Fukuyama Type Congenital Muscular Dystrophy as a Natural Model of Childhood Epilepsy Masaya Segawa, MD, YoshikoNomura, MD, Kei Hachimori, MD, Noriaki Shinoyama, MD, Akiko Hosaka, MD, and Yoshihiko Mizuno, MD
Fukuyama type Congenital Muscular Dystrophy, inherited autosomal-recessively, is characterized by muscular dystrophy associated with severe mental retardation and epileptic convulsions. By examining 56 cases, followed for more than three years, 75 EEG records from 40 patients and visual evoked potentials from 11 patients with reference to autopsied materials, the authors aimed at clarifying the causative relationship between congenital central nervous system (CNS) lesions and childhood epilepsy. In 36 out of 56 cases diffuse epileptic seizures were observed with onset at 1.64:i: 1.01 years average. In 32/36 cases seizures developed before 3 years of age. In 51/75 EEGs focal paroxysmal discharges (FPD), fronto-centro-parietal in younger and centro-occipital in older cases, were observed. Abnormal basic activities (ABA), diffuse-OI.-activity and/or abundant or extreme spindles, were observed more often in older than younger cases. The incidence of FPD was similar between convulsive and non-convulsive cases, but ABA predominated in the former. VEP revealed abnormal findings in 64% of 11 cases examined. Of the CNS pathology, consisting of cerebral and cerebellar gyral abnormalities and a hypoplastic corticospinal tract, the gyral lesions (verrucous polymicrogyria with adhesions of adjacent gyri and cellular disarrangement) were thought to be lesions causing epilepsy. Cortical non progressive gyral lesions occurring around the second trimester could cause FPD and clinical diffuse epileptic seizures develop with other factors concerned with ABA. Segawa M, Nomura Y, Hachimori K, Shinomiya N, Hosaka A, Mizuno Y: Fukuyama type congenital muscular dystrophy as a natural model of childhood epilepsy. BrainDev 2:113-119,1979
Fukuyama type congenital muscular dystrophy (FCMD) is an autosomally recessively inherited disorder, characterized by muscular dystrophy always combined with peripheral and central nervous system (CNS) lesions [3, 11, 12]. Clinically, these CNS lesions consist
of moderate to severe mental retardation and epilepsy. Recent neuropathological examinations of more than 10 autopsied cases clarified the main CNS abnormalities as marked gyral abnormalities and hypoplastic corticospinal tracts, suggesting influences acting around the
From Segawa Neurological Clinic for Children, Tokyo (MS, YN, NS), Department of Pediatrics, University of Tokyo, Tokyo (AH, YM), Metropolitan Komagome Hospital, Tokyo (KH).
Key words: Fukuyama type congenital muscular dystrophy, childhood epilepsy, foetal cortical lesion.
Received for pUblication: February 5, 1979. Accepted for pUblication : September 20, 1979.
Correspondence address: Dr. Masaya Segawa, Segawa Neurological Clinic for Children, 2-8 Surugadai, Kanda, Chiyoda-ku, Tokyo 101, Japan.
5th to 6th gestational months [1, 9, 11] . This disorder is important from the standpoint of myology for studying causal relationship between pathology of muscle and the nervous sytem, but it is also significant for detecting how the foetal cortical lesions develop to epileptic foci after birth. This paper is concerned, with the latter of these, particularly concentrating on the features of clinical seizures and EEG. Material and Methods From 84 personal cases of FCMD, 56 cases were selected which had been followed for more than three years and had had precise description of features of convulsive attacks. In 40 cases, a total of 75 EEG examinations was performed, mostly in either sleep or awake states. In 11 cases visual evoked potentials (VEP) were studied by routine methods. In younger cases they were examined during sleep, but in older cases they were examined in the awake state because of inability to induce sleep. These clinical and electrophysiological data were correlated with each other, and each with the grade of disability, which are shown as the age of acquiring the sitting position and divided into four groups. The electrophysiological findings were also correlated with the ages of patients. Results Epileptic seizures were observed in 36 (64%) out of 56 cases. In most cases convulsions were generalized with minimum asymmetry. The initial convulsions usually occurred after febrile disorders. However, in all cases, they were followed by afebrile, epileptic convulsions within one year. The average age of onset was 1.64 ± 1.01 years (Table 1). The incidence of cases with convulsions showed a tendency to increase with the motor disability, but it was rather high even in the least affected cases (Table 1). The average age of onset had a similar trend, that is, it was rather lower in those least disabled, though lowest in those most severely disabled (Table 1). In 32 (89%) cases with seizures, clinical convulsions developed before three years of 114 Brain & Development, Vol 1, No 2, 1979
age; in another four cases the initial attacks were observed 3:1, 3:6, 4:0 and 5:5 years respectively. So for those who had passed the first three years without clinical seizures the possibility of developing seizures became very low, during a follow-up of 2 to 10 years. Among affected siblings in familial cases, the ages of onset of seizures were quite similar to each other. However, in comparison with sporadic cases, the incidence of seizures was lower, but the age of onset was earlier. In spo· radic cases, those with perinatal abnorma1i.ties showed highest incidence of seizures, and thos~ without perinatal problems had a lower inci dence of seizures and highest age of onsel (Table 2). Abnormal EEG findings consisted of parox ysmal discharges, both focal and/or diffus( spike and wave complex, and abnormal basil activities such as diffuse synchronous alpha activity, and/or extreme or abundant spindles In 51 (68%) out of 75 records, abnorma paroxysmal discharges were observed. B: comparing these abnormalities with the age of patients, it was shown that the incidenc of having paroxysmal discharges was high i infancy and in children over 4 years of ag( but that they were lower in those betwee 1 to 4 years of age (Table 3). Abnormalities in basic activities, includin extreme or abundant spindles and diffus alpha-activity, could be observed throughol the courses but tended to be observed mOl frequently in the older age group (Table 3 When comparing these EEG abnormalitil of convulsive and non-convulsive cases, stati tically significant differences were observ~ in the incidence of abnormal basic activitie That is, they were substantially higher in tl convulsive group. On the other hand, the were no significant differences in the incidenl of either paroxysmal abnormalities, or tl ineffectiveness of hypnotics (Table 4). Paroxysmal discharges changed their fo and patterns with age. The main focus w observed in the central area throughout ; age groups. Additional foci were observed the frontal, temporal and parietal areas younger cases, but they were observed in t occipital area in older cases. Diffuse spike ill wave complexes were observed only in old cases (Table 5). These paroxysmal dischaq were focal and asymmetrical in almost
Table I Incidence and age of onset of seizures in Fukuyama type CMD against ages taking sitting position Age taking sitting position (mos)
Age of onset of seizures (yrs)
Number of cases with seizures
Total number of cases
6- 8
12
7 ( 58)
1.62 ± 1.23
9 - 12
18
9 ( 50)
1.95±1,41
13 - 23
18
12 ( 67)
1.61 ± 0.95
8
8 (l00)
1.34 ± 0.88
56
36 ( 64)
1.64 ± 1.01
24 Total ):%
Table 2 Incidence and age of onset of seizures in Fukuyama type CMD. Comparison between cases with affected siblings and sporadic cases Total number of cases
Number of cases with seizures
Age of onset of seizures (yrs)
Cases with affected siblings
18
10 (56)
1.14 ±0.60
Sporadic cases With perinatal problems Without perinatal problems
7 31
6 (85) 18 (64)
l.58±1.52 1.80 ± 0.85
):% In cases with affected siblings, those with perinatal problems were very small in number and omitted from this data.
Table 3 Incidences of EEG abnormalities and refractoriness to artificial sleep induction in Fukuyama type CMD in various age groups
Age at EEG examination (years)
Number of EEG examination
EEG abnormalities Abundant or extreme spindles (%)
Paroxysmal discharges (%)
Refractoriness to artificial sleep induction (%)
0-1
4
0
75
25
1-2
15
33
47
20
2-3
9
56
45
33
3-4
12
50
42
8
4-5
8
40
75
63
5- 6
9
44
78
33
6-7
6
50
67
33
7-8
6
67
83
83
8-
6
*
75
100
* No sleep EEG was obtained. Segawa, et al: Fukuyama type CMD
115
Table 4 EEG abnormalities in Fukuyama type CMD. Differences between cases with or without clinical seizures EEG abnormalities
Seizures (+)
Seizures (-)
Total
Paroxysmal discharge
30/48 (63)
17/23 (73)
47/71 * (66)
18/40 (45)
3/21 (14)
21/61 **(34)
Diffuse alpha-activity
4/ 8 (50)
0/ 3 ( 0)
4/11 **(36)
Normal
2/48 ( 4)
2/23 ( 9)
4/71
(36)
16/48 (33)
9/23 (39)
25/71
(35)
Abundant or extreme spindles
Refractoriness to artificial sleep induction
( ):% * Four records were omitted because these cases were under 3 years of age. ** EEGs subjected for examination on basic activity were 61 sleep and 11 waking records. With the exception of one, only either sleep or waking states were recorded.
Table 5 Frequency and focus of paroxysmal discharges in EEG (75 records) of the Fukuyama type CMD Age (years) No o/cases
-1
4
1-2 15
2-3 9
3-4 12
4-5 8
5-6 9
6-7 6
7-8 6
86
Cases with paroxysmal discharges
3
7
4
5
6
6
4
5
4
5
4
1
2
3
2
2
Focal-multiple
2
3
3
2
3
2
3
3
Diffuse
o
o
o
2
2
o
o o
2
o
3
2
2 2
2
2
1
2 2
1 6
1 3
4
2
2
o
Focal-single
Loci of focal paroxysmal discharge Frontal Anterior temporal Middle tern poral Central Parietal Occipital
1 3
o o
Cases without spikes Cases with normal EEG
o
o o 2
1
o o
5
4
6
2
o
cases. In severely disabled cases, they appeared multifocally, but in milder cases they tended to be localized in one or two foci. These tendencies were observed both in convulsive and non-convulsive cases. Abnormal VEPs were observed in seven (64%) out of 11 cases, in two other cases there were "borderline" abnormalities and in the other two cases normal patterns were observed (Table 6). With regard to the 1st response, six cases showed abnormalities; in two of them, 11 6 Brain & Development, Vol 1, No 2, 1979
o
1 1
2
1
1 3
o
2 2
2
2
o
o
2
o
o
1 4
2 3 1 3
2
o
o
low amplitude or positive deviation of the N2 components, in another three low amplitude or posit~ve deviation of the unilateral N2 components, and in the other asymmetry of total patterns were detected. Delay of the peak latency of N2 components was observed only in one case. In contrast, abnormalities of the 2nd response were relatively rare and slight. Only in two cases was asymmetry of the latencies, amplitude and pattern, observed. The abnormalities of the 1st components of YEP were more frequently observed in
Table 6
VEP in Fukuyama type CMD
Age (yrs:mos) Sex
Maximum motor achievement
Mental retardation
EEG
Recording condition
Spike
VEP
Basic activities
Primary Secondary component component
1:11
M
Head control
++
Sleep
+
B
(It)A
N
1: 9
F
Stand up
+
Sleep
+
N
N
N
4: 7
M
Sitting
+++
Sleep
+
A
(It)A
N
3:11
M
Sitting
+++
Sleep
+
A
N
N
0: 6
F
Head control
++
Sleep
+
B
(rt)A
N
5: 7
F
Sitting, roll over
+
Sleep
+
N
(rt)A
B
7: 0
F
Walking
+
Awake
+
N
N
B
9:11
F
Walking
+++
Awake
+
N
Low amp
B
11: 0
M M
Sitting
+++
Awake
B
B
Asym
Sitting
+++
Awake
B
A
N
Walking
++
Awake
+
A
Low amp
6: 7*
Awake
+
B
B
Asym
7: 2*
Awake
+
N
N
Asym (±)
9: 2 5:10*
F
B
N: normal, A: abnormal, B: borderline, Asym: asymmetry, It: left side, rt: right side, Amp: amplitude. * The same patient was examined three times at different ages.
severely disabled cases, and those of the 2nd components were observed mainly in older and more disabled cases. Discussion These studies show that in FCMD severity of clinical seizures correlate well with extent o? motor disability, and in familial cases affected siblings showed similar features to each other. This evidence strongly suggests that epileptic convulsions are one of the cardinal signs of FCMD and not an accidental association. Changes of the pattern of paroxysmal discharges and basic activities observed in EEG were different from those observed in complicated types of febrile convulsions, or in children who initially had febrile convulsions but at a later date had afebrile convulsions [6, 15]. There were also similarities to the course of the experimental epilepsies with focal cortical lesions [I 8] . In chronic cobalt experimental epilepsy in the rat, focal spiking appears in the electrocorticogram (ECoG) as early as the first few days, but spontaneous focal seizures with secondary generalization develops later, by the
4th to 7th day, with changing features between 6 and 12 days, with spike and wave discharges in addition to focal spikes. Although seizures subsided by the end of the 2nd week, the abnormal ECoG at the cobalt focus remained [2] . These focal discharges or high voltage slow activities were only elicited through more complex circuits such as corti co-subcortical circuits [I 8], or by a focal cortical focus inducing a secondary focus in subcortical cellular masses before inducing clinically recognizable seizures [17]. The subcortical structures involved in spindle generation and recruiting responses were considered as potent triggers for precipitating bilaterally synchronous epileptic discharges [5]. These structures were considered to be intralaminar and midline nuclei of the thalamus and some association nuclei particularly of the thalamic reticular system [5]. The cortical pathology of FCMD consisted of micropolygyria, which was caused by the fusion of already developed gyri with thickened leptomeninges penetrating between gyri with gliosis and disarrangement of the ganglion cells [1, 9] . This pathology was similar to that observed in cobalt experimental epilepsy [17], Segawa, et al: Fukuyama type CMD 117
or in alumina cream induced focal motor epilepsy [16]. The corticospinal tract showed abnormalities both in myelination and location, especially below the cerebral peduncle [1,7,9, 13] . In CT scanning marked low densities were observed in subcortical regions in most cases, mainly anteriorly in distribution [19]. These subcortical low densities were correlated with the occurrences of paroxysmal discharges in EEG [19]. Thus, epileptogenesis in FCMD is considered to occur as follows: a focal atypical spike, or spikes, develops initially due to local cortical lesions, and this later changes to spike and wave complexes, or diffuse bursts with abnormal basic activities and clinical convulsions triggered by additional subcortical lesions. In the non-seizure group, foci of spike are localized and too weak to induce abnormal circuits in the subcortical structures. In less disabled cases the. gyral abnormalities tended to be localized in the occipital area [7, 12, 13] which is known as one of the least susceptible areas for electrically induced after discharges [8] . The reasons that clinically recognizable convulsions were less likely to occur after 3 years of age were considered to be as follows: firstly the cortical lesions became too weak to produce subcortical secondary foci, and secondly some other mechanisms developed to suppress the epileptogenesis. We prefer the second consideration, because at these ages the activity of cortical foci should be increased because of greater incidence of paroxysmal discharges after 4 years of age. Recently we detected increased excretion of catecholamine (CA) metabolities in urine in cases of FCMD, particularly of older patients (unpublished data). This suggested the existence of exaggeration of CA turnover in FCMD, and in this condition chloral hydrate or its metabolites might cause a paradoxical effect instead of inducing sleep. This could cause the ineffectiveness of hypnotics in FCMD, and on the other hand could reduce the susceptibility of seizures in older cases. It was known that the effects of kindling subsided in states with exaggerated CA metabolism [10]. The cerebellum also has efferent connection with locus ceruleus [14], and with its tonically inhibitory effects on the nucleus, influence the amplitude of pontogeniculo-occipital (pGO) spikes [4]. This sug118 Brain & Development, Vol 1, No 2, 1979
gests cerebellar influence on norepinephrine (NE) metabolism [4]. Cerebellectomy caused increase in amplitude of PGO spikes and also increased NE turnover [4]. Cerebellar pathology of FCMD did some roles in subsiding epileptic mechanism by increasing NE or CA turnover. FCMD needs to be studied from these viewpoints. FCMD is a genetically determined disease with fundamentally identical CNS pathologies, which occur around the 5th to 6th gestational month and could be a natural model for studying the epileptogenesis of prenatal cortical lesions, which in turn could show some suggestion of neuronal influence on peripheral systems. Acknowledgment This work was supported by a grant from the Ministry of Health and Welfare, Japan. References 1. Chou SM: Reappraisal of neuropathology of Fukuyama type congenital muscular dystrophy. Presented at the Annual Meeting Research Group, 1976, Tokyo, Japan. 2. Colasanti BK, Hartman ER, Craig CR: Electrocorticogram and behavioral correlates during the development of chronic cobalt experimental epilepsy in the rat. Epi/epsia 15: 361-373, 1974. 3. Fukuyama Y, Kawazura M, Haruna H: A peculiar form of congenital muscular dystrophy. Pediat Univ Tokyo (Tokyo) 4: 5-8, 1960. 4. Gadea-Ciria M: Differential effects of cerebellecto my and frontal lobe lesions upon PGO waves during paradoxical sleep (PS) in the cat. In Koella WP, Levin P (eds): Sleep 1976. S Karger, Basel, 1977, pp 219-222, 5. Gloor P, Quesney LF, Zumstein H: Pathophysiology of generalized penicillin epilepsy in the cat: The role of cortical and subcortical structures. II. Topical applications of penicillin to the cerebral cortex and to subcortical structures. Electroencephalogr Clin Neurophysiol 43: 79-94,1977. 6. Kagawa K, Mori H, Fukuyama Y, et al: Clinical and electroencephalographic study in febrile convulsions. Brain Dev (Tokyo) (Domestic Ed) 8: 53-64,1976. 7. Kamoshita S, Konishi Y, Segawa M, et al: Congenital muscular dystrophy as a disease of the cen tral nervous system. Arch Neurol 33: 513516,1976. 8. Marson CA: Electrical stimulation. In Purpura DP, Penry JK, Tower DB, et al (eds): Experi· mental Model of Epilepsy. Raven Press, New York, 1972, pp 147-172. 9. Nomura Y, Segawa· M, Murakami T, et al: Reappraisal of CNS pathology of Fukuyama type
10.
11.
12. 13.
14. 15 .
congenital muscular dystrophy-On infection theory. Brain Dev (Tokyo) (Old Series) 3: 275, 1978. Sato M, Hikasa N, Tomoda T, et al: Seizure development and dopamine receptor sensitivity. Folia Psychiatr Neurol lpn (Tokyo) 32: 343344, 1978. Segawa M: Congenital type muscular dystrophy. Brain Dev (Tokyo) (Domestic Ed) 2:439-451, 1970. Segawa M: Congenital muscular dystrophy. Neurol Med (Tokyo) 3: 199-208,1975. Segawa M: Congenital muscular dystrophy. Adv Neurol Sci (Tokyo) 20: 68-80, 1976. Snider RS : A cerebellar ceruleus pathway . Brain Res 88 : 56-63, 1975 . Tsuboi T, Endo S: Febrile convulsions followed by nonfebrile convulsions. Neuro·paediatrie 8: 209-223,1977.
16. Velasco M, Velasco F , Cepeda C, et al:Alumina cream induced focal motor epilepsy in cat. I. Wakefulness sleep modulation of cortical paroxysmal EEG spikes. Electroencephalvgr Clin Neurophysiol43: 59-66, 1977. 17. Wilder B J: Projection phenomena and secondary epileptogenesis-Mirror foci. In Purpura DP, Penry JK, Tower DB, et al (eds): Experimental Model of Epilepsy. Raven Press, New York, 1972, pp 85-122. 18. Yamauchi T , Hirabayashi Y, Mohri Y, et al: Ontogenetic · studies of seizure patterns and seizure activities induced by cortical focus. Psychiat Neural lap (Tokyo) 30: 241-252, 1976. 19. Yoshioka M, Okuno T , Handa Y, et al : Central nervous system involvement in progressive mus· cular dystrophy. Presented at the IVth International Congress on Neuromuscular Diseases, Montreal, 1978.
Segawa, et al: Fukuyama type CMD 119
Fukuyama type Congenital Muscular Dystrophy, inherited autosomal-recessively, is characterized by muscular dystrophy associated with severe mental retardation and epileptic convulsions. By examining 56 cases, followed for more than three years, 75 EEG records from 40 patients and visual evoked potentials from 11 patients with reference to autopsied materials, the authors aimed at clarifying the causative relationship between congenital central nervous system (CNS) lesions and childhood epilepsy. In 36 out of 56 cases diffuse epileptic seizures were observed with onset at 1.64:i: 1.01 years average. In 32/36 cases seizures developed before 3 years of age. In 51/75 EEGs focal paroxysmal discharges (FPD), fronto-centro-parietal in younger and centro-occipital in older cases, were observed. Abnormal basic activities (ABA), diffuse-OI.-activity and/or abundant or extreme spindles, were observed more often in older than younger cases. The incidence of FPD was similar between convulsive and non-convulsive cases, but ABA predominated in the former. VEP revealed abnormal findings in 64% of 11 cases examined. Of the CNS pathology, consisting of cerebral and cerebellar gyral abnormalities and a hypoplastic corticospinal tract, the gyral lesions (verrucous polymicrogyria with adhesions of adjacent gyri and cellular disarrangement) were thought to be lesions causing epilepsy. Cortical non progressive gyral lesions occurring around the second trimester could cause FPD and clinical diffuse epileptic seizures develop with other factors concerned with ABA. Segawa M, Nomura Y, Hachimori K, Shinomiya N, Hosaka A, Mizuno Y: Fukuyama type congenital muscular dystrophy as a natural model of childhood epilepsy. BrainDev 2:113-119,1979
Fukuyama type congenital muscular dystrophy (FCMD) is an autosomally recessively inherited disorder, characterized by muscular dystrophy always combined with peripheral and central nervous system (CNS) lesions [3, 11, 12]. Clinically, these CNS lesions consist
of moderate to severe mental retardation and epilepsy. Recent neuropathological examinations of more than 10 autopsied cases clarified the main CNS abnormalities as marked gyral abnormalities and hypoplastic corticospinal tracts, suggesting influences acting around the
From Segawa Neurological Clinic for Children, Tokyo (MS, YN, NS), Department of Pediatrics, University of Tokyo, Tokyo (AH, YM), Metropolitan Komagome Hospital, Tokyo (KH).
Key words: Fukuyama type congenital muscular dystrophy, childhood epilepsy, foetal cortical lesion.
Received for pUblication: February 5, 1979. Accepted for pUblication : September 20, 1979.
Correspondence address: Dr. Masaya Segawa, Segawa Neurological Clinic for Children, 2-8 Surugadai, Kanda, Chiyoda-ku, Tokyo 101, Japan.
5th to 6th gestational months [1, 9, 11] . This disorder is important from the standpoint of myology for studying causal relationship between pathology of muscle and the nervous sytem, but it is also significant for detecting how the foetal cortical lesions develop to epileptic foci after birth. This paper is concerned, with the latter of these, particularly concentrating on the features of clinical seizures and EEG. Material and Methods From 84 personal cases of FCMD, 56 cases were selected which had been followed for more than three years and had had precise description of features of convulsive attacks. In 40 cases, a total of 75 EEG examinations was performed, mostly in either sleep or awake states. In 11 cases visual evoked potentials (VEP) were studied by routine methods. In younger cases they were examined during sleep, but in older cases they were examined in the awake state because of inability to induce sleep. These clinical and electrophysiological data were correlated with each other, and each with the grade of disability, which are shown as the age of acquiring the sitting position and divided into four groups. The electrophysiological findings were also correlated with the ages of patients. Results Epileptic seizures were observed in 36 (64%) out of 56 cases. In most cases convulsions were generalized with minimum asymmetry. The initial convulsions usually occurred after febrile disorders. However, in all cases, they were followed by afebrile, epileptic convulsions within one year. The average age of onset was 1.64 ± 1.01 years (Table 1). The incidence of cases with convulsions showed a tendency to increase with the motor disability, but it was rather high even in the least affected cases (Table 1). The average age of onset had a similar trend, that is, it was rather lower in those least disabled, though lowest in those most severely disabled (Table 1). In 32 (89%) cases with seizures, clinical convulsions developed before three years of 114 Brain & Development, Vol 1, No 2, 1979
age; in another four cases the initial attacks were observed 3:1, 3:6, 4:0 and 5:5 years respectively. So for those who had passed the first three years without clinical seizures the possibility of developing seizures became very low, during a follow-up of 2 to 10 years. Among affected siblings in familial cases, the ages of onset of seizures were quite similar to each other. However, in comparison with sporadic cases, the incidence of seizures was lower, but the age of onset was earlier. In spo· radic cases, those with perinatal abnorma1i.ties showed highest incidence of seizures, and thos~ without perinatal problems had a lower inci dence of seizures and highest age of onsel (Table 2). Abnormal EEG findings consisted of parox ysmal discharges, both focal and/or diffus( spike and wave complex, and abnormal basil activities such as diffuse synchronous alpha activity, and/or extreme or abundant spindles In 51 (68%) out of 75 records, abnorma paroxysmal discharges were observed. B: comparing these abnormalities with the age of patients, it was shown that the incidenc of having paroxysmal discharges was high i infancy and in children over 4 years of ag( but that they were lower in those betwee 1 to 4 years of age (Table 3). Abnormalities in basic activities, includin extreme or abundant spindles and diffus alpha-activity, could be observed throughol the courses but tended to be observed mOl frequently in the older age group (Table 3 When comparing these EEG abnormalitil of convulsive and non-convulsive cases, stati tically significant differences were observ~ in the incidence of abnormal basic activitie That is, they were substantially higher in tl convulsive group. On the other hand, the were no significant differences in the incidenl of either paroxysmal abnormalities, or tl ineffectiveness of hypnotics (Table 4). Paroxysmal discharges changed their fo and patterns with age. The main focus w observed in the central area throughout ; age groups. Additional foci were observed the frontal, temporal and parietal areas younger cases, but they were observed in t occipital area in older cases. Diffuse spike ill wave complexes were observed only in old cases (Table 5). These paroxysmal dischaq were focal and asymmetrical in almost
Table I Incidence and age of onset of seizures in Fukuyama type CMD against ages taking sitting position Age taking sitting position (mos)
Age of onset of seizures (yrs)
Number of cases with seizures
Total number of cases
6- 8
12
7 ( 58)
1.62 ± 1.23
9 - 12
18
9 ( 50)
1.95±1,41
13 - 23
18
12 ( 67)
1.61 ± 0.95
8
8 (l00)
1.34 ± 0.88
56
36 ( 64)
1.64 ± 1.01
24 Total ):%
Table 2 Incidence and age of onset of seizures in Fukuyama type CMD. Comparison between cases with affected siblings and sporadic cases Total number of cases
Number of cases with seizures
Age of onset of seizures (yrs)
Cases with affected siblings
18
10 (56)
1.14 ±0.60
Sporadic cases With perinatal problems Without perinatal problems
7 31
6 (85) 18 (64)
l.58±1.52 1.80 ± 0.85
):% In cases with affected siblings, those with perinatal problems were very small in number and omitted from this data.
Table 3 Incidences of EEG abnormalities and refractoriness to artificial sleep induction in Fukuyama type CMD in various age groups
Age at EEG examination (years)
Number of EEG examination
EEG abnormalities Abundant or extreme spindles (%)
Paroxysmal discharges (%)
Refractoriness to artificial sleep induction (%)
0-1
4
0
75
25
1-2
15
33
47
20
2-3
9
56
45
33
3-4
12
50
42
8
4-5
8
40
75
63
5- 6
9
44
78
33
6-7
6
50
67
33
7-8
6
67
83
83
8-
6
*
75
100
* No sleep EEG was obtained. Segawa, et al: Fukuyama type CMD
115
Table 4 EEG abnormalities in Fukuyama type CMD. Differences between cases with or without clinical seizures EEG abnormalities
Seizures (+)
Seizures (-)
Total
Paroxysmal discharge
30/48 (63)
17/23 (73)
47/71 * (66)
18/40 (45)
3/21 (14)
21/61 **(34)
Diffuse alpha-activity
4/ 8 (50)
0/ 3 ( 0)
4/11 **(36)
Normal
2/48 ( 4)
2/23 ( 9)
4/71
(36)
16/48 (33)
9/23 (39)
25/71
(35)
Abundant or extreme spindles
Refractoriness to artificial sleep induction
( ):% * Four records were omitted because these cases were under 3 years of age. ** EEGs subjected for examination on basic activity were 61 sleep and 11 waking records. With the exception of one, only either sleep or waking states were recorded.
Table 5 Frequency and focus of paroxysmal discharges in EEG (75 records) of the Fukuyama type CMD Age (years) No o/cases
-1
4
1-2 15
2-3 9
3-4 12
4-5 8
5-6 9
6-7 6
7-8 6
86
Cases with paroxysmal discharges
3
7
4
5
6
6
4
5
4
5
4
1
2
3
2
2
Focal-multiple
2
3
3
2
3
2
3
3
Diffuse
o
o
o
2
2
o
o o
2
o
3
2
2 2
2
2
1
2 2
1 6
1 3
4
2
2
o
Focal-single
Loci of focal paroxysmal discharge Frontal Anterior temporal Middle tern poral Central Parietal Occipital
1 3
o o
Cases without spikes Cases with normal EEG
o
o o 2
1
o o
5
4
6
2
o
cases. In severely disabled cases, they appeared multifocally, but in milder cases they tended to be localized in one or two foci. These tendencies were observed both in convulsive and non-convulsive cases. Abnormal VEPs were observed in seven (64%) out of 11 cases, in two other cases there were "borderline" abnormalities and in the other two cases normal patterns were observed (Table 6). With regard to the 1st response, six cases showed abnormalities; in two of them, 11 6 Brain & Development, Vol 1, No 2, 1979
o
1 1
2
1
1 3
o
2 2
2
2
o
o
2
o
o
1 4
2 3 1 3
2
o
o
low amplitude or positive deviation of the N2 components, in another three low amplitude or posit~ve deviation of the unilateral N2 components, and in the other asymmetry of total patterns were detected. Delay of the peak latency of N2 components was observed only in one case. In contrast, abnormalities of the 2nd response were relatively rare and slight. Only in two cases was asymmetry of the latencies, amplitude and pattern, observed. The abnormalities of the 1st components of YEP were more frequently observed in
Table 6
VEP in Fukuyama type CMD
Age (yrs:mos) Sex
Maximum motor achievement
Mental retardation
EEG
Recording condition
Spike
VEP
Basic activities
Primary Secondary component component
1:11
M
Head control
++
Sleep
+
B
(It)A
N
1: 9
F
Stand up
+
Sleep
+
N
N
N
4: 7
M
Sitting
+++
Sleep
+
A
(It)A
N
3:11
M
Sitting
+++
Sleep
+
A
N
N
0: 6
F
Head control
++
Sleep
+
B
(rt)A
N
5: 7
F
Sitting, roll over
+
Sleep
+
N
(rt)A
B
7: 0
F
Walking
+
Awake
+
N
N
B
9:11
F
Walking
+++
Awake
+
N
Low amp
B
11: 0
M M
Sitting
+++
Awake
B
B
Asym
Sitting
+++
Awake
B
A
N
Walking
++
Awake
+
A
Low amp
6: 7*
Awake
+
B
B
Asym
7: 2*
Awake
+
N
N
Asym (±)
9: 2 5:10*
F
B
N: normal, A: abnormal, B: borderline, Asym: asymmetry, It: left side, rt: right side, Amp: amplitude. * The same patient was examined three times at different ages.
severely disabled cases, and those of the 2nd components were observed mainly in older and more disabled cases. Discussion These studies show that in FCMD severity of clinical seizures correlate well with extent o? motor disability, and in familial cases affected siblings showed similar features to each other. This evidence strongly suggests that epileptic convulsions are one of the cardinal signs of FCMD and not an accidental association. Changes of the pattern of paroxysmal discharges and basic activities observed in EEG were different from those observed in complicated types of febrile convulsions, or in children who initially had febrile convulsions but at a later date had afebrile convulsions [6, 15]. There were also similarities to the course of the experimental epilepsies with focal cortical lesions [I 8] . In chronic cobalt experimental epilepsy in the rat, focal spiking appears in the electrocorticogram (ECoG) as early as the first few days, but spontaneous focal seizures with secondary generalization develops later, by the
4th to 7th day, with changing features between 6 and 12 days, with spike and wave discharges in addition to focal spikes. Although seizures subsided by the end of the 2nd week, the abnormal ECoG at the cobalt focus remained [2] . These focal discharges or high voltage slow activities were only elicited through more complex circuits such as corti co-subcortical circuits [I 8], or by a focal cortical focus inducing a secondary focus in subcortical cellular masses before inducing clinically recognizable seizures [17]. The subcortical structures involved in spindle generation and recruiting responses were considered as potent triggers for precipitating bilaterally synchronous epileptic discharges [5]. These structures were considered to be intralaminar and midline nuclei of the thalamus and some association nuclei particularly of the thalamic reticular system [5]. The cortical pathology of FCMD consisted of micropolygyria, which was caused by the fusion of already developed gyri with thickened leptomeninges penetrating between gyri with gliosis and disarrangement of the ganglion cells [1, 9] . This pathology was similar to that observed in cobalt experimental epilepsy [17], Segawa, et al: Fukuyama type CMD 117
or in alumina cream induced focal motor epilepsy [16]. The corticospinal tract showed abnormalities both in myelination and location, especially below the cerebral peduncle [1,7,9, 13] . In CT scanning marked low densities were observed in subcortical regions in most cases, mainly anteriorly in distribution [19]. These subcortical low densities were correlated with the occurrences of paroxysmal discharges in EEG [19]. Thus, epileptogenesis in FCMD is considered to occur as follows: a focal atypical spike, or spikes, develops initially due to local cortical lesions, and this later changes to spike and wave complexes, or diffuse bursts with abnormal basic activities and clinical convulsions triggered by additional subcortical lesions. In the non-seizure group, foci of spike are localized and too weak to induce abnormal circuits in the subcortical structures. In less disabled cases the. gyral abnormalities tended to be localized in the occipital area [7, 12, 13] which is known as one of the least susceptible areas for electrically induced after discharges [8] . The reasons that clinically recognizable convulsions were less likely to occur after 3 years of age were considered to be as follows: firstly the cortical lesions became too weak to produce subcortical secondary foci, and secondly some other mechanisms developed to suppress the epileptogenesis. We prefer the second consideration, because at these ages the activity of cortical foci should be increased because of greater incidence of paroxysmal discharges after 4 years of age. Recently we detected increased excretion of catecholamine (CA) metabolities in urine in cases of FCMD, particularly of older patients (unpublished data). This suggested the existence of exaggeration of CA turnover in FCMD, and in this condition chloral hydrate or its metabolites might cause a paradoxical effect instead of inducing sleep. This could cause the ineffectiveness of hypnotics in FCMD, and on the other hand could reduce the susceptibility of seizures in older cases. It was known that the effects of kindling subsided in states with exaggerated CA metabolism [10]. The cerebellum also has efferent connection with locus ceruleus [14], and with its tonically inhibitory effects on the nucleus, influence the amplitude of pontogeniculo-occipital (pGO) spikes [4]. This sug118 Brain & Development, Vol 1, No 2, 1979
gests cerebellar influence on norepinephrine (NE) metabolism [4]. Cerebellectomy caused increase in amplitude of PGO spikes and also increased NE turnover [4]. Cerebellar pathology of FCMD did some roles in subsiding epileptic mechanism by increasing NE or CA turnover. FCMD needs to be studied from these viewpoints. FCMD is a genetically determined disease with fundamentally identical CNS pathologies, which occur around the 5th to 6th gestational month and could be a natural model for studying the epileptogenesis of prenatal cortical lesions, which in turn could show some suggestion of neuronal influence on peripheral systems. Acknowledgment This work was supported by a grant from the Ministry of Health and Welfare, Japan. References 1. Chou SM: Reappraisal of neuropathology of Fukuyama type congenital muscular dystrophy. Presented at the Annual Meeting Research Group, 1976, Tokyo, Japan. 2. Colasanti BK, Hartman ER, Craig CR: Electrocorticogram and behavioral correlates during the development of chronic cobalt experimental epilepsy in the rat. Epi/epsia 15: 361-373, 1974. 3. Fukuyama Y, Kawazura M, Haruna H: A peculiar form of congenital muscular dystrophy. Pediat Univ Tokyo (Tokyo) 4: 5-8, 1960. 4. Gadea-Ciria M: Differential effects of cerebellecto my and frontal lobe lesions upon PGO waves during paradoxical sleep (PS) in the cat. In Koella WP, Levin P (eds): Sleep 1976. S Karger, Basel, 1977, pp 219-222, 5. Gloor P, Quesney LF, Zumstein H: Pathophysiology of generalized penicillin epilepsy in the cat: The role of cortical and subcortical structures. II. Topical applications of penicillin to the cerebral cortex and to subcortical structures. Electroencephalogr Clin Neurophysiol 43: 79-94,1977. 6. Kagawa K, Mori H, Fukuyama Y, et al: Clinical and electroencephalographic study in febrile convulsions. Brain Dev (Tokyo) (Domestic Ed) 8: 53-64,1976. 7. Kamoshita S, Konishi Y, Segawa M, et al: Congenital muscular dystrophy as a disease of the cen tral nervous system. Arch Neurol 33: 513516,1976. 8. Marson CA: Electrical stimulation. In Purpura DP, Penry JK, Tower DB, et al (eds): Experi· mental Model of Epilepsy. Raven Press, New York, 1972, pp 147-172. 9. Nomura Y, Segawa· M, Murakami T, et al: Reappraisal of CNS pathology of Fukuyama type
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14. 15 .
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16. Velasco M, Velasco F , Cepeda C, et al:Alumina cream induced focal motor epilepsy in cat. I. Wakefulness sleep modulation of cortical paroxysmal EEG spikes. Electroencephalvgr Clin Neurophysiol43: 59-66, 1977. 17. Wilder B J: Projection phenomena and secondary epileptogenesis-Mirror foci. In Purpura DP, Penry JK, Tower DB, et al (eds): Experimental Model of Epilepsy. Raven Press, New York, 1972, pp 85-122. 18. Yamauchi T , Hirabayashi Y, Mohri Y, et al: Ontogenetic · studies of seizure patterns and seizure activities induced by cortical focus. Psychiat Neural lap (Tokyo) 30: 241-252, 1976. 19. Yoshioka M, Okuno T , Handa Y, et al : Central nervous system involvement in progressive mus· cular dystrophy. Presented at the IVth International Congress on Neuromuscular Diseases, Montreal, 1978.
Segawa, et al: Fukuyama type CMD 119
