Partial Seizures in Two Cases of Metachromatic Leukodystrophy: Electrophysiologic and
Neuroradiologic Findings Michio Fukumizu, MD; Kiyoshi Matsui, MD; Shigeru Hanaoka, MD; Norio Sakuragawa, MD; Toru Kurokawa, MD
Abstract This report concerns two cases of metachromatic leukodystrophy presenting partial seizures. One was a 2-year-old boy with a late infantile type and the other a 17-year-old girl with a juvenile type. The former had tonic-clonic seizures on the left with concomitant twitching of the left side of the face and adversive conjugate deviation of the eyes. After a while, his interictal sleep electroencephalogram (EEG) showed spikes in the right central area. The second case had hemiconvulsions on the right side, consisting mainly of tonic flexion of the upper limb followed by clonic flexions, and accompanied by adversive conjugate deviation of the head and eyes. Her ictal EEG showed rhythmic 6- to 7-Hz wave bursts in the left frontal area. To this date, no report has given a detailed discussion of the type of seizures and ictal EEG in metachromatic leukodystrophy. In addition, there have been few detailed reports of magnetic resonance imaging (MRI) in the juvenile type. It is interesting that typical partial seizures were observed in a hereditary metabolic disorder characterized by diffuse demyelination of the white matter, and the pathophysiology is discussed here mainly in relation to MRI findings of the case with the juvenile type. (J Child Neurol 1992;7:381-386).
is
Metachromatic leukodystrophy lysosomal storage an
autoso-
mal recessive inherited
disorder caused by a deficiency of arylsulfatase A. Metachromatic leukodystrophy is characterized by diffuse demyelination in the white matter of the central nervous system and in the peripheral nerves. Metachromatic leukodystrophy is divided into three types: late infantile, juvenile, and adult.1 According to recent studies, clinical heterogeneity may reflect genetic heterogeneity.2 This report concerns two cases: one being of the late infantile type and the other of the juvenile type. Concerning the latter only three cases have been reported in Japan,3- and to
type,
Received August 9, 1991. Received revised Jan 6, 1992. Accepted for publication Jan 21, 1992. From the Division of Child Neurology (Drs Fukumizu, Matsui, Hanaoka, and Kurokawa), National Center Hospital for Mental, Nervous, and Muscular Disorders, and the Division of Inherited Metabolic Disease (Dr Sakuragawa), National Institute of Neuroscience, National Center of Neurology and Psychiatry,
Kodaira, Tokyo, Japan. Address correspondence
to Ur Michio lukumizu, Division ot Child Neurology, National Center Hospital for Mental, Nervous, and Muscular Disorders, Kodaira, Tokyo 187, Japan.
date, magnetic
resonance
imaging (MRI) findings
have been described in some reports, 6-10 including case reports from throughout the world. Although seizures are one of the clinical symptoms of the disease, details of the seizures have not been reported. Here we describe partial seizures in the two cases in relation to electrophysiologic and neuroradiologic
findings. Report
of Cases
Case 1 This patient was a 2-year-old Japanese boy. His elder sister had the same disease and died at the age of 5 years. The patient was born in a normal full-term spontaneous delivery. He began to walk at 11 months of age. He showed normal development until 1 year 10 months of age, when pes equinus was noticed when he was walking. At the age of 2 years, he was unable to walk or stand alone. He was diagnosed as having the late infantile type of metachromatic leukodystrophy through clinical findings and en0; zyme assay (arylsulfatase A in leukocytes, patient controls 53.7 ± 11.5 nmol/mg protein/hour). Motor and =
=
381
Downloaded from jcn.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 6, 2015
mental deterioration progressed rapidly and spastic tetraplegia became apparent. At 2 years 4 months of age, he began to have tonic-clonic seizures on the left side, with twitching of the face and adversive conjugate deviation of the eyes. His seizures worsened and became status epilepticus. They were then stopped by rectal diazepam. The interictal sleep electroencephalogram (EEG) showed intermittent rhythmic 7- to 8-Hz wavebursts, with spikes in the left frontal area and high-voltage slow waves dominant on the right hemisphere. There were diffuse low-density areas in the white matter on the brain computed tomographic (CT) scan. Cerebrospinal fluid showed that total protein increased to 78 mg/dL. Motor and sensory nerve conduction velocities were delayed. Latency between waves I and V of brain-stem auditory evoked potentials was prolonged on the left side. Although he was on phenobarbital, status epilepticus appeared again at the age of 2 years 6 months. The interictal sleep EEG at that time showed spike waves in the right central area (Figure 1). Additioned oral diazepam was administered, and the seizures did not develop thereafter. However, startle response gradually became apparent, and muscle tonus remarkably increased intermittently. He died of bronchopneumonia at 5 years 7 months of age. A postmortem sural nerve biopsy revealed marked degeneration of the myelin sheath and numerous inclusion bodies in the Schwann cells.
Case 2 The patient was a 17-year-old Japanese girl. Both of her brothers were normal. She was born in a full-term uncomplicated vaginal delivery. Early developmental milestones were normal until 6 years of age, when she became ex-
.
FIGURE 1 Interictal EEG of
case
1.
was observed, and she smiled less. She walked fast on pes equinus. At age 7 years, she was diagnosed as having juvenile type metachromatic leukodystrophy because of a deficiency of arylsulfatase A activity of the leukocytes (patient 4.8; controls 72.8 ± 23.7 nmol/mg protein/hour). She stopped walking alone at 8 years 5 months and stopped speaking at 8 years 6 months of age. Startle response, increased muscle tonus, and myoclonus on the left side of the body gradually appeared. She had frequent seizures for the first time at 17 years 3 months and was admitted to our ward. On admission, right hemiconvulsions characterized by longlasting tonic flexion of the upper right limbs and followed by a clonic phase were observed almost every 5 minutes. These seizures were accompanied by adversive conjugate deviation of the head and eyes and twitching on the right side of the mouth that lasted 40 to 60 seconds. The ictal EEG showed rhythmic 6- to 7-Hz wave bursts in the left frontal area at the beginning of the seizures (Figure 2). Intravenous phenytoin and oral acetazolamide were very effective in stopping the seizures. Cerebrospinal fluid examination revealed an increased total protein level of 60 mg/dL and a myelin basic protein level of less than 0.5 ng/mL (normal). The brain MRI revealed the following: a decrease in the volume of white matter including corpus callosum, with diffuse low-signal intensity dominant in the frontal white matter; entire atrophy dominant in the frontal lobe (right more than left), brain stem, and basal ganglia, with marked dilation of the frontal horns and third ventricle on the T1-weighted images; high signal intensity of the cerebral white matter, the cerebral peduncle, pars ventralis pontis, and periaqueductal area; prominently decreased signal intensity in the globus pallidus on the T2 weighted
tremely forgetful. Urinary incontinence
=
=
Spike waves appeared in the right central areas.
382
Downloaded from jcn.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 6, 2015
FIGURE 2 Ictal EEG of
case 2. (1) Seizure discharges of theta-range waves were observed in the left frontal area before the onset of a clinical seizure of the upper right limb. (2) The nature of the seizure gradually changed from tonic to clonic. (3) The seizure ended as the electromyogram indicated.
images; CT
scan
and
a relatively intact cerebellar white matter. The findings were almost the same as the Tl-weighted
and white matter on the CT scan was not enMotor nerve conduction velocity was delayed, especially in the lower extremities. Brain-stem auditory evoked potentials showed poor discrimination of each I-V wave and prolonged latency of each wave (left greater than right), and the threshold was increased to 80 dB on the left side. The I-V interval, however, was almost within normal limits. Central conduction time was normal on short-latency somatosensory evoked potentials. The blink reflex showed delayed Rl, R2, and R2’, and delayed response of direct stimulation on the facial nerve was seen. A positron emission computed tomographic (PET) scan at 15 years 2 months of age revealed decreased blood flow in the bilateral frontal areas.
images, hanced
(Figure 3).
Discussion
Hagberg’ subdivides the clinical course of late infantile metachromatic leukodystrophy into four stages. Case 1 at the time of the onset of seizures belonged to stage III. Case 2 was also at stage III. White matter is mainly involved, and the cerebral and cerebellar cortex, claustrum, putamen, caudate nucleus, and certain brain-stem nuclei tend to be spared in metachromatic leukodystrophy.11 Therefore, convulsions are observed at a relatively late stage. To date,
generalized convulsions,12,13 petit mal variant,14 petit mal, 15 hemiconvulsions,3 and astatic seizures5 have been reported. Partial seizures have not been described precisely in relation to electrophysiologic and computerized image findings in metachromatic leukodystrophy. In patients with metachromatic leukodystrophy with seizures, discharges in the EEG tended to be irregular, often with variable focal distribution, and on no occasion did regular spike-andwave complexes appear, regardless of the age of the child. 6 In white-matter diseases, the EEG character-
shows high-amplitude irregular delta activity, whereas in corticosubcortical gray-matter diseases, bisynchronous paroxysmal discharges consisting of rhythmic delta activity or bisynchronous spike-wave activity are described. 17 The regional selectivity of storage in metachromatic leukodystrophy differs from the diffuse storage in many other lipidoses. 18 The two cases presented here showed diffuse involvement of the white matter. Demyelination affects preferentially long tracts, which produces a delay in synaptic transmission, and conduction on corpus callosum may not be sufficient to produce secondary generalization. This may explain the reason for the occurrence of partial seizures. The MRI showed severe involvement of the white matter
istically
383
Downloaded from jcn.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 6, 2015
FIGURE 3
of case 2. A. CT (enhanced). The CT scan showed a decrease in the volume of the white matter, with diffuse low density dominant in the frontal white matter and marked dilation of the anterior horns and third ventricle. The white matter was not enhanced. B. MRI (coronal section; TR SE 2100; TE 100; field strength 2.0 T). The MRI showed atrophy of basal ganglia and prominently decreased signal intensity in the globus pallidus. C. MRI (coronal section; TR SE 2100; TE 100; field strength 2.0 T). The MRI showed a relatively intact cerebellum and a diffuse high signal intensity of the cerebral white matter. D. MRI (transverse section; TR SE 2100; TE 100; field strength 2.0 T). The MRI showed a high signal intensity of pars ventralis pontis.
Neuroradiologic findings
384
Downloaded from jcn.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 6, 2015
in the frontal area with a concentration on the right side, and the positron emission tomographic scan indicated a decreased flow in the bilateral frontal area. These findings were compatible with the discharge focus detected on the EEG of case 2. To date, there have been some reports of MRI
of
metachromatic leukodystroof the basal ganglia; involvement of the cerebral peduncle, pons, and periaqueductal area; and relative preservation in cerebellar white matter were noted in stage III of our case. A prominently decreased signal intensity in the globus pallidus on T2 weighted MRI scans was also observed in case 2. On the other hand, decreased signal level was mild in reticular substantia nigra, red nucleus, and dentate nucleus in case 2. A prominently decreased signal intensity in these regions was reported in correlation with normal distribution of brain iron in subjects ranging in age from 8 years to 76 years, by a high-field-strength MRI system.l9 The finding of globus pallidus in case 2 would be meaningful. In some patients with metachromatic leukodystrophy, the thalamus, the posterior limb of the internal capsule, the cerebellum, and the quad-
findings
juvenile
phy.6-1O Atrophy
rigeminal plate may have a shortened T2 and lengthened Tl, and these patients were suspected of having a higher level of microdispersed iron due to dopamine depletion.9,10 But concentration in iron may exist due to atrophic change of the globus pallidus in case 2, and globus pallidus has the most preferental iron accumulation in the brain. 9 Considering the above-mentioned facts, this finding may be within normal limits. Lesions in the basal ganglia and the brain stem have been rarely described.9,10 The field strength of MRI was 2.0 T in our cases, in contrast to 0.5 T in the majority of past reports. Differences in the resolving powers, clinical courses, and stages of the disease may explain our new findings. In the juvenile type, demyelination is more severe in the cranial portions and the peripheral nerves, but less in the pyramidal tracts of the brain stem and spinal cord. The degree of intensity on the T2-weighted images was higher in the white matter than in the cerebral peduncle and pons, a fact that is compatible with the pathology report. White matter in the cerebellum was, on the other
hand,
the T2-weighted images of case 2. However, the cerebellum has been said to be atrophic, with severe demyelination, prominent gliosis, and storage granules in late infantile type.21 Takashima et al reported that the cerebellum of both types showed a severe loss of myelin sheaths, Purkinje cells, and granular cells; proliferation of Berg-
relatively preserved
on
man
astrocytes; and torpedo formation, but that
with metachromatic granules in the white matter and torpedo formation in the cortex were seen less in the juvenile type than in the late infantile type.2° The MRI findings in case 2 may reflect these pathologic changes. Abnormality of evoked potentials and nerve conduction velocity revealed involvement of the brain stem as well as the cranial and peripheral nerves, a fact that coincides with the MRI findings. However, the normal central conduction time seen in case 2 may reflect a selectively preserved somatosensory pathway. This collaborative study of electrophysiologic and MRI examinations was useful in elucidating the pathophysiologic process of metachromatic leukodystrophy.
macrophages
References 1.
B: Clinical
Hagberg symptoms, signs and tests in metachromatic leukodystrophy, in Folch-Pi J, Bauer H (eds): Brain Lipids and Lipoproteins and the Leukodystrophies. Amsterdam,
Elsevier North-Holland, 1963, pp 134-146. 2. Andreas P, Arvan LF, Claire BF, et al: Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med
1991;324:18- 22. 3. Tanaka H, Arima M, Suzuki Y, Takahashi K: A case of the juvenile form of metachromatic leukodystrophy with low serum levels of β-lipoprotein and vitamin E [in Japanese]. Rinsho
Shinkeigaku 1975;15:355-364. Segawa M, Suzuki Y, et al: A case of juvenile metachromatic leukodystrophy [in Japanese]. No To Hattatsu
4. Mizuno Y,
1979;11:59-64. 5. Mizuno Y, Nakamura Y, Sugaya A, Komiya K: A case of juvenile metachromatic leukodystrophy—the third case in Japan. Brain Dev 1988;10:50-53. 6. Reider-Grosswasser I, Bornstein N: CT and MRI in late-onset metachromatic leukodystrophy. Acta Neurol Scand 1987;75: 64-69. 7. Fisher NR, Cope SJ, Lishman WA: Metachromatic leukodystrophy. Conduct disorder progressing to dementia.J Neurol
Neurosurg Psychiatry 1987;50:488-489. 8. Miller DH, Robb SA, Ormerod IEC, et al: Magnetic resonance imaging of inflammatory and demyelinating white-matter diseases of childhood. Dev Med Child Neurol 1990;32:97-107. 9. Valk J, Van der Knaap MS: Metachromatic leukodystrophy, in Valk J, Van der Knaap MS (eds): MR of myelin, myelination and myelin disorders. Berlin, Springer-Verlag, 1988, pp 68- 76. 10. Demaerel P, Faubert C, Wilms G, et al: MR findings in leu-
kodystrophy. Neuroradiology 1991;33:368-371. 11. Abraham K, Lampert P: Intraneuronal lipid deposits in metachromatic leukodystrophy. Histochemical and topographic observations. Neurology 1963;13:686-692. 12. Haltia T, Palo J, Haltia M, Icen A: Juvenile metachromatic leu-
kodystrophy. Clinical,
biochemical and
neuropathologic stud-
ies in nine new cases. Arch Neurol 1980;37:42-46. 13. Haberland C, Brunngraber E, Writting L, et al: Juvenile metachromatic leukodystrophy. Case report with clinical, histo-
385
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pathological, ultrastructural and biochemical observations. Acta Neuropathol 1973;26:93-106. 14. Toga M, Berard-Badier M, Pinsard N, et al: Étude clinique, histologique et ultrastructurale de quatre cas de leucodystrophie metachromatique infantile et juvénile. Acta Neuropathol
lates of gray and white matter lesions. Brain 1968;91: 779-802. 18. Friede RL: Metachromatic lukodystrophy (sulfatase A deficiency) and multiple sulfatase deficiency, in Friede RL (ed):
Developmental Neuropathology. Berlin, Springer-Verlag, 1989, pp 461-469.
1972;21:23-38. 15. Clark JR, Miller RG,
Vidgoff JM: Juvenile-onset
matic leukodystrophy. Biochemical and studies. Neurology 1979;29:346-353.
16.
17.
metachro-
19.
electrophysiologic
Mastropaolo C, Pampiglione G, Stephens R: EEG studies in 22 children with sulfatide lipidosis (metachromatc leukodystrophy). Dev Med Child Neurol 1971;13:20-31. Gloor P, Kalabay O, Giard N: The electroencephalogram in diffuse encephalopathies. Electroencephalographic corre-
20.
Drayer B, Burger P, Darwin R, et al: Magnetic resonance imaging of brain iron. AJNR 1986;7:373-380. Takashima S, Matsui A, Fujii Y, Nakamura H: Clinicopathological differences between juvenile and late infantile meta-
chromatic leukodystrophy. Brain Dev 1981;3:365-374. 21. Yamano T, Ohta S, Shimada M, et al: Neuronal depletion of cerebellum in late infantile metachromatic leukodystrophy. Brain Dev 1980;2:359-364.
386
Downloaded from jcn.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 6, 2015
Neuroradiologic Findings Michio Fukumizu, MD; Kiyoshi Matsui, MD; Shigeru Hanaoka, MD; Norio Sakuragawa, MD; Toru Kurokawa, MD
Abstract This report concerns two cases of metachromatic leukodystrophy presenting partial seizures. One was a 2-year-old boy with a late infantile type and the other a 17-year-old girl with a juvenile type. The former had tonic-clonic seizures on the left with concomitant twitching of the left side of the face and adversive conjugate deviation of the eyes. After a while, his interictal sleep electroencephalogram (EEG) showed spikes in the right central area. The second case had hemiconvulsions on the right side, consisting mainly of tonic flexion of the upper limb followed by clonic flexions, and accompanied by adversive conjugate deviation of the head and eyes. Her ictal EEG showed rhythmic 6- to 7-Hz wave bursts in the left frontal area. To this date, no report has given a detailed discussion of the type of seizures and ictal EEG in metachromatic leukodystrophy. In addition, there have been few detailed reports of magnetic resonance imaging (MRI) in the juvenile type. It is interesting that typical partial seizures were observed in a hereditary metabolic disorder characterized by diffuse demyelination of the white matter, and the pathophysiology is discussed here mainly in relation to MRI findings of the case with the juvenile type. (J Child Neurol 1992;7:381-386).
is
Metachromatic leukodystrophy lysosomal storage an
autoso-
mal recessive inherited
disorder caused by a deficiency of arylsulfatase A. Metachromatic leukodystrophy is characterized by diffuse demyelination in the white matter of the central nervous system and in the peripheral nerves. Metachromatic leukodystrophy is divided into three types: late infantile, juvenile, and adult.1 According to recent studies, clinical heterogeneity may reflect genetic heterogeneity.2 This report concerns two cases: one being of the late infantile type and the other of the juvenile type. Concerning the latter only three cases have been reported in Japan,3- and to
type,
Received August 9, 1991. Received revised Jan 6, 1992. Accepted for publication Jan 21, 1992. From the Division of Child Neurology (Drs Fukumizu, Matsui, Hanaoka, and Kurokawa), National Center Hospital for Mental, Nervous, and Muscular Disorders, and the Division of Inherited Metabolic Disease (Dr Sakuragawa), National Institute of Neuroscience, National Center of Neurology and Psychiatry,
Kodaira, Tokyo, Japan. Address correspondence
to Ur Michio lukumizu, Division ot Child Neurology, National Center Hospital for Mental, Nervous, and Muscular Disorders, Kodaira, Tokyo 187, Japan.
date, magnetic
resonance
imaging (MRI) findings
have been described in some reports, 6-10 including case reports from throughout the world. Although seizures are one of the clinical symptoms of the disease, details of the seizures have not been reported. Here we describe partial seizures in the two cases in relation to electrophysiologic and neuroradiologic
findings. Report
of Cases
Case 1 This patient was a 2-year-old Japanese boy. His elder sister had the same disease and died at the age of 5 years. The patient was born in a normal full-term spontaneous delivery. He began to walk at 11 months of age. He showed normal development until 1 year 10 months of age, when pes equinus was noticed when he was walking. At the age of 2 years, he was unable to walk or stand alone. He was diagnosed as having the late infantile type of metachromatic leukodystrophy through clinical findings and en0; zyme assay (arylsulfatase A in leukocytes, patient controls 53.7 ± 11.5 nmol/mg protein/hour). Motor and =
=
381
Downloaded from jcn.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 6, 2015
mental deterioration progressed rapidly and spastic tetraplegia became apparent. At 2 years 4 months of age, he began to have tonic-clonic seizures on the left side, with twitching of the face and adversive conjugate deviation of the eyes. His seizures worsened and became status epilepticus. They were then stopped by rectal diazepam. The interictal sleep electroencephalogram (EEG) showed intermittent rhythmic 7- to 8-Hz wavebursts, with spikes in the left frontal area and high-voltage slow waves dominant on the right hemisphere. There were diffuse low-density areas in the white matter on the brain computed tomographic (CT) scan. Cerebrospinal fluid showed that total protein increased to 78 mg/dL. Motor and sensory nerve conduction velocities were delayed. Latency between waves I and V of brain-stem auditory evoked potentials was prolonged on the left side. Although he was on phenobarbital, status epilepticus appeared again at the age of 2 years 6 months. The interictal sleep EEG at that time showed spike waves in the right central area (Figure 1). Additioned oral diazepam was administered, and the seizures did not develop thereafter. However, startle response gradually became apparent, and muscle tonus remarkably increased intermittently. He died of bronchopneumonia at 5 years 7 months of age. A postmortem sural nerve biopsy revealed marked degeneration of the myelin sheath and numerous inclusion bodies in the Schwann cells.
Case 2 The patient was a 17-year-old Japanese girl. Both of her brothers were normal. She was born in a full-term uncomplicated vaginal delivery. Early developmental milestones were normal until 6 years of age, when she became ex-
.
FIGURE 1 Interictal EEG of
case
1.
was observed, and she smiled less. She walked fast on pes equinus. At age 7 years, she was diagnosed as having juvenile type metachromatic leukodystrophy because of a deficiency of arylsulfatase A activity of the leukocytes (patient 4.8; controls 72.8 ± 23.7 nmol/mg protein/hour). She stopped walking alone at 8 years 5 months and stopped speaking at 8 years 6 months of age. Startle response, increased muscle tonus, and myoclonus on the left side of the body gradually appeared. She had frequent seizures for the first time at 17 years 3 months and was admitted to our ward. On admission, right hemiconvulsions characterized by longlasting tonic flexion of the upper right limbs and followed by a clonic phase were observed almost every 5 minutes. These seizures were accompanied by adversive conjugate deviation of the head and eyes and twitching on the right side of the mouth that lasted 40 to 60 seconds. The ictal EEG showed rhythmic 6- to 7-Hz wave bursts in the left frontal area at the beginning of the seizures (Figure 2). Intravenous phenytoin and oral acetazolamide were very effective in stopping the seizures. Cerebrospinal fluid examination revealed an increased total protein level of 60 mg/dL and a myelin basic protein level of less than 0.5 ng/mL (normal). The brain MRI revealed the following: a decrease in the volume of white matter including corpus callosum, with diffuse low-signal intensity dominant in the frontal white matter; entire atrophy dominant in the frontal lobe (right more than left), brain stem, and basal ganglia, with marked dilation of the frontal horns and third ventricle on the T1-weighted images; high signal intensity of the cerebral white matter, the cerebral peduncle, pars ventralis pontis, and periaqueductal area; prominently decreased signal intensity in the globus pallidus on the T2 weighted
tremely forgetful. Urinary incontinence
=
=
Spike waves appeared in the right central areas.
382
Downloaded from jcn.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 6, 2015
FIGURE 2 Ictal EEG of
case 2. (1) Seizure discharges of theta-range waves were observed in the left frontal area before the onset of a clinical seizure of the upper right limb. (2) The nature of the seizure gradually changed from tonic to clonic. (3) The seizure ended as the electromyogram indicated.
images; CT
scan
and
a relatively intact cerebellar white matter. The findings were almost the same as the Tl-weighted
and white matter on the CT scan was not enMotor nerve conduction velocity was delayed, especially in the lower extremities. Brain-stem auditory evoked potentials showed poor discrimination of each I-V wave and prolonged latency of each wave (left greater than right), and the threshold was increased to 80 dB on the left side. The I-V interval, however, was almost within normal limits. Central conduction time was normal on short-latency somatosensory evoked potentials. The blink reflex showed delayed Rl, R2, and R2’, and delayed response of direct stimulation on the facial nerve was seen. A positron emission computed tomographic (PET) scan at 15 years 2 months of age revealed decreased blood flow in the bilateral frontal areas.
images, hanced
(Figure 3).
Discussion
Hagberg’ subdivides the clinical course of late infantile metachromatic leukodystrophy into four stages. Case 1 at the time of the onset of seizures belonged to stage III. Case 2 was also at stage III. White matter is mainly involved, and the cerebral and cerebellar cortex, claustrum, putamen, caudate nucleus, and certain brain-stem nuclei tend to be spared in metachromatic leukodystrophy.11 Therefore, convulsions are observed at a relatively late stage. To date,
generalized convulsions,12,13 petit mal variant,14 petit mal, 15 hemiconvulsions,3 and astatic seizures5 have been reported. Partial seizures have not been described precisely in relation to electrophysiologic and computerized image findings in metachromatic leukodystrophy. In patients with metachromatic leukodystrophy with seizures, discharges in the EEG tended to be irregular, often with variable focal distribution, and on no occasion did regular spike-andwave complexes appear, regardless of the age of the child. 6 In white-matter diseases, the EEG character-
shows high-amplitude irregular delta activity, whereas in corticosubcortical gray-matter diseases, bisynchronous paroxysmal discharges consisting of rhythmic delta activity or bisynchronous spike-wave activity are described. 17 The regional selectivity of storage in metachromatic leukodystrophy differs from the diffuse storage in many other lipidoses. 18 The two cases presented here showed diffuse involvement of the white matter. Demyelination affects preferentially long tracts, which produces a delay in synaptic transmission, and conduction on corpus callosum may not be sufficient to produce secondary generalization. This may explain the reason for the occurrence of partial seizures. The MRI showed severe involvement of the white matter
istically
383
Downloaded from jcn.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 6, 2015
FIGURE 3
of case 2. A. CT (enhanced). The CT scan showed a decrease in the volume of the white matter, with diffuse low density dominant in the frontal white matter and marked dilation of the anterior horns and third ventricle. The white matter was not enhanced. B. MRI (coronal section; TR SE 2100; TE 100; field strength 2.0 T). The MRI showed atrophy of basal ganglia and prominently decreased signal intensity in the globus pallidus. C. MRI (coronal section; TR SE 2100; TE 100; field strength 2.0 T). The MRI showed a relatively intact cerebellum and a diffuse high signal intensity of the cerebral white matter. D. MRI (transverse section; TR SE 2100; TE 100; field strength 2.0 T). The MRI showed a high signal intensity of pars ventralis pontis.
Neuroradiologic findings
384
Downloaded from jcn.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 6, 2015
in the frontal area with a concentration on the right side, and the positron emission tomographic scan indicated a decreased flow in the bilateral frontal area. These findings were compatible with the discharge focus detected on the EEG of case 2. To date, there have been some reports of MRI
of
metachromatic leukodystroof the basal ganglia; involvement of the cerebral peduncle, pons, and periaqueductal area; and relative preservation in cerebellar white matter were noted in stage III of our case. A prominently decreased signal intensity in the globus pallidus on T2 weighted MRI scans was also observed in case 2. On the other hand, decreased signal level was mild in reticular substantia nigra, red nucleus, and dentate nucleus in case 2. A prominently decreased signal intensity in these regions was reported in correlation with normal distribution of brain iron in subjects ranging in age from 8 years to 76 years, by a high-field-strength MRI system.l9 The finding of globus pallidus in case 2 would be meaningful. In some patients with metachromatic leukodystrophy, the thalamus, the posterior limb of the internal capsule, the cerebellum, and the quad-
findings
juvenile
phy.6-1O Atrophy
rigeminal plate may have a shortened T2 and lengthened Tl, and these patients were suspected of having a higher level of microdispersed iron due to dopamine depletion.9,10 But concentration in iron may exist due to atrophic change of the globus pallidus in case 2, and globus pallidus has the most preferental iron accumulation in the brain. 9 Considering the above-mentioned facts, this finding may be within normal limits. Lesions in the basal ganglia and the brain stem have been rarely described.9,10 The field strength of MRI was 2.0 T in our cases, in contrast to 0.5 T in the majority of past reports. Differences in the resolving powers, clinical courses, and stages of the disease may explain our new findings. In the juvenile type, demyelination is more severe in the cranial portions and the peripheral nerves, but less in the pyramidal tracts of the brain stem and spinal cord. The degree of intensity on the T2-weighted images was higher in the white matter than in the cerebral peduncle and pons, a fact that is compatible with the pathology report. White matter in the cerebellum was, on the other
hand,
the T2-weighted images of case 2. However, the cerebellum has been said to be atrophic, with severe demyelination, prominent gliosis, and storage granules in late infantile type.21 Takashima et al reported that the cerebellum of both types showed a severe loss of myelin sheaths, Purkinje cells, and granular cells; proliferation of Berg-
relatively preserved
on
man
astrocytes; and torpedo formation, but that
with metachromatic granules in the white matter and torpedo formation in the cortex were seen less in the juvenile type than in the late infantile type.2° The MRI findings in case 2 may reflect these pathologic changes. Abnormality of evoked potentials and nerve conduction velocity revealed involvement of the brain stem as well as the cranial and peripheral nerves, a fact that coincides with the MRI findings. However, the normal central conduction time seen in case 2 may reflect a selectively preserved somatosensory pathway. This collaborative study of electrophysiologic and MRI examinations was useful in elucidating the pathophysiologic process of metachromatic leukodystrophy.
macrophages
References 1.
B: Clinical
Hagberg symptoms, signs and tests in metachromatic leukodystrophy, in Folch-Pi J, Bauer H (eds): Brain Lipids and Lipoproteins and the Leukodystrophies. Amsterdam,
Elsevier North-Holland, 1963, pp 134-146. 2. Andreas P, Arvan LF, Claire BF, et al: Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med
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