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Muscle - eye - brain disease

Authors:
Seetharam Raghavendra at Manipal Hospital
Seetharam Raghavendra
Bobby Devasia
Bobby Devasia
Bobby Devasia
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Sanjeev V Thomas
Sanjeev V Thomas
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49
Images in Neurology
Muscle - eye - brain disease
S. Raghavendra, Bobby Devasia, Sanjeev V. Thomas
Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum - 695011. India
For correspondence:
S. Raghavendra, Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum - 695011,
India. E-mail: raghus@sctimst.ac.in
A one-year-old girl, born of first-degree
consanguineous parentage, presented with motor
predominant global developmental delay. She had
no seizures or family history of similar illness.
Examination revealed a convergent squint, normal
head circumference, generalized hypotonia, normal
muscle bulk, and poor neck control and truncal
weakness. Limb power was well preserved. Deep
tendon relfexes were normal. The ophthalmic
examination showed a high myopia. Serum creatine
phospho kinase (CPK) was elevated at 1363 U/l.
Visual evoked potentials (VEP) showed normal P100
latency. Motor nerve conduction studies and EEG
were normal. Electromyography showed a
myopathic pattern. Muscle biopsy showed
myopathic changes with normal
immunohistocytochemistry.
Cranial MRI, showed disorganized cerebellar folia,
polymicrogyria and multiple subcortical cysts.
(Figures A, B) Cortical dysplasia was seen involving
both the parieto-occipital region. (Figure C) The
frontal lobes sulcations were abnormal. There was
abnormal diffuse symmetrical increased signal from
the white matter of all the lobes including the
subcortical U-fibres and the periventricular white
matter. (Figure D) There was marked hypoplasia of
pons, inferior vermis. The midbrain colliculi were
fused but corpus callosum was normal. (Figures A,
E) MR spectroscopy from the area of altered signals
was suggestive of hypomyelination. (Figure F)
Discussion
The clinical possibilities in this floppy infant with
delayed milestones and raised CPK includes muscle
eye brain disease (MEB), Walker-Warburg Syndrome
(WWS) and Fukuyama type congenital muscular
dystrophy (F-CMD). The extent of ocular
involvement can help to distinguish them to some
extent. Severe
malformations, including
malformation of the anterior chamber and persistent
primary vitreous, aretypical of WWS. Simple myopia
without structural changes
occurs in some FCMD
patients. The characteristic ocular malformation of
MEB is
that of progressive myopia, as seen in this
patient. The other manifestations include
strabismus, congenital glaucoma, lens opacity,
retinal hypoplasia or atrophy and optic atrophy. The
CNS abnormalities include severe mental
retardation, hydrocephalus and seizures. They can
have low or isoelectric retinograms due to the retinal
hypoplasia or atrophy. The VEP may be delayed but
giant (>50
µV) in amplitude.[1]
Figure 1: A. Coronal section showing disorganized cerebellar folia
with polymicrogyria, multiple subcortical cysts in the vermis,
cerebellum and cerebrum (short white arrows) with hypoplastic brain
stem (long arrow). B. Coronal section showing subcortical cysts in
the cerebral hemispheres, maximal in the temporal lobes (short
white arrow). C. Axial section T2WI. Cortical dysplasia involving
bilateral parieto-occipital region is seen as thick cortex and
heterotopia (arrow). D. Axial section T2WI. The frontal lobes have
bizarre shallow sulci. Mild ventriculomegaly and abnormal diffuse
symmetrical increased signal from the subcortical white matter
including the U-fibres and the periventricular white matter are
evident. E. The midline sagittal image shows marked hypoplasia of
pons, inferior vermis, fused midbrain colliculi and intact corpus
callosum. F. MR spectroscopy shows decrease in all metabolites
without any increase lactate suggestive of hypomyelination.
Annals of Indian Academy of Neurology - March 2006
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50
Patients with MEB have muscle weakness and
hypotonia at birth or during first few months of life.
Elevated CPK may occasionally be the only sign of a
muscular dystrophy. Electromyography (EMG),
raised CPK and muscle biopsy
findings were
compatible dystrophinopathy. MEB is a rare
autosomal recessive
disorder characterized by
congenital muscular dystrophy, structural
eye
abnormalities, and cortical neuronal migration
disorder, and type II (cobblestone) lissencephaly.[2]
Ventriculomegaly as observed in this patent or
communicating hydrocephalus is due to obliteration
of the subrachnoid space secondary to migration of
heterotopic young neurons beyond the marginal zone
(future layer I) leading to impaired absorption of the
CSF.[3]
The MRI findings of MEB disease, as seen in this
patient, include cerebellar polymicrogyria with
subcortical cysts, diffuse cerebral cortical dysplasia,
pontine and cerebellar vermian hypoplasia and
patchy hypomyelination. The cerebral cortex
showed frontal pachygyria with relatively less severe
gyral abnormalities in the occipital region. Other
features such as callosal hypogenesis, hydrocephalus
and absence of the septum pellucidum were not seen
in this patient. Other MRI features also may help to
distinguish between these three conditions. The
cerebellum is less involved than in Walker-Warburg
Syndrome, and the midline may be hypoplastic, but
hemispheres are usually normal. Cerebellar
polymicrogyria is associated with tiny cysts in the
cerebellum. Dandy-Walker malformation and
cephaloceles are not seen in MEB (these are features
seen in Walker- Warburg Syndrome). Diffuse
Raghavendra S, et al: Muscle - eye - brain disease
periventricular white matter changes that are
observed in late infancy may decrease in severity
with age.[5] The nodular cortical migration defect is
similarin MEB and FCMD; but the brain stem, which
is characteristically flatin MEB, is normal in FCMD.[6]
Clinical and MRI characteristics may help to
distinguish MEB from other autosomal recessive
congenital muscular dystrophies such as WWS and
F CMD. Estimation of CPK in all cases of
malformation of cortical development may pick up
more such cases since muscular dystrophy may often
be clinically subtle.
References
1. Santavuori P, Valanne L, Autti T, Haltia M, Pihko H, Sainio K
(1998) Muscle-eye-brain disease: clinical features, visual evoked
potentials, and brain imaging in 20 patients. Eur J Paed Neurol
1:41-7.
2. Santavuori P, Somer H, Sainio, K, Rapola, J, Kruus, S, Nikitin,
et al. (1989) Muscle–eye–brain disease (MEB). Brain Devl, 11,
147-53.
3. Bornemann A, Aigner T, Kirchner T. 1997. Spatial and temporal
development of the gliovascular tissue in type II lissencephaly.
Acta Neuropathol 93:173-7.
4. Gelot A, de Villemeur TB, Bordarier C, Ruchoux MM, Moraine
C, Ponsot G. 1995. Developmental aspects of type II
lissencephaly. Comparative study of dysplastic lesions in fetal
and post-natal brains. Acta Neuropathol 89:72-84.
5. Zolkipli Z, Hartley L, Brown S, et al. Occipito-temporal
polymicrogyria and subclinical muscular dystrophy.
Neuropediatrics 2003;34:92-5.
6. Haltia M, Leivo I, Somer H, Pihko H, Paetau A, Kivela T,
Tarkkanen A, et al. (1997) Muscle-eye-brain disease: A
neuropathological study. Ann Neurol 41:173-80.
Received: 28-12-05, Revised: 02-02-06, Accepted: 05-02-06
Annals of Indian Academy of Neurology - March 2006
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Pediatric neurodegenerative white matter processes: Leukodystrophies and beyond
Article
  • Aug 2008
Pediatric neurodegenerative white matter processes are complex, numerous and result from a vast array of causes ranging from white matter injury or inflammation to congenital metabolic disorders. When faced with a neurodegenerative white matter process on neuroimaging, the first step for the radiologist is to determine whether the findings represent a congenital metabolic leukodystrophy or one of various other white matter processes. In this review we first describe a general approach to neurodegenerative white matter disorders. We will briefly describe a few white matter diseases that mimic metabolic leukodystrophies. In the second half of the review we discuss an approach to distinguishing and classifying white matter leukodystrophies.
View
Muscle-eye-brain disease
Article
  • Dec 1998
  • EUR J PAEDIATR NEURO
Correspondence: Pirkko Santavuori, Hospital for Children and Adolescents, Department of Child Neurology, University of Helsinki, Lastenlinnantie 2, 00250 Helsinki, Finland.
View
Muscle-eye-brain disease (MEB)
Article
  • Feb 1989
  • BRAIN DEV-JPN
Clinical features of a rare congenital myopathy, muscle-eye-brain (MEB) disease, are described in 19 patients. The pedigree data suggest an autosomal recessive inheritance. The patients presented with congenital hypotonia and muscle weakness. Serum CK was elevated, EMG was myopathic and muscle biopsy showed slight or moderate changes compatible with muscular dystrophy. Ophthalmological findings included severe visual failure and uncontrolled eye movements associated with severe myopia. The flash VEPs were exceptionally high, whereas non-corneal ERG was unrecordable. The EEG showed progressive abnormalities after the age of 6 months. Psychomotor development was slow during the first years of life, and mental retardation was severe. Most patients began to deteriorate around age 5 years. This change included spasticity and joint contractures. CT scans showed ventricular dilatations and abnormally low white matter density in several patients. Spasticity, high VEPs and ocular manifestations differentiate MEB from the Fukuyama type congenital muscular dystrophy.
View
Developmental aspects of type II lissencephaly. Comparative study of dysplastic lesions in fetal and post-natal brains
Article
  • Feb 1995
We report neuropathological studies of five cases of type II lissencephaly from three fetuses and two infants. This comparative study allowed us to determine the developmental course of the cerebral lesions. Two distinct developmental events seem to generate this type of brain malformation: firstly, an early disturbance in cortex formation, which results both from a disorder of radial migration and a pial barrier disruption; secondly, a late perturbation of cerebral surface organization, resulting in fusion of the cerebral surface. All these features can be related to a primitive meningeal pathology, and more generally, to a neurocristopathy. Accordingly to our observations, this brain malformation appears during both migrational and post-migrational stages and may be considered more like a polymicrogyria than a lissencephaly.
View
Muscle-eye-brain disease: A neuropathological study
Article
  • Mar 1997
A combination of congenital central nervous, ocular and muscular abnormalities is characteristic of muscle-eye-brain disease (MEB), of Fukuyama congenital muscular dystrophy (FCMD), and of Walker-Warburg syndrome (WWS). The nosological relationship of these inherited malformative disorders is still unestablished, although the genetic locus for FCMD has been excluded in MEB. We present the first postmortem neuropathological study of MEB based on 2 male patients. Apart from sharply limited occipital agyric areas, their brains showed coarse gyri with an abnormally nodular surface ("cobblestone cortex"). Both the cerebral and cerebellar cortices showed a total disorganization without horizontal lamination. The haphazardly oriented cortical neurons formed irregular clusters or islands, separated by gliovascular strands extending from the pia. The ocular abnormalities included a pronounced glial preretinal membrane. Although MEB shares the cobblestone cortex-type malformation with FCMD and WWS, the cerebral and ocular manifestations are less severe than in WWS. Furthermore, a consistently weak staining for laminin alpha2 chain (merosin) was found in muscle biopsy specimens from 4 MEB patients, while normal immunoreactivity was observed for the laminin beta2 chain, reported to be severely deficient in WWS. These findings support nosological independence of MEB.
View
Spatial and temporal development of the gliovascular tissue in type II lissencephaly
Article
  • Mar 1997
Type II lissencephaly is a complex cortical malformation in which mesenchymal and central nervous components are intermingled. It is generally believed that the histological pattern is created by migration of heterotopic neuroblasts into the leptomeninges through defects in the superficial basement membrane. Defects of the extracellular matrix have been suggested to be the primary cause of type II lissencephaly. To elucidate the underlying pathogenetic mechanisms, we immunostained extracellular matrix and basement membrane components of the cerebral cortex from six fetal and two infantile brains. We found that the pattern of collagen subtypes I, III and VI was not altered in type II lissencephaly brains when compared to normal controls. As to the pathogenesis of type II lissencephaly, a polymicrogyria-like pattern is created, which results in considerable cortical enlargement. The microgyri do not fuse but remain separated from each other by gliovascular tissue, i.e., leptomeninges which contain astrocytes. At the interface between the enlarged brain surface and the gliovascular tissue, neuronal migration takes place through gaps in the external basement membrane. Thus, the cortical dysplasia encountered in type II lissencephaly is only due to a limited amount to neuronal heterotopia in the leptomeninges.
View
Muscle–eye–brain disease: clinical features, visual evoked potentials and brain imaging in 20 patients
Article
  • Feb 1998
  • EUR J PAEDIATR NEURO
Clinical features, magnetic resonance imaging and visual evoked potentials were analysed and correlated in 20 Finnish patients with muscle-eye-brain disease. Significantly enhanced visual evoked potentials were found in 15 patients (giant in 14 of them). Magnetic resonance images were available in 17 cases. The images of 12 patients with giant visual evoked potentials showed typical brain malformation pachygyria with a nodular cortical surface i.e. cobblestone cortex, midline defect and hypoplastic pons but no significant abnormalities in the grey-white matter. One male had typical structural changes but flat visual evoked potentials. His extreme hydrocephalus with optic nerve compression may explain the findings. No structural changes on magnetic resonance images were found in the remaining four patients; however, in two of them marked alterations in the white matter were found. Three of these patients showed normal and one flat visual evoked potentials. Only one patient with giant visual evoked potentials and typical structural findings on magnetic resonance imaging had changes in a large area in the white matter (several attacks of status epilepticus might have caused the alterations in the white matter). Thus, the combination of giant visual evoked potentials and typical structural changes on magnetic resonance imaging with normal intensities of white matter and deep grey matter seems to be a good marker for patients with muscle-eye-brain disease.
View
Occipito-Temporal Polymicrogyria and Subclinical Muscular Dystrophy
Article
  • May 2003
We report a two-year-old Caucasian boy who had neonatal seizures and was found to have bilateral occipito-temporal polymicrogyria on neonatal brain MRI. The child had no additional neurological abnormality other than the neonatal seizures, but serum CK was found to be elevated (5 - 7 times normal values) and the muscle biopsy showed evidence of early muscular dystrophy. Detailed protein and genetic studies did not allow the identification of a known form of muscular dystrophy. The boy has been followed regularly and he currently has mild global developmental delay but no clinical signs of muscle involvement. The association of polymicrogyria and muscular dystrophy is known to occur in Fukuyama and Walker Warburg muscular dystrophies, in muscle-eye-brain disease and in some patients with merosin deficient CMD. However the absence of weakness and of eye involvement, the normal expression of merosin and alpha dystroglycan and the pattern of brain involvement make it very unlikely that the child is affected by one of these forms. As the pattern of brain involvement and the muscle pathology is not typical of one of the forms of neuronal migration disorders secondary to a known gene defect, we suspect that the combination of muscle and brain involvement found in this child is not coincidental. Our findings suggest that serum CK should be determined in children with undiagnosed polymicrogyria, even in the absence of weakness. This may lead to an expansion of our understanding of muscle dystrophies and cortical dysplasias.
View