Arq. NeuroPsiquiatr. vol.68 número5

Arq Neuropsiquiatr 2010;68(5):816-818

816

Letter

Optic nerve enlargement

and leukodystrophy

An unusual inding of the infantile

form of Krabbe disease

Antonio Milton Lima Garcia1_{, Norma Martins Menezes Morais}1_, Lygia Ohlweiler1_{, Maria Isabel Bragatti Winckler}1_{, Josiane Ranzan}1_, Osvaldo Alfonso Pinto Artigalás2_{, Luise Lapagesse de Camargo Pinto}2_, Cristina Brinckmann Oliveira Netto3_{, Patrícia Ashton-Prolla}4_,

Leonardo Vedolin5_{, Rudimar dos Santos Riesgo}6_{, Newra Tellechea Rotta}7

Correspondence

Antonio Milton Lima Garcia Rua Dr Raul Lafayette 80 / 50 51021-220 Recife PE - Brasil E-mail: [email protected]

Received 6 September 2009 Received in final form 14 October 2009 Accepted 26 October 2009

ESPESSAMENTO DE VIAS ÓPTICAS E LEUCODISTROFIA: UM ACHADO POUCO FREQÜENTE DA FORMA INFANTIL DA DOENÇA DE KRABBE

1_{Pediatric Neurology Unit, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre RS, Brazil;} 2_{Genetic Department, HCPA;} 3_{Medical Genetic Service, HCPA;} 4_{Professor of the Genetic Department, HCPA;} 5_{Neuroradiology Department of Hospital}

Moinhos de Vento, Porto Alegre RS, Brazil; 6_{Pediatric Neurologist, Head of the Pediatric Neurology Unit, HCPA. Adjunct} Professor, Universidade Federal do Rio Grande do Sul, Porto Alegre RS, Brazil; 7_{Pediatric Neurologist, Adjunct Professor,} Universidade Federal do Rio Grande do Sul, Porto Alegre RS, Brazil.

Leukodystrophies are a heterogeneous group of inherited neurological disorders characterized by progressive demyelination that causes loss of motor, sensory and in-tellectual functions leading to a fatal out-come. These disorders result from dys-functions in myelin metabolism as a conse-quence of genetic enzymatic defects specif-ic to each leukodystrophy subtype1_{. Krabbe}

disease (KD), also called globoid cell leu-kodystrophy (GCL), is inherited in an auto-somal recessive pattern and has an estimat-ed incidence of 1 in each 100,000/200,000 live births. It afects the peripheral and cen-tral nervous system (CNS)2_.

We report on two cases of the infantile form of KD and describe MRI indings that suggest optic nerve enlargement (ONE).

CASES

Case 1

A 6-month-old white female patient was hospitalized due to respiratory infec-tion symptoms. Her neuropsychological and motor development had been normal up to 3 months of age when she had bron-chiolitis followed by progressive loss of de-velopmental landmarks and slow progres-sion of spasticity, but no seizures. he pa-tient had a brother with a similar

neuro-logical condition that died at 6 months of age due to intestinal obstruction. Neuro-logical examinations revealed generalized hypertonicity of the 4 limbs and decreased muscle mass, irritability and inconsolable crying, increased phasic-type myotatic re-lexes and bilateral extensor plantar relex. Cerebrospinal luid was normal. Electro-encephalogram showed signs of severe dif-fuse encephalopathy. Brain CT findings were suggestive of difuse cerebral atrophy. MRI changes are described in Fig 1. Serum concentration of galactocerebrosidase was much lower than normal. he patient died due to respiratory complications.

Case 2

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Optic nerve enlargement in Krabbe disease Garcia et al.

total protein content. Brain CT scan showed bilateral symmetrical hyperdensities located in the thalami, corona radiata and caudate nucleus. MRI indings are described in Fig 2. Serum B-galactocerebrosidase was not detected.

In both cases, the parents signed an informed consent for this publication.

DISCUSSION

KD is associated with a defective gene in the 14q31 chromosome, which leads to a reduction in the produc-tion of galactosylceramidase, a lysosomal enzyme respon-sible for the hydrolysis of galactosylceramide into cer-amide and galactose3,4_{. Consequently,}

galactocerebrosi-dase, as well as galactosylsphingosine, which causes ce-rebral toxicity, accumulate in macrophages2_{. heir}

intra-cytoplasmic accumulation in macrophages and CSF cells leads to the formation of globoid cells, degeneration of oligodendrocytes, and, consequently, myelin deiciency and demyelination of white matter5_.

he onset of the infantile form of the disease, the most common subtype, occurs at about 6 months of age. In-fants usually present with neurodegenerative symptoms that progress to spastic quadriparesis, tonic spasms, ex-treme irritability, inconsolable crying, secondary blind-ness, progressive optic atrophy, and death usually due to severe respiratory infection at about the second year of life. he juvenile and adult forms are characterized by

in-sidious visual compromise, cognitive deterioration and gait disorders6-8_.

Brain CT scans in KD show characteristic hyperden-sities in the thalami, the corona radiata, the body of the caudate nucleus, the cerebellum and the brainstem3,9_.

Cal-ciications or globoid cell grouping may hypothetically ex-plain the appearance of such images, but the real patho-genesis keep unexplained10_.

MRI shows signal abnormalities of similar distribu-tion. Hypointense signs in T2-weighted images and hy-perintense signs in T1-weighted images are seen in the early stages of the disease, but they later progress into hy-perintense lesions on T2-weighted images, which suggest defective myelination and demyelization9_{. In the}

cerebel-lum, the dentate nucleus and the white matter are typi-cally afected. Clear cerebral and cerebellar atrophy can be seen in the late stages of the disease11_.

Recent case reports described MRI scans of the spinal cord of patients with KD and found, after contrast injec-tion, difuse enhancement at the nerve roots of the lum-bar spine and low thoracic spine, which suggests the com-promise of CNS at this level3,12_.

Histological indings reported in pioneering studies conducted in the last century showed optic nerve enlarge-ment (ONE) in KD, particularly in its initial phase1,13,14_.

ONE, which was found in the brain MRI scans of our two patients, was also described in recent studies that stressed

Fig 1. Krabbe disease. T1- and T2-weighted and FLAIR images

show important reduction of brain volume, difuse reduction of thickness of periventricular white matter marked by hyperinten-sity of periventricular signal in T2 sequences [A]. Chiasm [C] and optic nerve [B and D] enlargement are also seen.

Fig 2. Krabbe disease. T1- and T2-weighted and FLAIR images

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Optic nerve enlargement in Krabbe disease Garcia et al.

the importance of these radiological indings1-3,15_.

Hitt-mair et al. reported on the association of this inding with hypertrophy of other intracranial nerves15_.

he following disorders should be included in the dif-ferential diagnosis of KD: optic nerve glioma with dur-al ectasia, frequently in type 1 neuroibromatosis; nerve sheath meningioma; granulomatous or histiocytic inil-tration of optic nerves, leukemia, orbit pseudotumor, ju-venile xanthogranuloma, post viral optic neuritis; optic nerve medulloepithelioma; and retinoblastoma with op-tic nerve compromise9_.

Spectroscopic indings in KD may include a low N-acetylaspartate (NAA) concentration, choline peaks (Cho), and an abnormally high Cho:NAA ratio in white matter. his relects the presence of difuse axonal de-generation and the proliferation of glial cells2_{. Marked}

in-creases in the inositol (Ins)-to-NAA ratio is a sign of ele-vated astrocytosis in cerebral white matter6_.

Evaluation of the degree of anisotropy in the white mat-ter of patients with KD using a new imaging method, difu-sion tensor MR imaging (DTI), suggests that this method may detect changes in white matter earlier than MRI16,17_.

he diagnosis of KD is challenging because of the large number of demyelinating diseases and leukodystrophies, as well as the similarities between their clinical and im-aging indings. Speciic neuroimim-aging indings may help to establish this diagnosis. he detection of ONE on MRI scans, not found in other types of leukodystrophies, is an auxiliary tool in the diferential diagnosis of KD.

In a pacient with the clinical features of a metabolic dis-ease, KD should be the main diagnostic hypothesis when-ever there is evidence of ONE, particularly when associat-ed with their typical intracranial neuroimaging indings.

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