UNIFESP-EPM Department of PediatricsFederal University of São Paulo Department of Neurology and Neurosurgery Division of Child NeurologyHospital Heliopolis Department of RadiologyFederal University of São Paulo EPM Department of Neurology and NeurosurgeryUNIFESP, EPM, Department of PediatricsUNIFESP, Department of Neurology and Neurosurgery Division of Child NeurologyUNIFESP, EPM, Department of Neurology and NeurosurgerySciEL

Arita, Juliana Harumi

Faria, Eliete Chiconelli

Lin, Jaime

Masruha, Marcelo Rodrigues

Peruchi, Mirella Maccarini

Vilanova, Luiz Celso Pereira

Arquivos de Neuro-Psiquiatria

Faria, Eliete Chiconelli [UNIFESP]

Arita, Juliana Harumi [UNIFESP]

Peruchi, Mirella Maccarini [UNIFESP]

Lin, Jaime [UNIFESP]

Masruha, Marcelo Rodrigues [UNIFESP]

Vilanova, Luiz Celso Pereira [UNIFESP]

LAReferencia - Red Federada de Repositorios Institucionales de Publicaciones Científicas Latinoamericanas

Leucoencefalopatia cística sem megalencefalia

Repositório Institucional UNIFESP

Arq Neuropsiquiatr 2008;66(2-A):261-263 261CYSTIC LEUKOENCEPHALOPATHY WITHOUT MEGALENCEPHALYEliete Chiconelli Faria1, Juliana Harumi Arita1, Mirella Maccarini Peruchi2,  Jaime Lin3, Marcelo Rodrigues Masruha4, Luiz Celso Pereira Vilanova5LEUCOENCEFALOPATIA CÍSTICA SEM MEGALENCEFALIADivision of Child Neurology / Department of Neurology and Neurosurgery, Federal University of Sao Paulo, Sao Paulo SP, Brazil (UNIFESP-EPM): 1Resi-dent, Department of Pediatrics, UNIFESP-EPM; 2Resident, Department of Radiology, Hospital Heliopolis, Sao Paulo SP, Brazil; 3Resident, Division of Child Neurology / Department of Neurology and Neurosurgery, UNIFESP-EPM; 4Associated Physician, Division of Child Neurology / Department of Neurology and Neurosurgery, UNIFESP-EPM; 5Professor and Chairman, Division of Child Neurology / Department of Neurology and Neurosurgery, UNIFESP-EPM.Received 14 September 2007, received in final form 29 November 2007. Accepted 4 February 2008.Dra. Eliete Chiconelli Faria – Rua Jacinto de Lima Santos 263 - 03738-090 São Paulo SP - Brasil. E-mail: e.faria@ig.com.brThe coming of magnetic resonance imaging (MRI) into clinical practice added advances in understanding the white matter diseases in children1. Previously, white mat-ter and metabolic diseases were found to have a relative-ly specific pattern that could help in differential diagnosis, and primary defects in many inborn leukoencephalopa-thies have been elucidated including disorders from lysos-somal storage, amino and organic acids, muscle and mito-chondrial dysfunction1,2. Recent reports have described an apparently non-progressive condition characterized by se-vere psychomotor delay with variable degrees of tone and reflex abnormalities, normo- or microcephaly, and MRI findings consisting of bilateral anterior temporal cystic le-sions with pericystic abnormal myelination and symmetric patchy lesions with increased signal in the frontal and oc-cipital periventricular white matter regions3. Few patients with this condition have been described in literature1-4. In some aspects, this condition may resembles other leuko-encephalopathies such as “megalencephalic leukoenceph-alopathy with subcortical cysts” and “leukoencephalopa-thy with vanishing white matter”, due to the presence of subcortical cysts and white matter abnormalities, howev-er, the clinical presentation and other neuroimaging fea-tures are distinct3.We describe the clinical, laboratory and neuroimaging characteristics of a patient with this rare entity.CASEA one-year-old boy was born to healthy and non-consan-guineous parents at 36 weeks of gestation. There was no family history of neurological diseases. Birth weight was 2,2 kg (25–50th centile), length 45 cm (25–50th centile) and head circumference 31 cm (below 5th centile). Apgar indices were 6 and 9 (at one and ten min). Right after birth, he had transient respiratory discom-fort and hypomagnesaemia with no further complications and he was discharged at the third day of life. It was already record-ed that this child was hypotonic, with poor movements and ad-ducted thumbs since the first weeks of life. He also presented a delay in neuropsychomotor acquisitions. The infant was admit-ted in our service at the age of 12 months. On examination he presented good overall condition with a head circumference of 44 cm (below 5th centile). Neurological examination revealed a good contact with the examiner but he did not either fix on or catch an offered object. It was also observed increased limb muscle tone, brisk tendon reflexes in contrast with axial and ap-endicular hypotonia. Evaluation of cranial nerves was normal.Hematological tests and blood screening for metabolic dis-eases, including those for concentrations of very long-chain fat-ty acids, lactate and pyruvate, gave results in the normal ranges. Cerebrospinal fluid lactate concentration was normal. Serolog-Fig 1. CT image shows well-circumscribed low attenuation lesions in the temporal lobes. Arq Neuropsiquiatr 2008;66(2-A)262Encephalopathy without megalencephalyFaria et al.ical markers for CMV, herpes virus, toxoplasmosis and syphilis were undetectable.Brainstem auditory evoked potentials detected severe bilat-eral sensorineural deafness and electroencephalogram showed discrete disorganized background activity with an epileptiform activity in the median line.Noncontrast-enhanced cranial computed tomography (CT) revealed hipoatenuation of parietal white matter and well-cir-cumscribed temporal subcortical cysts bilaterally (Fig 1). MRI showed bilateral lesions with signal intensity that is isointense to the one of cerebrospinal fluid in both temporal lobes, compati-ble with cysts (Fig 2) and patchy areas of high signals intensity in the white matter of temporal, frontal and parietal lobes (Fig 3).Although the patient presented severely handicapped he al-so continued to make slow developmental progress in motility, speech, and cognitive function.The hospital ethic commission approved this case report and the parents gave informed consent for publication.DISCUSSIONCystic leukoencephalopathy without megalencephaly was first described by Olivier et al. in 1998 and since then, fewer than 30 cases have been described4. The distinctive findings of this rare condition are bilateral temporal lobe cysts combined with a specific pattern of multifocal white matter lesions, normo- or microcephaly, and severe psy-chomotor retardation in a non-progressive clinical course2,3.Considerable effort has been done into distinguishing these patients from another leukoencephalopathy known as “megalencephalic leukoencephalopathy with subcorti-cal cysts” (MLC)3,5. Firstly described in 1995, this entity is characterized by dramatic MRI changes including a typical pattern of diffuse white matter lesions and swelling with invariable frontoparietal and anterotemporal subcortical cysts, but mild clinical manifestations initially, develop-ment of macrocephaly and functional deterioration later in course2,3,6. Mutations in MLC1 gene have been shown to cause MLC, although there are patients with the condition in whom mutations of MLC 1 cannot be found2-5.In our patient, we did not perform MLC1 testing be-cause of its non-availability; however, clinical and neuro-imaging features of cystic leukoencephalopathy without megalencephaly are clearly distinct from MLC. Patients with cystic leukoencephalopathy without megalencephaly are severely involved from the beginning with a non-pro-gressive course, they have normal or small head circumfer-ence and MRI findings contrast to the patients with MLC.Another recently described cystic leukoencephalopa-thy called “childhood ataxia with central nervous system hypomyelination” (CACH) or “leukoencephalopathy with vanishing white matter” superficially resembles cystic leu-Fig 2. MRI, serial T1-weighted (A), T1-weighted after gadolinium injec-tion (B), fluid-attenuated inversion recovery (FLAIR) sequence (C) ax-ial images and T2-weighted sagital image (D) show bilateral lesions with signal intensity that is isointense to the one of cerebrospinal flu-id in both temporal lobes, compatible with cysts. Fig 3. Axial FLAIR sequence from MRI shows patchy areas of high signals intensity in the white matter of temporal, frontal and parietal lobes.Arq Neuropsiquiatr 2008;66(2-A) 263Encephalopathy without megalencephalyFaria et al.koencephalopathy without megalencephaly7. Patients with CACH syndrome have extensively dramatic cystic changes in the cerebral white matter; however, the temporal lobes are not preferentially involved7. Furthermore, the clinical picture in CACH syndrome is characterized by a mild ini-tial course, with later deterioration and bouts of sudden decline in function associated with minor head trauma7.It was proposed that the MRI abnormalities found in cystic leukoencephalopathy without megalencephaly could be the result of congenital CMV infection and not a leukodystrophy8. Late CMV infection is one important condition to be considered in the differential diagnosis of cystic leukoencephalopathy without megalencephaly, once it could lead to microcephaly, retarded psychomo-tor development in a clinically static encephalopathy, and sensorial deafness1,8,9. Neonatal signs of intrauterine CMV infection include systemic signs of jaundice, hepato-splenomegaly and petechiae. Most commonly neurologi-cal impairment includes sensorineural hearing deficits and decreased vision caused by chorioretinitis. The severity of the neurological impairment may vary from mild learning, behavioral, and motor coordination problems to serious mental deficiency and motor handicap1,9. In CMV congeni-tal infection, MRI studies can be normal or demonstrate several abnormal findings such as cerebellar hypoplasia, disorders of neuronal migration and white matter abnor-malities including hemorrhage, calcifications and the pres-ence of anterior temporal lobe cysts. Those findings as a result of late infection (third trimester) can be regarded as a result of infection at a time when neuronal migration and cortical plate formation had already occurred result-ing in a more selective lesion of glial cells1,9,10.It is important to note that, in this case, both mother and the patient were tested for CMV with negative results. Additionally, in our patient neither signs of systemic CMV infection nor signs of calcifications, which are commonly associated with congenital CMV infection, were found. Therefore, according to serological, clinical, and neuroim-aging findings, CMV infection is extremely unlikely.In conclusion, we have reported a patient affected by non-progressive cystic leukoencephalopathy without megalencephaly. The identification of patients with this new white matter disease depends on the recognition of the characteristic of MRI findings of bilateral anterior temporal lobe cystic lesions, with abnormal myelynation in the pericystic region, and patchy symmetric white-mat-ter lesions. It is important to remember that this clinical condition, the neuroimaging confirmation is necessary to avoid mistaken with cerebral palsy.REFERENCES	 1.	 Gomes	AL,	Vieira	JP,	Saldanha	J.	Non-progressive	leukoencephalopa-thy	with	bilateral	temporal	cysts.	Eur	J	Ped	Neurol	2001;5:121-125.	 2.	 Henneke	M,	Preuss	N,	Engelbrecht	V,	et	al.	Cystic	leukoencephalop-athy	without	megalencephaly:	a	distinct	disease	entity	in	15	children.	Neurology	2005;64:1411-1416.	 3.	 Bodensteiner	JB,	Kerrigan	JF,	Johnsen	SD.	Leukoencephalopathy	with	bilateral	anterior	temporal	lobe	cysts.	J	Child	Neurol	2006;21:419-422.	 4.	 Olivier	M,	Lenard	HG,	Aksu	F,	Gärtner	J.	A	new	leukoencephalopathy	with	bilateral	anterior	temporal	lobe	cysts.	Neuropediatrics	1998;29:	225-228.	 5.	 Grosso	S,	Cerase	A,	De	Stefano	N,	et	al.	Non-progressive	leukoenceph-alopathy	with	bilateral	anterior	temporal	cysts:	a	case	report	and	re-view	of	the	literature.	Brain	Dev	2005;27:73-77.	 6.	 Van	der	Knaap	M,	Barth	P,	Stroink	H.	Leukoencephalopathy	with	swell-ing	and	discrepantly	mild	clinical	course	in	eight	children.	Ann	Neurol	1995;37:324-334.	 7.	 Schiffman	R,	Moller	J,	Trapp	B.	Childhood	ataxia	with	diffuse	central	nervous	system	hypomyelination.	Ann	Neurol	1994;35:331-340.	 8.	 Tatli	B,	Ozman	M,	Aydinli	N,	Caliskan	M.	Not	a	new	leukodistrophy	but	a	congenital	cytomegalovirus	infection.	J	Child	Neurol	2005;20:525-527.	 9.	 Van	der	Knaap	M,	Vermeulen	G,	Barkhof	F,	Hart	AA,	Loeber	JG,	Weel	JF.	Pattern	of	white	matter	abnormalities	at	MR	imaging:	use	of	poly-merase	chain	reaction	testing	of	Guthrie	cards	to	link	pattern	with	con-genital	cytomegalovirus	infection.	Radiology	2004;230:529-535.10.	 Barkovich	A,	Lindan	C.	Congenital	cytomegalovirus	infection	of	the	brain:	imaging	analysis	and	embryologic	considerations.	Am	J	Neuro-radiol	1994;15:703-715.

Eliete Chiconelli Faria

Juliana Harumi Arita

Mirella Maccarini Peruchi

Jaime Lin

Marcelo Rodrigues Masruha

Luiz Celso Pereira Vilanova

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Cystic leukoencephalopathy without megalencephaly Leucoencefalopatia cística sem megalencefalia

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Leucoencefalopatia cística sem megalencefalia

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