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emimegalencephaly in aatient With a Neurocutaneous Syndrome

evin Chapman, MD, and Javier F. Cardenas, MD

A 5-year-old girl with a history of hypomelanosis of Ito and intractable epilepsy wasevaluated for possible resective surgery. Magnetic resonance imaging showed an enlargedright hemisphere, whereas electrographic seizures were arising from the right hemisphereor had a generalized onset. The patient was believed to be a good candidate for hemi-spherectomy, but the family was hesitant and started a modified Atkins diet. Her seizurecontrol has improved, but she continues to have weekly seizures. Hypomelanosis of Ito isa well-known cause of hemimegalencephaly and is often associated with intractableepilepsy and hemiparesis. Hemispherectomy can often be an effective treatment in intrac-table cases.Semin Pediatr Neurol 15:190–193 © 2008 Elsevier Inc. All rights reserved.

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he patient began having seizures at 8 months of age thatwere initially well controlled on medications in Mexico.

er seizures at the time of evaluation consisted of deviationf her head and eyes to the left with generalized tonic pos-uring progressing to clonic activity. These would last lesshan 1 minute and were occurring 2 to 3 times per day. Theatient was also experiencing brief, atonic seizures describeds either a head drop or falling to the ground if standing. Herother reported a gradual decline in the left hand, arm, and

eg function.The patient had an unremarkable prenatal and perinatal

ourse, except for abnormal skin pigmentation noted overhe right side of her body. She had global developmentalelay achieving independent ambulation at 19 months of agend speech at 23 months of age. She was previously evaluatedith magnetic resonance imaging (MRI) that was interpreted

s normal. High-resolution analysis of peripheral lympho-ytes and fibroblasts from skin biopsy failed to show anyhromosomal alteration.

On examination, she had linear areas of hypopigmentationffecting the right side of her body (Fig 1) and a mild leftemiparesis associated with increased deep tendon reflexes.he underwent a video electrocencephalographic monitoringtudy that captured 23 seizures. Two events consisted ofomplex partial seizures that appeared to arise from the rightemisphere, whereas 21 atonic seizures were associated with

rom the Division of Child Neurology, Barrow Neurological Institute and StJoseph’s Hospital & Medical Center, Phoenix, AZ.

ddress reprint requests to Kevin Chapman, MD, Division of Child Neurol-ogy, Barrow Neurological Institute, 500 West Thomas #400, Phoenix,

nAZ 85013. E-mail: Kevin.Chapman003@chw.edu

90 1071-9091/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.spen.2008.10.010

generalized electroencephalographic change. MRI imagingf the brain showed an asymmetry in the volume between theemispheres with the right hemisphere being larger than the

eft (Fig 2). These findings were interpreted as being consis-ent with right-sided hemimegalencephaly. Based on the pre-iously described studies, the patient was believed to be atrong candidate for a right functional hemispherectomy.

When presented with the option of hemispherectomy forheir daughter, the family decided to continue medical man-gement. The patient was begun on a modified Atkins dietith a reduction in her seizure frequency to 3 to 4 times pereek. She is tolerating the diet without significant side ef-

ects.

ypomelanosis of Itoypomelanosis of Ito (HI) was initially described in a 22-ear-old patient by Ito in 1952 and has been widely writtenbout in the literature.1 The skin manifestations consist ofypopigmented lesions frequently along the lines of Blaschkohat may be asymmetric and typically involve the arms, legs,nd trunk, while only rarely involving the head. The lesionsre often described as “whorled” or “zig-zag” in appearance inhe trunk or abdomen and can form a V-shape when crossinghe midline along the back. The lesions tend to be more linearlong the shoulders and extremities.2 The lesions may not bepparent at birth but typically appear by the second year ofife.3 The most common genetic association with HI is so-

atic chromosomal mosaicism; however, about one half ofatients in the literature do not have any demonstrable ge-

etic abnormality. Although peripheral lymphocyte karyo-

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Hemimegalencophaly 191

yping has identified mosaic abnormalities in some cases,aryotyping of fibroblasts from skin biopsies in affected andnaffected areas is often necessary for characterization. Men-elian transmission has been suggested through the pedi-rees of case reports, but there are no definitive loci, andonflicting modes of transmission argue against a simple mo-ogenic disorder.2

The overall prevalence of HI is unclear, but it has beenstimated to occur in 1 in every 8,000 to 10,000 patients in aospital setting and 1 in 82,000 in the general population.2

esides the apparent cutaneous manifestations, other abnor-alities may be seen, including ocular and craniofacial ab-ormalities, somatic asymmetry, cardiac malformation, andkeletal abnormalities.4 Mental retardation is frequently seenn patients with HI comprising between 57% and 70% in thearger series.3,4 Autistic features are often present in HI pa-ients with developmental delay. Seizures are frequently ex-erienced in patients with HI and seem to occur most com-only in the newborn and early childhood years. Nearly

0% of patients experience seizures, including partial, gen-

igure 1 Images of the linear hypopigmented skin findings in theatient. (Color version of figure is available online.)

ralized, or infantile spasms.3-5 As in our case, patients may i

e refractory to medical therapy, and epilepsy surgery may ben effective treatment.

Neuroimaging often detects abnormalities within therain, although there is no specific or constant malformationeen in HI. A nonspecific abnormal T2 signal in the whiteatter has been seen in 12% to 50% of patients and do not

ppear to progress over time.5 Malformations of cortical de-elopment, hemispheric atrophy, porencephaly, and agene-is of the corpus callosum have also been reported in patientsith HI.2 Hemimegalencephaly has often been describedith HI and may be either ipsilateral or contralateral to the

kin abnormalities.6

The diagnosis of HI is based on typical cutaneous findings.ther disorders that may mimic HI include incontinentiaigmenti and nevus depigmentosus. The former can be ex-luded by the progression through different clinical stagesnd an X-linked dominant mode of inheritance. The latteronsists of localized, nonlinear, congenital lesions that do notvolve and are not associated with extracutaneous alter-tions.2,3 Neuroimaging and electrophysiologic testing is notoutinely indicated and should be guided by clinical historynd presentation. The skin findings do not warrant any spe-ial treatment.

emimegalencephalyemimegalencephaly is a rare overgrowth affecting 1 hemi-

phere and often leading to intractable epilepsy and othereurologic abnormalities. Hemimegalencephaly was initiallyescribed in the autopsy series of Sims in 1835.7 Since then,emimegalencephaly has been described numerous times inase reports and small series, but its incidence and prevalenceas not been described.Neuroimaging of hemimegalencephaly typically shows

ignificant enlargement of 1 hemisphere that may be associ-ted with dysplastic cortex, whereas other patients have al-ost normal appearing imaging with slight asymmetry of the

entricular system. Four abnormalities of the ventricular sys-em on imaging have been described: (1) straightening of therontal horn of the lateral ventricle, (2) mild to extreme dila-ion of the lateral ventricle, (3) reduced size of the lateralentricle suggesting mass effect, and (4) colpocephaly of theccipital horns of the lateral ventricle.7

Pathologic studies have found a variety of abnormalitiesffecting neuronal size, density, and laminar architecture.bnormal laminar architecture has varied from a simplistic-layered cortex consistent with lissencephaly to subtle lossf distinction of the gray white-matter junction and ectopiceurons.8,9 Various abnormal cell types can be found includ-

ng giant cytomegalic neurons, “balloon” cells, and enlargedlial cells. A persistent immature radial neuronal pattern haseen described in some studies.10 Some studies have sug-ested an increase in neuronal size associated with a decreasen cellular density, but this has been inconsistent.8

The underlying pathophysiology of hemimegalencephaly re-ains unclear. The formation of a megalencephalic brain may

ccur through more than one process—create more neurons or

nhibit the natural pruning of neurons during development (ap-

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192 Chapman and Cardenas

ptosis). The latter process has been seen in mice with muta-ions in caspase 9 leading to major cerebral malformations withnlargement of the brain mass but is not reported in humans.11

utations leading to increased expression of mouse �-catenin, aell-cycle regulatory protein, also lead to brain enlargementhrough an increase in the number of proliferative neuronalrecursors.12 The mTOR (mammalian target of rapamycin) pro-ein is a major regulator of cell growth and has been found to bepregulated in hamartoma syndromes such as tuberous sclero-is. Recently, neuropathologic studies in resected human hemi-egalencephaly tissue have shown expression of cyclin D1 and

hosphor-ribosomal S6 (PS-6) protein suggesting activation of r

he �-catenin and the mTOR protein pathways, respectively.13

ultiple genes have been identified as important for left-rightymmetry and may prove to be involved in the unilaterality ofemimegalencephaly.7

As expected, many patients with hemimegalencephalyresent for evaluation of recurrent seizures, developmentalelay, or hemiparesis early in infancy. Epilepsy associatedith hemimegalencephaly is often intractable to medical

herapy, requiring multiple medication trials and often con-inuing to hemispherectomy. Hemispherectomy generallyas favorable outcomes with reported seizure freedom rates

gure 2 MRI imaging showing hemispheric asymmetry with theght hemisphere being larger than the left. A, axial view; B, axialew; C, coronal view.

Firivi

anging from 40% to 71%. The remaining patients often have

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Hemimegalencophaly 193

significant improvement in seizure control.14,15 Hemi-pherectomy is usually safe in large series with the expectedemiparesis and homonymous hemianopsia. Less frequentomplications include hydrocephalus requiring shunting,leeding, infection, and rarely death. This case report dis-usses the unusual combination of Hypomelanosis of Ito andemimegalencephaly in a single patient with intractable ep-

lepsy. Numerous questions remain about the pathophysiol-gy of both of these syndromes, but this case highlights thathere may be a single underlying genetic cause leading tohese uncommon findings.

eferences1. Ito M: Studies on melanin. Incontinentia pigmenti achromians. A sin-

gular case of nevus depigmentosis systematicus bilateralis Tohoku JExp Med 55:57-59, 1952

2. Ruggieri M, Pavone L: Hypomelanosis of Ito: clinical syndrome or justphenotype? J Child Neurol 15:635-644, 2000

3. Ruiz-Maldonado R, Toussaint S, Tamayo L, et al: Hypomelanosis of Ito:Diagnostic criteria and report of 41 cases. Pediatr Dermatol 9:1-10,1992

4. Pascual-Castroviejo I, Roche C, Martinez-Bermejo A, et al: Hypomela-nosis of ITO. A study of 76 infantile cases. Brain Dev 20:36-43, 1998

5. Ruggieri M, Tigano G, Mazzone D, et al: Involvement of the white

matter in hypomelanosis of Ito (incontinentia pigmenti achromiens).Neurology 46:485-492, 1996

6. Battistella PA, Peserico A, Bertoli P, et al: Hypomelanosis of Ito andhemimegalencephaly. Childs Nerv Syst 6:421-423, 1990

7. Flores-Sarnat L: Hemimegalencephaly: Part 1. Genetic, clinical, andimaging aspects. J Child Neurol 17:373-384, 2002

8. De Rosa MJ, Secor DL, Barsom M, et al: Neuropathologic findings insurgically treated hemimegalencephaly: Immunohistochemical, mor-phometric, and ultrastructural study. Acta Neuropathol 84:250-260,1992

9. Robain O, Chiron C, Dulac O: Electron microscopic and Golgi study ina case of hemimegalencephaly. Acta Neuropathol 77:664-666, 1989

0. Takashima S, Chan F, Becker LE, et al: Aberrant neuronal developmentin hemimegalencephaly: Immunohistochemical and golgi studies. Pe-diatr Neurol 7:275-280, 1991

1. Kuida K, Haydar TF, Kuan C, et al: Reduced apoptosis and cytochromec–mediated caspase activation in mice lacking Caspase 9. Cell 94:325-337, 1998

2. Chenn A, Walsh CA: Regulation of cerebral cortical size by control ofcell cycle exit in neural precursors. Science 297:365-369, 2002

3. Aronica E, Boer K, Baybis M, et al: Co-expression of cyclin D1 andphosphorylated ribosomal S6 proteins in hemimegalencephaly. ActaNeuropathol 114:287-293, 2007

4. Kossoff EH, Vining EP, Pillas DJ, et al: Hemispherectomy for intractableunihemispheric epilepsy: Etiology vs outcome. Neurology 61:887-890,2003

5. González-Martínez JA, Gupta A, Kotagal P, et al: Hemispherectomy for

catastrophic epilepsy in infants. Epilepsia 46:1518-1525, 2005