Spectrum of EEG findings in Menkes disease

Electroencephalography and clinical Neurophysiology, 87 (1993) 57-61

57

© 1993 Elsevier Scientific Publishers Ireland, Ltd. 0013-4694/93/$06.00

EEG92209

Short communication

Spectrum of EEG findings in Menkes disease * Steven R. White • *, Karen Reese, S u s u m u Sato and Stephen G. Kaler a EEG Section, Office of the Clinical Director, National Institute of Neurological Disorders and Stroke and a Human Genetics Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (USA) ( A c c e p t e d for publication: 10 M a r c h 1993)

Summary We evaluated electroencephalograms (EEGs) in 10 boys with Menkes disease, ranging in age from 9 days to 27 months. Three of 10 tracings were normal (the newborn, his 27-month-old half-brother with the classic phenotype, and a 27-month-old mildly affected patient). Plasma copper levels were low in all patients except the newborn and tended to be lowest in patients whose EEGs were moderately or severely abnormal. EEG differences in Menkes patients could reflect biochemical and molecular heterogeneity with respect to copper availability and utilization in the brain. Key words: Menkes disease; Electroencephalogram; Plasma copper

Menkes disease is an X-linked recessive disorder with a primary defect in copper transport (Menkes et al. 1962; Chelly et al. 1993; Mercer et al. 1993; Vulpe et al. 1993). The disease commonly presents in early infancy with poor feeding, failure to thrive, hypothermia, hypotonia and seizures. The hair has a characteristic appearance, giving rise to the terms "kinky hair" or "steely hair" disease to describe the condition. There is progressive neurological deterioration, although rare patients have survived into their teens (French 1977). Serum copper and ceruloplasmin levels are low, while high levels of copper accumulate in duodenal mucosa and in cultured fibroblasts (Danks et al. 1972; Menkes 1988). Copper replacement therapy, if commenced within the first several weeks of life, has been associated with improved, though not normal, clinical outcomes in some patients (Danks 1989; Sherwood et al. 1989). Computed tomography and magnetic resonance imaging in Menkes patients often show cerebral atrophy, areas of cortical hypodensity, and subdural effusion (Menkes 1988). Neuropathologically, there is widespread degeneration of cerebral grey matter, secondary degeneration of the white matter, atrophy of the cerebellar cortex and tortuosity of the cerebral vessels (Menkes et al. 1962; Menkes 1988). Allelic variants of the classical phenotype of Menkes disease, with a milder clinical picture, have been recognized (Procopis 1981; Danks 1988; Westman et al. 1988). In the original description of this phenotype (Menkes et al. 1962), electroencephalograms (EEGs) in 4 patients showed multifocal spike and wave discharges. Subsequent authors (Aguilar et al. 1966; Billings and Degnan 1971; French et al. 1972; Singh and Bresnan 1973;

Correspondence to: S.G. Kaler, M.D., National Institutes of Health, Building 10, Room 9S242, 9000 Rockville Pike, Bethesda, MD 20892 (USA). Tel.: 301 496-9101; Fax: 301 402 0234. * Presented in part at British Society for Clinical Neurophysiology, London, October 1992. * * Present address: Department of Clinical Neurophysiology, Middlesex Hospital, Mortimer Street, London WlN 8AA, UK.

Friedman et al. 1978) reported similar neurophysiological findings. Here, we report EEG findings in a series of 10 patients with Menkes disease, including 1 newborn infant, 1 mildly affected individual and 8 with the classic phenotype.

Methods

Ten patients with Menkes disease were studied at the National Institutes of Health Clinical Center. The protocol was approved by the National Institute of Child Health and Human Development Institutional Clinical Research Subpanel. The diagnosis of Menkes disease was based upon clinical findings including neurodevelopmental abnormalities, characteristic facies and hair, failure to thrive, and biochemical criteria including low plasma copper and serum ceruloplasmin levels, abnormal copper uptake by cultured fibroblasts, and characteristic plasma catecholamine pattern (Kaler et al. 1993). The patients ranged in age from 9 days to 27 months and represented 8 different families. Eight patients were affected with the classic form of the disease. One patient had a mild variant with less profound developmental delay. One infant had been diagnosed prenatally by study of copper uptake in cultured chorionic villi (performed by T. Tonnesen, Glostrup, Denmark) in the context of a positive family history for classic Menkes disease. None was receiving copper replacement therapy. All patients had a 21-channel EEG, using the international 10-20 system for electrode placement (Jasper 1958). Recordings were of 30-45 min duration. In 5 cases, recordings were carried out entirely during sleep, with 2 patients being sedated with chloral hydrate. In 5 patients, recordings were carried out during both wakefulness and drowsiness/sleep, with 1 patient sedated with chloral hydrate. Photic stimulation was performed in all patients. All recordings were read by a board-certified electroencephalographer (S.S.), who was aware of the diagnosis of Menkes disease, but not of other clinical information concerning the patients. Epileptiform discharges were identified using the criteria outlined by Gloor (1975).

58

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Fig. 1. Range of EEG findings in Menkes disease, a: patient no. 9 (mild variant). Normal sleep. Symmetrical theta in posterior head region and sleep spindles in central regions, b: patient no. 5. Multifocal spike and sharp wave discharges during sleep, c: patient no. 2. Continuous high amplitude slow spike and wave, 2.5-3 c/sec in left temporal and central regions.

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TABLE I Summary of EEG findings for 10 patients. Pt. no.

Age (months)

Plasma copper (~g/dl) 22

EEG summary

1 *

0.3

2

3

<10

3

5

33

Normal background activity of drowsiness and sleep. Occasional bifrontal sharp waves. Isolated right fronto-temporal spike and slow wave discharge.

4

6

11

Shifting background asymmetry. Right posterior temporal polyspike and slow wave activity.

5

6

11

Intermittent background asymmetry, with amplitude at times higher on the left than the right. Partially discontinuous pattern during quiet sleep. Posterior high amplitude delta activity, with multifocal spike and wave discharges.

6 **

8

13

Frequent multifocal spike and polyspike discharges. Intermittent electrodecremental episodes.

7

9

12

Background asymmetry - less well formed on the righL Diffuse beta activity (probably barbiturate-induced). Intermittent right posterior spike and slow wave discharges.

8 **

20

53

Slight background asymmetry, higher in amplitude on the right, especially in mid-temporal and posterior regions. Prominent beta activity, probably due to phenobarbital. Spike and sharp wave discharges near the vertex, with a slight left-sided predominance.

9

27

59

Normal sedated sleep.

10 *

27

26

Normal. Quite prominent beta activity.

Normal for age, in quiet and active sleep. Bilateral spike and slow wave discharges with shifting right-left predominance. Recurrent electrographic seizures involving both hemispheres.

Normal: 70-150; 9-46 in newborns (Lockitch et al. 1988). * Half-brothers. ** First cousins.

60

S.R. WHITE ET AL. EEG: 20.3 ~g/dl_+16.6 S.D.; normal EEG: 35.7/xg/dl+20.3 S.D., respectively) excluded a statistically significant difference in this sample ( P > 0.10, non-parametric Mann-Whitney U test; DawsonSaunders and Trapp 1990). Plasma copper in the 9-day-old infant (22 /xg/dl) was within the range established for normal newborns (9-46 /zg/dl; Lockitch et al. 1988).

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Abnormal EEG Normal EEG (n=7) (n=3) Fig. 2. Plasma copper levels in Menkes patients with abnormal versus normal EEGs. Normal plasma copper level is 7 0 - 1 5 0 / z g / d l , except in newborns for whom the normal range is 9 - 4 6 / z g / d l . * Patient no. 1, 9 days old.

Results

E E G results (Table I) showed that 7 of 10 patients had abnormal EEGs. In 6 (no. 2, nos. 4-8) the abnormality was pronounced, with slow or asymmetric background and multifocal spike and slow wave discharges. One of the abnormal EEGs (patient no. 3) was relatively less severe, with a normal background rhythm and isolated spike and wave discharges. All patients with abnormal EEGs had clinical seizures, with frequent infantile spasms in 1 case (no. 6). Six of 7 showed an overall level of neurodevelopment less than or equal to 2 months. One patient (no. 8) showed a higher level of personal-social development (5-7 months, at 20 months of age). Three patients (nos. 1, 9, and 10) had normal EEGs. These included the clinically asymptomatic 9-day-old infant (patient no. 1) and his 27-month-old half-brother (no. 10) with the classic phenotype. The latter patient had a history of clinical seizures beginning at 8 months of age, but was seizure-free for 6 months prior to this EEG. His level of neurodevelopment was approximately 2 months. The other normal E E G was recorded in a 27-month-old patient (no. 9) with no history of clinical seizures and milder neurodevelopmental abnormalities (personal-social development: 15 month level, fine motor-adaptive: 12 months, language: 15 months, gross motor: 10 months). Fig. 1 shows representative samples of EEGs from patients no. 9 (Fig. la), no. 5 (Fig. lb) and no. 2 (Fig. lc). Individual plasma copper levels were profoundly reduced ( < 15 /xg/dl) in 5 of 7 patients with abnormal EEGs (Fig. 2). However, comparison of mean plasma copper levels in the 2 groups (abnormal

Previous case studies have documented that the EEG in Menkes patients 8 weeks of age and older may be severely abnormal (Menkes et al. 1962; Aguilar et al. 1966; Billings and Degnan 1971; French et al. 1972; Singh and Bresnan 1973). E E G data for a series of 8 boys with the classic Menkes phenotype were reported by Friedman et al. (1978). All but one patient had clinical seizures and all had abnormal EEGs, with excess slow activity and an absence of age-appropriate rhythmic activity in the occipital or rolandic regions. Spikes, sharp waves and complex wave forms were common. Particular EEG features associated with earlier and later stages of the disease were distinguished. Between 3 and 5 months of age, high amplitude, localized sharp waves with shifting distribution were seen, with circumscribed areas of amplitude attenuation. After 5 months, generalized epileptiform discharges were common. A hypsarrhythmialike pattern with high amplitude, multifocal discharges and irregular slow wave activity was felt to be characteristic. In our sample, many of the E E G abnormalities previously associated with Menkes disease were evident. However, severe EEG disturbances were not present in all our patients, several of whose tracings had more moderate abnormalities consisting of background asymmetries and localized spike and wave discharges without frequent multifocal discharges. Our findings also indicate that electrocerebral activity is not invariably deranged in Menkes disease and can be normal in the first several weeks of life (patient no. 1), as suggested by Grover and Scrutton (1975). E E G findings in 2 older patients with the mild phenotype were not described (Procopis 1981; Danks 1988; Westman et al. 1988). Neither had clinical seizures. In contrast to Friedman et al. (1978) who noted minimal change in the E E G during sleep and an absence of sleep spindles, 2 patients in our series (nos. 1 and 9) showed age-appropriate sleep rhythms, including well-formed vertex waves and sleep spindles (patient no. 9, EEG shown in Fig. la). Also in contrast to findings by Friedman et al. (1978), several of our patients had lateralizing or focal features that were present consistently. In this series, there appeared to be some relationship between the degree of E E G abnormality and the severity of neurodevelopmental impairment. The 7 patients with moderately-to-severely abnormal EEGs were all markedly impaired neurodevelopmentally. Conversely, 2 of the 3 children with normal EEGs were relatively better functioning: one, the essentially normal-appearing newborn (no. 1) and the other, a patient with a mild variant of Menkes disease (no. 9). Similarly, an extremely low plasma copper level ( < 15/zg/dl) was invariably associated with an abnormal E E G (Fig. 2). The plasma copper level in 2 patients with normal EEGs was somewhat higher and, in patient no. 1 was normal for age. In a patient studied by Friedman et al. (1978), a higher serum copper level was associated with relatively later onset of seizures. These observations suggest that electrocerebral activity in some Menkes patients may be influenced by the level of circulating copper. Our findings indicate that the spectrum of EEG patterns in Menkes disease may be wider than previously recognized. While moderate to severe abnormalities are most common, some patients show only mild changes, and some have normal EEGs. Heterogeneity in the E E G in Menkes patients could reflect biochemical and molecular heterogeneity in this disorder.

EEG IN MENKES DISEASE References

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