9 months, progressive loss in volume of the malformed hemisphere, which remained larger than the contralateral, and interpreted it as arrested growth, rather than
atrophy. Description of seizure characteristics and EEG correlates in these three cases differ in accuracy but, in general,
they indicate that the typical picture with severe seizures
starting from the first days or months of life, accompanied by
episodes of status, was present in all three patients and had
been fully expressed between the first and subsequent
scan(s). In none of these three patients could clinical or
imaging evidence of hypoxic, ischemic, vasculitic, infective,
or exogenous toxic factors be demonstrated. In all three
patients, poorly controlled seizures were hypothesized to
have contributed to progressive atrophic changes, and
arrested growth of the malformed hemisphere, although
pathology was not available for study.
In the patient reported here, neuropathological study of
the resected tissue, in addition to the classical cyto-architectural abnormalities of HME,9,10 uncovered morphological
signs of HI damage, possibly suggesting a role for a chronic
continuous insult in the pathogenesis of hypotrophy. A role
in seizure-induced neuronal damage in the human epileptic
brain, has been hypothesized for cell death regulatory genes,
such as B-cell leukaemia ⁄ lymphoma 2 (Bcl-2) and caspase, as
suggested by increased immunoreactivities for their products.11 Caspase-3 mediates neuronal apoptosis, which follows trophic factor withdrawal, exposures to inhibitors of
protein kinases or phosphatases, or HI brain injury.12 Using
cleaved caspase-3 IHC, we demonstrated an elevated number
of cells exhibiting the morphological and biochemical features of apoptosis. Excitotoxic cell death, caused by excessive
stimulation of excitatory amino acid receptors is considered
to be the fundamental process underlying HI neuronal damage and has been demonstrated in different models of seizures induced brain injury.13,14 Seizure-induced acute energy
deprivation leads to a cascade which leads to irreversible
neuronal injury and death through excessive release of extracellular glutamate, uncontrolled activation of the ionotrophic
glutamate receptors N-methyl-D-aspartic acid (NMDA),
Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid
(AMPA), and kainate, impaired energy-dependent re-uptake
of glutamate, and rise in intracellular Ca2+ concentration.9
Considering that HME is often accompanied by intractable
epilepsy with recurrent status epilepticus, the number of
reported cases of progressive hemispheric shrinking might
appear to be exiguous, should intrinsic epileptogenicity of
the malformed hemisphere be the sole causative factor. Different reasons may account for the rarity of this association.
First, most children with HME and intractable seizures do
not undergo repeat imaging studies because they are either
operated on early in life or no anatomical changes are
expected to occur over time. Therefore, the phenomenon may be underreported. Second, HME is causally

heterogeneous as suggested by its association with different
disorders including epidermal nevus syndrome, Proteus syndrome, hypomelanosis of Ito, type 1 neurofibromatosis, and
tuberous sclerosis,15 making it possible that only some
patients are anatomically predisposed to seizure-induced
brain damage. Third, different patients carry different
degrees of structural abnormality in the brain parenchyma
and outside it. For example, vascular dysplasia, with vascular
dilatations are observed in the affected hemisphere in about
40% of patients and can involve either deep or superficial
cerebral vessels, or both.16 Such associated vascular abnormalities might differently influence the susceptibility to, and
consequences of, seizure-induced brain injury.
Accepted for publication 19th October 2007.
References
1. Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB.
A developmental and genetic classification for malformations of
cortical development. Neurology 2005; 65: 1873–87.
2. Kiernan C, Jones M. Behaviour assessment battery: assessment
of cognitive, communicative and self-help skills of severely
handicapped children. Windsor: NFER Nelson, 1982.
3. Sparrow SS, Balla DA, Cicchetti DV. Vineland Adaptive Behaviour
Scales. Circle Pines, MN: American Guidance Service, 1984.
4. Griffiths R. The abilities of young children. London: University of
London Press, 1970.
5. Gown AM, Willingham MC. Improved detection of apoptotic
cells in archival paraffin sections: immunohistochemistry using
antibodies to cleaved Caspase-3. J Histochem Cytochem 2002;
50: 449–54.
6. Wolpert SM, Cohen A, Libenson MH. Hemimegalencephaly: a
longitudinal MR study. AJNR Am J Neuroradiol 1993;
15: 1479–82.

7. Sakuma H, Ohsuke I, Masayuki S. Longitudianl MR findings in
a patient with hemimegalencephaly associated with tuberous
sclerosis. Brain Dev 2005; 27: 458–61.
8. Parmar H, Patkar D, Shah J, Patankar T. Hemimegalencephaly
with tuberous sclerosis: a longitudibal imaging study. Australas
Radiol 2003; 47: 438–42.
9. Robain O, Floquet C, Heldt N, Rozenberg F. Hemimegalencephaly: a clinicopathological study of four cases. Neuropathol Appl
Neurobiol 1988; 14: 125–35.
10. Thom M. Epilepsy Part I: Hemimegalencephaly. In: Golden JA,
Harding B, editors. Developmental Neuropathology. Basel: ISN
Neuropath Press, 2004: 67–72.
11. Henshall DC, Clark RS, Adelson PD, Chen M, Watkins SC,
Simon RP. Alterations in bcl-2 and caspase gene family protein
expression in human temporal lobe epilepsy. Neurology 2000; 55:
250–57.
12. Tanaka M, Momoi T, Marunouchi T. In situ detection of activated
caspase-3 in apoptotic granule neurons in the developing
cerebellum in slice cultures and in vivo. Brain Res Dev Brain Res
2000; 121: 223–28.
13. Ben-Ari Y, Holmes GL. Effects of seizures on developmental
processes in the immature brain. Lancet Neurol 2006; 5: 1055–63.
14. Hossain MA. Molecular mediators of hypoxic–ischemic injury and
implications for epilepsy in the developing brain. Epilepsy Behav
2005; 7: 204–13.
15. Guerrini R, Marini C. Genetic malformations of cortical
development. Exp Brain Res 2006; 173: 322–33.
16. Sato N, Yagishita A, Oba H, et al. Hemimegalencephaly: a study
of abnormalities occurring outside the involved hemisphere.
AJNR Am J Neuroradiol 2007; 28: 678–82.

List of abbreviations
HI
HME
IHC

Hypoxic–ischemic
Hemimegalencephaly
Immunohistochemistry

Case Report 557