The term genetic leukodystrophy (GL) is commonly applied to a group of genetic disorders in which the white matter of the central nervous system (CNS) is predominantly affected. In GLs, the fundamental genetic defects may be located in the metabolic pathway of a constituent unique to myelin or its parents cells, the oligodendroglia or Schwann cells. The main GLs consist of metachromatic leukodystrophy (MLD), globoid cell leukodystrophy (GLD), adrenoleukodystrophy (ALD), and Pelizaeus–Merzbacher disease (PMD).
Epileptic seizures may occur in practically all the hereditary metabolic or degenerative encephalopathies, but are a constant or major feature in only some of them. They may constitute an early manifestation of most of the gray matter diseases and are often rare in white matter diseases (Markand, 1984). The precise pathogenesis of epileptic seizures in the GLs is not fully understood, and the EEG features have not well been described. Additionally, because the initial presenting manifestations and EEG changes are similar, differentiation between the GLs and cerebral palsy is usually unlikely by single EEG study. There were only a few serial EEG examinations reported in the individual GLs (Balslev et al., 1997; Bloms and Hagberg, 1967; Kliemann et al., 1969; Verma et al., 1985). The purpose of this study is to analyze and compare the electroclinical features and their evolution in 27 patients with the various types of GL.
Twenty-seven patients with a variety of GLs were enrolled in this study. All of these patients were diagnosed at the Department of Pediatrics, National Taiwan University Hospital, from 1986 through 1996.
These 27 patients consisted of 14 cases of MLD (late infantile form, n = 13; juvenile form, n = 1), one case of GLD, seven cases of ALD (X-linked childhood form, n = 6; autosomal recessive neonatal form, n = 1), and five cases of PMD (classic form, n = 4; connatal form, n = 1). MLD and GLD were confirmed by the measurement of serum arylsulfatase A and leukocyte galactocerebrosidase respectively (Wang et al., 1992). The diagnosis of ALD was based on clinical characteristics combined with a series of tests to determine peroxisomal function, including very long chain fatty acids (VLCFA), and pipecolic acid in plasma (Wang et al., 1992). Duplication of the proteolipid protein gene was demonstrated as the cause of the four classic PMD cases using comparative multiplex polymerase chain reaction and restriction fragment length polymerase analysis (Wang et al., 1997). The conventional diagnosis of connatal PMD was based on clinical features of nystagmus and more progressive neurologic deterioration in conjunction with MRI findings.
Complete clinical data were gathered from medical records, particularly concerning the symptomatology of seizures. Two or more complete EEG studies with both awake and sleep traces were obtained in each patient. A total of 69 EEG examinations during the varying clinical stages from these 27 patients were analyzed. All EEGs were performed with the patient in the stationary state without any systemic conditions (such as fever, pneumonia) complicating the diseases. EEGs were performed with a 14-channel Nihonkoden machine. Electrodes were placed according to the 10–20 system.
Because grading the EEG background activity is helpful in comparing the serial EEG studies in patients with GLs, the background activities on awake traces were graded tentatively on a scale of four in the current study.
Grade I was considered a normal or near-normal background consisting of the presence of dominant posterior rhythms within normal limits for age (normal dominant occipital activity, 5 Hz at 6 months, 6–7 Hz at 6–18 months, 7–8 Hz at 2 years, and 9 Hz at 7 years) and predominant δ − θ (<1 year), δ = θ (1 year–18 months), and predominant θ − δ (>18 months; the θ-to-δ ratios depend on age).
Grade II consisted of a mildly abnormal background consisting of (1) slowing of dominant posterior rhythms for age, (2) predominant δ − θ (≥15 months), predominant δ-little θ (<15 months), and/or (3) clearly predominant regional δ activity.
Grade III consisted of a moderately abnormal background consisting of loss of dominant posterior rhythms and/or the larger amounts (up to semicontinuous) of diffuse high-voltage rhythmic or arrhythmic δ activity with little activity at fast frequencies.
Grade IV consisted of a severely abnormal background consisting of (1) continuous or invariable δ activity with no activity, (2) suppression–burst pattern, or (3) nearly flattened electrocerebral activity.
The development milestones before the onset of disease were normal in all 13 cases with late infantile MLD. The disease manifested between 10 and 22 months of age, with progressive decline in psychomotor development. Because the progression rate of clinical features for each patient was variable, staging the clinical severity was helpful in prognosis, in the follow-up of the patients, and in comparing the serial EEG studies. Hagberg (1963) divided the clinical course of late infantile MLD into four stages based primarily on the degree of handicap. During clinical stage I the patient has already learned to walk but has become unsteady and requires support to stand or walk. During clinical stage II the patient can sit unsupported but can no longer stand. During stage III the patient is bedridden and quadriplegic, and speech is no longer distinct. During stage IV the patient appears to have lost all meaningful contact with his surroundings. A total of 34 EEGs of the varying clinical stages of these 13 patients are summarized in Table 1. Five of eight patients (62%) had normal EEGs (grade I), and the remaining three patients showed mild slowing of background activity (grade II) as to their ages in clinical stage I. The EEG background became more severe slow waves often in parallel with the clinical severity, except in two patients who had normal EEGs at clinical stage II. Fourteen EEGs obtained from seven patients during clinical stages II to IV disclosed epileptiform discharges including single or multiple focal spikes. Five of these seven patients were found to have epileptic seizures, beginning at 14, 21, 32, 38, and 47 months after the onset of disease. Nitrazepam was administered and revealed a benefit not only for seizure control but also abolished spasticity.
One patient with juvenile MLD showed the same clinical features, but onset was later (4 years of age) and the clinical course was more protracted. The EEGs at age 8 years and 10 years displayed moderately diffuse slowing of background activity (grade III). The patient developed erratic focal motor seizures, and secondarily generalized seizures since the age of 16 years. The EEG showed severe slow-wave background activity (grade IV), with frequent spikes arising from the bilateral frontocentral regions.
Globoid Cell Leukodystrophy
Our patient with GLD manifested hyperirritability, hypertonic spasms, spasticity, optic atrophy, and psychomotor deterioration since the fourth month of life. Serial brain computed tomographic (CT) studies showed progressive brain atrophy with symmetric lucency in the white matter. The clinical stages of GLD was divided into three stages (Hagberg et al., 1970). The prominent characteristics of stage I are hyperirritability and limb stiffness. During stage II, rapid and severe motor and mental retardation are observed. During stage III the patient exhibits no spontaneous movement. The initial EEG of our patient at age 5 months (clinical stage I) showed mildly diffuse, slow background activity (grade II). No EEG changes could be detected coinciding with episodes of startle response or hypertonic spasms, suggestive of nonepileptic events. The patient’s condition gradually deteriorated, and she became bedridden and quadriplegic (clinical stage II). She developed myoclonic seizures and generalized tonic–clonic seizures at 8 months. Superimposed on the EEG slow background were bilateral, synchronous or asynchronous, irregular spike–wave complexes and independent multifocal spikes (Fig. 1). At age 17 months (clinical stage III), the background became nearly flat in between the periodic spike–wave complexes (grade IV). The seizures remained intractable despite numerous adjustments in antiepileptic drugs. The patient died at 3 years of age.
The age at onset of neurologic symptoms in our six patients with X-linked ALD (XALD) was between 4 and 13 years. The time of seizure onset, the EEG findings, and their evolution in these six patinets are shown in Figure 2. During the early stage, the EEGs were normal in three patients, and there was slowing of rhythm with a maximum in the posterior regions (grade II) in the remaining three patients corresponding to localization of the white matter lesions demonstrated by MRI (Figs. 3A and 4 A). Slow-wave abnormalities became progressively widespread, sometimes together with paroxysmal discharges, in conformity with the deteriorated demyelinating process despite bone marrow transplantation or diet therapy (Figs. 3B and 4 B). Three ALD patients developed clinical seizures including adversive seizures, focal motor seizures, and partial-onset generalized seizures between 2 and 4 years after the onset of symptoms. The mean interval between first neurologic symptom and an apparent vegetative state was 2.6 ± 1.2 years (range, 0.9–4 years).
One patient with neonatal ALD (NALD) presented psychomotor arrest and ophthalmologic abnormalities including glaucoma, optic atrophy, pigmentary retinopathy, and clouding cornea since birth. Mild slowing of EEG background (grade II) was recorded at age 4 months. The patient began to have tonic seizures characterized by motionless staring, tonic extension of limbs and trunk, and cyanosis lasting for 10 to 25 seconds. Interictal EEG showed moderately diffuse and disorganized slow waves with superimposed multifocal spikes. Ictal EEG showed electrodecremental events preceded by high-voltage slow waves in short runs, coinciding with her tonic seizures. The seizures were refractory to antiepileptic drugs.
Four patients with classic PMD shared common clinical features including hypotonia, slowing of motor development, nystagmus, head tremor, and trunk ataxia since early infancy. The EEG findings and their evolution in these four patients are shown in Figure 5. The initial EEGs performed before 1 year of age were normal in all four patients. Five follow-up EEGs from 2 to 6 years after the onset of symptoms showed mild to moderate slowing of background rhythms (grade II to III). One patient developed focal motor seizures and generalized tonic–clonic seizures at age 5.5 years, and EEG documented sporadic spikes originating from the right frontal area.
One patient was thought to have connatal PMD according to clinical features and MRI findings. In comparison with classic PMD, the patient had brain atrophy and hypoplasia of the brainstem and cerebellum as evidenced by MRI (Fig. 6). He began having recurrent febrile seizures at 7 months and developed epileptic spasms with series formation at 15 months. The EEG documented a hypsarrhythmic pattern, which confirmed the diagnosis of West syndrome. The combination of valproic acid and pyridoxine failed to reveal a benefit with regard to seizure control and the follow-up EEGs. ACTH was not recommended because of the prediction of poor prognosis. The patient died of pneumonia at 2.5 years of age.
GLs are rare heredofamilial disorders involving primarily the white matter of the CNS. The correct diagnosis is important to determine prognosis and genetic counseling. Clinically, leukodystrophies express themselves by evidence of dysfunction of the major cerebrospinal tract, cerebellum, optic nerves, and possibly a demyelinating polyneuropathy. Evidence of white matter dysfunction includes increased reflexes, upturned toes, spasticity, cortical blindness, and deafness. It is generally agreed that epileptic seizures are seldom recognized as a major sign in white matter diseases.
Both MLD and GLD are now known to be the result of a congenital deficiency of a lysosomal enzyme, and hence constitute inborn errors of metabolism. MLD is an autosomal recessive disorder resulting from congenital deficiency of arylsulfatase A, and is characterized by an accumulation of large amounts of sulfatide in the brain, diffuse demyelination of the CNS, and the presence of metachromatic material. Bloms and Hagberg (1967) reported EEG findings in five patients with MLD and found that EEG was normal to minimally affected during the early stages but showed slowing of the background activity during the later stages of the disease. Only rarely were epileptiform discharges noted. However, Balslev et al. (1997) reported that recurrent seizures with paroxysmal discharges on EEG are common in MLD and may occur at any stage of disease. Early EEGs in clinical stage I were normal or minimally altered in the current series. Serial EEGs could reflect the severity of this process, with prominent and persistent arrhythmic δ waves, loss of dominant posterior rhythms, and the presence of epileptiform discharges. The patients developed epileptic seizures often during the later stages. GLD is a familial autosomal recessive disorder of early infancy and runs a rapid course, with death usually by age 2 years. Kliemann et al. (1969) studied the EEGs of seven patients with GLD. EEG changes were observed even at early stages of disease, including an excess of irregular slow activity with the appearance of multifocal spikes. Our patient with GLD developed frequent seizures during clinical stage II. EEG showed bilateral, synchronous, or asynchronous irregular spike–wave complexes as well as independent multifocal spikes over slow background activity. In addition to white matter lesions, progressive brain atrophy was evidenced by serial CT studies. The primary defect in GLD is galactocerebrosidase. The deficiency of this lysosomal enzyme not only blocks the degradation of galactocerebroside, but also that of psychosine (Igisu et al., 1983). Psychosine, with its free amine group, is known to be extremely cytotoxic (Igisu and Nakamura, 1986). The role of psychosine in the epileptogenesis of GLD needs further research.
ALD has been classified recently as a peroxisomal disorder. These are newly established, noteworthy entities because both biochemical abnormalities and neonatal migration disorders contribute to the neuropathologic characteristics. The most common variant of ALD is an X-linked recessive disorder. Histologically, demyelination is not focal, but starts bilaterally in the occipital regions. Gradually, the demyelinating process spreads outward and forward as a confluent lesion until most of cerebral white matter is affected. In XALD, the initial EEGs may be normal or minimally abnormal, with diffuse slowing of posterior rhythms, corresponding to the localization of pathology initially to the occipital areas of the brain. Slow-wave abnormality progressively becomes widespread and bilateral, with superimposed epileptiform discharges. One patient in the current series received bone marrow transplantation therapy, which corrected the excess content of VLCFA in plasma but did not arrest the deterioration of neurologic status and electroclinical features (Figs. 3 and 4). NALD is distinctly different from XALD with regard to genetic inheritance, which is autosomal recessive, in more severe prognosis, and in the presence of characteristic ophthalmologic abnormalities. In addition to tissue accumulation of VLCFA, NALD patients have an impaired capacity to synthesize plasmalogens and to oxidize phytanic acid, and have increased plasma levels of pipecolic acid (Poulos et al., 1985; Vamecq et al., 1986; Wanders et al., 1987). Intractable seizures are a well-known clinical correlate of NALD (Takahashi et al., 1997; Verma et al., 1985). The intractability of seizures may be attributed to the nature of generalized seizures such as tonic seizures or infantile spasms. Neuronal migration defects such as heterotopia or polymicrogyria may be present, but are not constant findings in patients with NALD (Jaffe et al., 1982). It is postulated that the pathologic mechanism and superimposed metabolic alteration also may be possible causative factors for their intractable seizures.
Classic PMD is a rare X-linked recessive disorder affecting myelination of the CNS. Some investigations, including ours (Inoue et al., 1996; Wang et al., 1997; Woodward et al., 1998), demonstrated that in addition to mutation, duplication of the proteolipid protein gene is also a major cause of classic PMD. There was only an EEG observation reported in one patient with classic PMD (Wilkus and Farrell, 1976). Our data disclose that seizures seldom constitute a prominent manifestation in patients with classic PMD. EEG abnormalities may appear late in the disease. Connatal PMD starts at birth or during early infancy and has a more severe clinical course. Our patient, similar to two previously reported patients (Haenggeli et al., 1989; Vander Knapp and Valk, 1989), demonstrated brain atrophy and hypoplasia of the brainstem and the cerebellum. The relationship between these brain abnormalities and their intractable seizures remains unclear.
In conclusion, EEGs are often normal or demonstrate only minimal slowing at the beginning of the diseases in all types of GLs. In patients with MLD, XALD, and classic PMD, the EEGs showed more slowing of background activity, usually together with paroxysmal discharges during later stages. EEG changes are nonspecific, except posteriorly accentuated δ activity during the initial stage of XALD. The most common seizure patterns in these three GLs were of partial origin. Conversely, serial EEGs reflected the more rapid progression of disease process, with prominent arrhythmic δ waves, loss of background features, and the presence of abundant paroxysmal discharges, even during the early course in patients with GLD, NALD, and connatal PMD. The main seizure patterns in these three GLs were generalized in nature. Gloor et al. (1968) attempted to correlate the distinct EEG features with the distribution of pathologic process. The following principles could be established from their comparative study. Bilateral synchronous paroxysms occur only with cortical and subcortical gray matter diseases. These discharges may consist of bilaterally synchronous slow waves, spike–wave complexes, spikes, and sharp waves. In diseases that essentially involve the white matter, the prominent EEG features are the presence of diffuse high-voltage polymorphic δ background activities and the virtual lack of paroxysmal discharges. From the EEG point of view, our data provided evidence that GLs may involve not only white matter but also gray matter. The involvement of gray matter seems to be earlier and more prominent in GLD, NALD, and connatal PMD than in MLD, XALD, and classic PMD. These results hence suggest that the contribution of EEG in differentiating GLs from gray matter diseases is rather limited. However, in any type of GL there is good correlation between the severity of EEG changes, the severity of the disease, and the clinical state of the patient. Serial EEG studies are helpful in separating GLs from static brain insult, such as cerebral palsy, and in measuring objectively the severity of the disease.
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