EXPERIENCE OF ANTIOXIDANT TREATMENT IN NEURONAL CEROID-LIPOFUSCINOSIS OF SPIELMEYER-SJDGREN TYPE 1 P. Santavuori and R. Moren
Santavuori, P. and Moren, R.: Experience of antioxidant treatment in neuronal ceroid-lipofuscinosis of Spielmeyer-Sjogren type. Neuropadiatrie 8: 333—344 (1977). A therapeutic trial with antioxidants in neuronal ceroid lipofuscinonis (NCL) of Spielmeyer-Sjogren type is presented. The series consisted of 46 patients, 23 of whom received antioxidants while 23 served as controls. At the start of the trial the patients were classified into two groups on the basis of their IQs. Eleven children, aged 6V2 to 12 years, were of low normal or subnormal intelligence (treatment group I). After an observation period of 5 to 6 years a significant change in IQ was seen in 6 children; an improvement was noticed in 2 boys and a deterioration in 4 patients. The IQs were higher, the neurological signs less marked and epilepsy less frequent among the patients receiving antioxidants than among the controls. The therapy did not benefit vision and it was unsuccessful in advanced cases. The results are discussed and compared with those reported by other authors. NCL
Spielmeyer-Sjogren's disease
antioxidants
The slowly progressive type of neuronal ceroid-lipofuscinosis (NCL) called Spielmeyer-Sjogren's disease (Zeman and Dyken 1969) is characterized by gradual loss of vision, beginning at the age of 4 to 8 years, accompanied by progressive dementia and impairment of speech and motor functions and usually leading to death by the age of 18 years. Only a few therapeutic attempts have been published. Trials with cholestyramine resin, centrophenoxine and synthetic and vitamin antioxidants have been reported (von Crevald et al. Received: March 16, 1977
1967, Zeman et al. 1970> Melchior et al. 1972, Koppang 1975). Zeman et al. (1970) put forward the hypothesis that NCL is due to the peroxidation of polyunsaturated fatty acids and that this reaction could be counteracted by antioxidant therapy. This hypothesis encouraged us to carry out a clinical trial with antioxidant treatment in Spielmeyer-Sjogren's disease. Material and methods The total series consisted of 46 patients, 23 of whom were subjected to
Accepted: March 29, 1977
Address: P. S., Children's Hospital, University of Helsinki, Stenbackink. 11, 00290 Helsinki 29, Finland Acknowledgements: We are indebted to Prof. W. Zeman and Prof. E. Kivalo, who encouraged us to start antioxidant treatment in Spielmeyer-Sjogren's disease, and to Messrs. Orion Oy, Drug Manufacturers for supplying us with the drugs. We are also indebted to Associate Professor Jaakko Perheentupa for valuable discussions and to the personnel of the Finnish Blind Schools and Institutes for the Mentally Retarded. 1 This work was supported by grants from Paulo Foundation, Foundation for Pediatric Research and The Research Department Rinnekoti Institution for Mentally Retarded.
333
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Children's Hospital, University of Helsinki, Finland
Vol. 8, No. 4, 1977
treatment. They were divided into two groups, I and 11, on the basis of their intelligence quotients (by WHO'S classification) at the institution of therapy. Treatment group I consisted of 11 children, 7 male and 5 female, aged 6l/2 to 12 years. Six had a low normal intelligence and 5 were mentally subnormal (Table I). The children were neurologically and psychologically tested at the Children's Hospital, University of Helsinki, before the institution of treatment and subsequently once a year. The verbal Wechsler Intelligence Scale for Children was used because in our experience this test is reliable in repeat, without bias from school training or visual failure. During the last two years some of the children were tested by a psychologist working at the Blind School of Jyvaskyla. The patients have been followed up for 5 to 6 years. Table I Intelligence quotients a t the start of therapy in treatment groups (WHO'S classification) -
Intelligence Levels Average Low normal 85-95 Subnormal 68-85 Mental retardation Mild 52-67 Moderate 36-51 Severe 35-20 Profound 20
Treatment Treatment group I group I1
1
Neuropidiatrie
Treatment group 11 consisted of 12 mentally retarded patients, six male and six female, at the institution of therapy aged 10'12 to 20 years (Table I). These patients were examined at the Rinnekoti Institute (an institute for the mentally retarded) or occasionally at the Children's Hospital, University of Helsinki. Seven patients have been followed up for 6 years. Because of the death of the patients the observation time in the remaining 5 cases has been 6 months, 3 years, 4l/s years, 5 years and 5l/z years, respectively. I t soon became evident that it would be difficult to evaluate the treatment without a control group. All Finnish schools for blind children and all institutes for the mentally retarded were searched for suitable candidates. Children of about the same age, with the same duration of illness and with about the same IQ at the onset of the disease were chosen as controls. In some cases psychological tests were not performed, but the children were considered normal. Control group I consisted of 4 boys and 7 girls. At the beginning of the observation time 8 children were inmates at schools for the blind, one girl visited a school for mentally subnormal children and 2 were inmates at an institute for the mentally retarded. The patients were subjected to neurological and psychological tests once a year. The observation time ranged from 2 to 4 years. Control group I I consisted of 12 mentally retarded patients, 8 male and 4 female. The patients were examined
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Santavuori and Moren
Antioxidant treatment in ceroid-lipofuscinosis
Intelligence
An additional control group, group ZZZ, consisted of 20 patients born in 1940-1956. Fourteen of them had died before this study was started, but their hospital records were available. These patients were examined only once or twice.
A significant (9-10 points) change in the intelligence quotient was observed in 6 patients (Table 11). An improvementwas noticed in 2 boys (cases 5 and 6) and a deterioration in 4 children (cases 3, 7, 8 and 9). The deterioration was marked in 3 patients (cases 7, 8, 9). (See Tables I1 and 111).
All patients of both the treatment and control groups showed vacuolated lymphocytes in the peripheral blood. The lymphocytes were also studied electronmicroscopically in 10 cases. Electron-dense lamellary particles, with regard to structure and dimension identical with the so-called fingerprint bodies (Aula et a1 1975) were observed in all cases. All patients in treatment group I and in control group I had an abolished electroretinogram (ERG). A typical clinical course with tapetoretinal degeneration was seen in all cases in treatment group I1 and control groups I1 and 111. Patients who died during the observation period were examined neuropathologically (Haltia). The therapy consisted of butulated hydroxy toluene (BHT) in a daily dose of 0.5 mg/kg (the highest dose allowed in Finland), 1.0 g vitamin E, 0.5 g vitamin C and 1.0 g methionine. In four patients (cases 1, 2, 6, 7) the vitamin E dose was increased to 1.5 g after one year of treatment.
Results The results are summarized in Tables 11, 111, IV, V and VI.
Neurological signs (Table IV)
The neurological signs were classified as slight in 4 children. In these, only a slight aggravation of the abnormalities was noted during the observation time (cases 3, 5, 10 and 11). One boy (case 10) showed slight speech impairment, but his motoric clumsiness nearly disappeared. Definite, though not marked, deterioration was obvious in 5 cases (cases 1, 2, 4, 6 and 7). In these, the neurological signs were classified as significant. A marked increase in neurological signs was noticed in one boy (case 8) and one girl (case 9). None of the patients was severely affected. Vision
Two patients (cases 2 and 3) had a vision of finger count 50 cm; the remainder were blind. Epilepsy
During the observation period 5 children (cases 3, 4, 7, 9 and 11) developed epileptic fits. In most cases the seizures were occasional. One boy (case 8) had convulsions before the institution of treatment.
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Treatment group I
once a year or every 2 years. The observation period is 4 years.
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Santavuori and Moren
Table I I IQs at the end of the observation time in treatment group I and control group I Treatment Control group I group I 1 3
1
Subnormal
5
5
Mentally retarded
2
5
Table I l l
Treatment group I1 One boy aged 15.9 years showed definite, though not marked, aggravation of the neurological signs, but no significant change in IQ. One girl aged 15.11 years definite thought not marked, deterioration in both IQ and neurologically. These two patients are relatively independent in their daily life.
IQs in treatment group I
Case
Present
IQ
I Q during the observation period
number
age
Initial
1 yr
2 yrs
3 yrs
11.0 yrs
85
89
90
11.3 yrs
90
92
11.11 yrs
90
87
12.6 yrs
72
4 yrs
5 yrs
91
85
81
96
89
85
85
81
85
81
81
69
67
66
76
72
13.7 yrs
85
96
85
99
100
100
14.7 yrs
72
71
77
86
80
85
14.8 yrs
94
89
96
90
87
84
15.10 yrs
79
74
79
62
69
67
60
15.11 yrs
69
74
74
70
57
55
47
16.1 yrs
70
71
77
75
70
72
74
17.3 yrs
90
96
90
86
90
91
3 yrs
4 yrs
95
Table IV Table V Case number
Neuropidiatrie
Present age
1
9.6 yrs
85
10.9 yrs
75
3
11.5 yrs
80
4
13.4 yrs
75
5
13.4 yrs
80
6
13.5 yrs
89
7
14.2 yrs
73
8
(15.0 yrs :>)
79
9
15.10 yrs
81
10
(15.6 yrs :>)
70 "
11
16.6 yrs
89
'" According hospital records
104 72
see pages 337 and 338
Intelligence quotients in control group I
IQs at the start of the observation time
2
6 yrs
Observation time 1 yr 2 yrs
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Average Low normal
1
Duration of therapy
5 yrs
4 yrs
5 yrs
5 yrs
6 yrs
5 yrs
6 yrs
6 yrs
6 yrs
5 yrs
5 yrs
Present age
10.0 yrs
10.3 yrs
10.11 yrs
11.6 yrs
12.7 yrs
13.7 yrs
13.8 yrs
14.10 yrs
14.11 yrs
15.1 yrs
16.1 yrs
Normal
light perception
blind
blind
blind
0.2 0.a.
Slight dysdiadochocinesis
Slight motor clumsiness
blind
light perception
Slight hypotonia
blind
blind
0.1 0.a.
f.c. 1'12 m
blind
Slight dysdiadochocinesis clumsy finger movements Brisk patellar yerks
Within normal limits
Normal
f. c. 'In m
0.110.1
1.011.0
Brisk tendon jerks
f. c. 'In m
blind
0.210.2
Within normal limits
blind
Vision
perception light
f.c. 3 m
Within normal limits
Within normal limits
Vision
Neurological signs
Slight occasional tremor
Slight dysarthria
Dysarthris speech. Slight rigidity. Unable to stand or jump on one foot. Dysdiadochocinesis
Severe dysarthria. Rigidity. Tremor. N o t able t o jump or stand on one foot. Walks with short steps. Straight stature.
Slight dysdiadochocinesis, dysarthria Tremor. Difficulties to stand and jump on one foot
Dysdiadochocinesis Brisk tendon jerks
Slight dysdiadochocinesis Brisk patellar jerks
Brisk tendon jerks, ancle clonus o n the right Difficulty in standing on one foot. Slight tremor
Slight rigidity and spasticity. Difficulty in standing or jumping on one foot. Brisk tendon jerks
Slight dysdiadochocinesis difficulty in standing on one foot
Neurological signs
Examinations in spring 1976 Tests
Neurological signs in treatment group I
Examinations before the start of medication
Tuble IV
15 yrs
-
-
8,6 yrs
11.8 yrs
-
-
9.6 yrs
10.9 yrs
-
-
Age at onset of epilepsy
8
00
13.4 yrs
13.4 yrs
4
5
(3 ~ r s )
4 yrs 'i
Brisk tendon jerks :>
Normal "
Slight motor clumsiness
4 yrs
11.5 yrs
3
6 yrs
Normal ::.
4 yrs" (2 yrs)
10.9 yrs
2
Brisk tendon jerks
4 yrs
9.6 yrs
Observation Neurological signs time
1
Case Present num- age ber
Test in spring 1976
light perception
blind
blind
0.110.1
light perception
0.110.1 blind
blind
f. c. l12 m
f. c. 112 m
Vision
Vision
Initial tests
7.6 yrs
7.1 1 yrs
7.5 yrs
Onset of epilepsy
Unable to stand on one foot, difficulty in jumping on one foot. Short steps. Dysdiadochocinesis. Slight spasticity. Brisk tendon jerks.
10.8 yrs
Dysarthric speech. Forewardbent stature and bent knees when walking. Tremor. Rigidity. Dysdiadochocinesis.
Dysarthric speech. Bent knees when walking. Unable to stand or jump on one foot. Muscular h~pertonia. Brisk tendon jerks.
Unable to jump on one foot. Slight rigidity. Week tendon jerks.
Slightly bent stature. Unable t o stand and jump on one foot. Dysdiadochocinesis. Slight muscular hypertonia. Brisk tendon jerks.
Neurological signs
Table VZ Neurological signs in control group I
10 yrs "o'rma1 (2.5 yrs)
4 y r s ' m i t h i n normal limits (4 months) except for sensorineural hearing loss (Diagnosed at 2 yrs)
10 yrs
15.10 yrs
12.10 yrs (16.6 yrs)
16.6 yrs
9
10
11
a According hospital records
2.2 yrs
13.7 yrs (15.0 yrs)
S
Normal "
" Behavioural disturbances
Motor clumsiness
Slightly forward-bent stature. Unable to stand or jump on one foot. Rigidity
4 yrs
14.2 yrs
Slight dysdiadochocinesis
7
4 yrs
13.5 yrs
Observation Neurological signs time
6
Case Present num- age ber
Test in spring 1976
light perception
light perception
Vision
9.6 yrs
13.6 yrs
Aged 12.6: Marked cervical scoliosis. Rigidity of upper extremities. Brisk tendon jerks in lower limbs. Slightly bent knees when walking. Dysdiadochocinesis. Brisk tendon jerks. Slight muscular hypertonia.
blind
blind
9.0 yrs
Aged 13: Unable to walk and sit. Died after an epileptic fit.
light perception
13.6 yrs
10.6 yrs
Anarthria. Unable to walk or sit. Marked rigidity and spasticity.
blind
Dysarthric speech. Unable to stand or jump on one foot. Tremor. Slight muscular hypertonia. Brisk tendon jerks.
9.0 yrs
Slight dysarthria. Unable to jump on one foot and difficulty in standing on one foot. Slight tremor and rigidity.
light perception
blind
Onset of epilepsy
Neurological signs
Vision
Initial tests
Table VI Cont.
In the remaining cases marked impairment of all skills was observed during the observation period. All these patients showed severe dysarthria and none of them was able to walk. Five patients died. Their ages at death were 15.10, 17.0, 17.11, 20.0, and 21.4 years, respectively. Control group I Intelligence (Table V)
One girl had a low normal IQ, 5 patients had subnormal IQs and 5 patients were mentally retarded. A significant deterioration was noticed in 8 patients (cases 1, 3, 4, 6, 7, 8, 9 and 10) during the observation period. The impairment was very marked in four patients (cases 6, 7, 8 and 10). One boy (case 2) was discharged from a school for the blind because of behavioural disturbances. Neurological signs (Table VI)
One girl (case 11) showed only slight aggravation of her neurological signs, which were classified as significant. In the remaining cases moderate or marked neurological impairment occurred. The neurological signs were considered marked in 7 children (1, 2, 3, 4, 5, 6 and 9) and severe in 3 (cases 7, 8 and 9). Two of the latter (cases 8 and 10) died during the observation time. Vision
Three patients still had some light perception, although of no significance in their daily life. The remainder were completely blind. Epilepsy
Nine children had epileptic fits, which were relatively frequent (several per
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NeuropZdiatrie
month or week) in three cases (nos. 2, 3Y6). Control group I1 All patients showed a definite deterioration of all skills during the observation period. Five patients died at the age of 16.0, 16.4, 17.4 and 23.6 years, respectively. Only two patients were able to walk with support; the remainder were severely affected and unable to move about. Control group I11 In one girl of this group progression of the disease was slower than usual. At the age of 14 she still had an I Q of 89, and she was not considered mentally retarded until she was 18. Since the age of 28 she has been entirely helpless. In the remainder of cases the course of the disease was typical. Discussion Sjogren described Spielmeyer-Sjogren's disease in detail in an extensive report (1931). The children of his large series (1 15 patients) showed normal development until the age of 5 to 8 years, when visual failure was noticed. Mental retardation was observed some years later, and at that time a typical impairment of speech appeared. The first epileptic seizure occurred at an average age of 11.0 years. By that time the patients were already mentally retarded. Mental retardation was noticed before the visual symptoms in 10 cases only. . However, in some of Sjogren's patients the onset of mental impairment occurred at a later age. Owing to this varia-
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Santavuori and Moren
Antioxidant treatment in ceroid-lipofuscinosis
Starting our trial we felt that a double blind test in a progressive encephalopathy was not justified. For this reason all patients with Spielmeyeu-Sjogren's disease admitted to the Children's Hospital, University of Helsinki, were treated (9 cases with an observation time ranging from only 3 months to 2 years are not included in this report). Later, it became evident that a reliable evaluation of the results of our therapeutic trial would not be possible without a control group. Sjogren's material seemed somewhat out-of-date for comparison. It is unfortunate that the controls were not as thoroughly examined at the onset of illness as the children of treatment group I. However, according to the records of the local hospitals, where the first examinations were performed, all these patients were mentally quite normal at the onset of visual impairment. We tried to discover a possible correlation between the initial test results (non-treated patients) and the clinical course, which might be of significance in evaluating the therapy given, but none was observed. Several factors may be assumed to influence the I Q of patients with Spielmeyer-Sjogren's disease. When a child rather suddenly finds that his vision is impaired, the situation is alarming to both the child and his family. Therefore, the patients are usually anxious when first seen, and the scores on psychological tests may be falsely low. La-
ter, when the children have got used to their handicap, they are capable of better achievements. Stimulation of various kinds, regular attendance at school and an independent, normal life without overprotection from the family keep the patients more alert. It is clear that the situation varies in different families with children suffering from Spielmeyer-Sjogren's disease, but such differences can hardly explain the present results. A significant difference was observed between treatment group I and control group I. The IQs in treatment group I were higher, the neurological signs were less marked and epilepsy was less common than in control group I. As these groups were rather small, it is of course possible that children with an unusually show progression of the disease were overrepresented by change in treatment group I., However, control groups I1 and I11 consisted of a total of 42 patients, and only one of these showed an atypical clinical course. After an observation time of 5 and 6 years, respectively, two patients (cases 5 and 6) in treatment group I had significantly higher IQs than at the institution of antioxidant treatment. In control group I only three patients did not show significant decreases of their IQs, and an increased I Q was observed in none. It may be presumed that the antioxidant medication had at least some favourable effect on the course of the disease in the patients of treatment group I. Visual impairment in the children of treatment group I increased significantly during the observation period.
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tion in the course of Spielmeyer-Sjogren's disease a clinical trial is difficult.
As regards this defect antioxidant therapy thus proved ineffective. The difference between treatment group I1 and control group I1 was very slight. Consequently, no benefit seemed to be derived from antioxidants in advanced cases. The neuropathological findings were typical in all examined cases (Haltia, personal communication). The difference between the present results, except in treatment group I, and those of Sjogren is not great. It is amazing that, in spite of all modern therapeutic resources, the mean age at death in Spielmeyer-Sjogren's disease is today about the same (18.8 years in the present series) as 40 years age (17.818.2 years in Sjogren's series), Melchior et al. (1972) have published a pilotstudy on the treatment of patients with Spielmeyer-Sjogren's disease a. m. Zeman. They described three patients who received vitamin E, vitamin C and methionine intermittently for 26, 24 and 14 months, but no BHT. The doses were the same as in the present trial. The patient who was treated longest seemed to make some progress during the therapy, whereas the other two were uncertain. One boy had an episode of nausea, vomiting and anorexia, which disappeared when methionine was reduced. In the present trial no side-effects or complications from the treatment occurred. Zeman treated 7 patients (1974) with antioxidants. The daily dose consisted of BHT 0.2 mg or Santoquin 100 mg, vitamin E 2.0 g, vitamin C 0.5 g and methionine 1.0 g. Zeman's series contained 3 girls aged 7 to 8 years, who
Vol. 8, No. 4, 1977
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NeuropZdirtrie
were in the process of being discharged from their public schools, but were able to continue at school after the institution of treatment. Their behaviour was normalized. Zeman noticed improvement even in severely affected patients. In this respect the results of the present trial are not compatible with those of Zeman. We found no significant difference in behaviour between treatment group I and control group I. No difference was observed between the patients who received 1.5 g of vitamin E and those given a daily dose of 1.0 g. Trials with cholestyramine resin and centrophenoxine have been unsuccessful (von Crevald et al. 1967). Koppang performed a therapeutic trial on English Setters with autosomal recessive disease, in which homozygous animals exhibit a clinical and morphological picture similar to that seen in Spielmeyer-Sjogren's disease (Koppang 1973, 1975). In serial brain biopsies Koppang noticed that pigment was stored in the neurons, already at birth and increased linearly in amount with age. The first clinical signs appeared wheqthe intracellular storage had reached an advanced stage, usually during the second year of life. Treatment was instituted at the age of 2 to 3 months. Untreated litters showed clinical signs 2 to 3 months earlier than treated litters. Koppang used three different therapeutic combinations: I) tocopherol 1.0 IE daily, 2) tocopherol 1.0 IE vitamin C 0.5 g methionine 1.0 g BHT 0.2 g daily, 3) parenteral tocopherol 1.0 g twice a week. There were no differences in results with the va-
+
+ +
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Santavuori and Moren
rious therapies. In the present trial no difference was noticed between the patients present receiving an additional dose of vitamin E and the other patients of treatment group I. Sjogren (1931) and Zeman (1974) assumed that mental impairment in Spielmeyer-Sjogren's disease sets in some years later than the visual failure. However, none of the children of the present study had an average intelligence quotient when first tested. The parents and siblings of these children are of average, bright normal or superior in intelligence. Perhaps the mental retardation sets in early, but the progress is in most cases slow during the first few years. The frequent school problems as well as the behavioural disturbances of patients with Spielmeyer-Sjogren's disease may at least partly be attributed to early mental impairment, which is hardly noticeable without careful psychological testing. On the basis of previous reports (Melchior et al. 1972, Zeman 1974, Koppang 1975) and the present results, antioxidant therapy in Spielmeyer-Sjogren's disease seems to be indicated. However, the medication used so far is unfortunately only able to retard the progress of the disease, they do not cure the patients. Therefore, the patients and their families are in need of support to be able to lead a happy life as long as possible. Furthermore, trials with other antioxidants are required. Zusammenf assung Ein Versuch der therapeutischen Wirkung der Antioxydantien in der neuro-
nalen Ceroidlipofuscinose (NCL) vom Spielmeyer-Sjogren-Typus wird dargestellt. Die Serien urnfafiten 46 Patienten, von denen 23 Antioxydantien erhielten, wahrend die anderen 23 zur Kontrollgruppe gehorten. Zu Beginn des Versuchs wurden die Patienten in zwei Gruppen aufgrund ihrer I Q eingeteilt. Der Intelligenz nach gehorten elf Kinder im Alter von 6 l / 2 bis 12 Jahren zu den Minderbegabten oder zu den Grenzfallen in Richtung Schwachsinn (Therapiegruppe I). Nach einer Observationszeit von 5 bis 6 Jahren war eine signifikante Veranderuq des IQ bei 6 Kindern zu beobachten; eine Verbesserung wurde bei 2 Jungen und eine Verschlechterung bei 4 Patienten gesehen. Die I Q waren hoher, die neurologischen Befunde weniger auffallig, und epileptische Anfalle waren weniger haufig unter den Patienten zu beobachten, die Antioxydantien erhielten, als in der Kontrollgruppe. Von der Therapie war kein Vorteil fur das Sehvermogen zu erzielen, und in den vorgeruckten Fallen war sie nutzlos. Es werden die Resultate diskutiert sowie mit denen der anderen Autoren verglichen. References Aula, P., Rapola, J. and Anderson, L. J.: Distribution of cytoplasmic vacuoles in blood T and B lymphocytes in two lysosomal disorders. Virchows Arch. & Cell Path. 1 8 : 263 (1975). Von Crevald, S. and Hooghwinkel, G . J. M.: Lipids in blood plasma and erythrocytes in juvenile amaurotic idiocy. Arch. Neurol. 17: 225 (1967). Koppang, N. : Canine ceroid-lipofuscinosis - A model for human neuronal ceroidlipofuscinosis and aging. Mechan. Aging Dev. 74: 421 (1973). - -
~
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Antioxidant treatment in ceroid-lipofuscinosis
4. Koppang,
N.: Ceroid-lipofuscinosis hos engelsk setter. Terapiforsok. Syndr. Spielmeyer-vogt. Symp. Dianalund, Danmark 1975. 5. MelQior, J. C., Clausen, J., Konat, C. and Brandt, S.: Are there abnormalities in the fatty acid metabolism in cerioid lipofuscinosis (Spielmeyer-Vogt's syndrome)? Psykiskt utveddingsstorda. Symp. Lidingo, Sweden 1071 171L.
6. Sjogren, T.: Die juvenile amaurotische Idiotie. Hereditas. 14: 197 (1931). 7. Zeman, W. and Dyken, P.: "Neuronal ceroid-lipofuscinosis (Batten's disease). Re-
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Neuropddiatrie
lationship to amaurotic family idiocy." Pediatrics. 44: 570 (1969). 8. Zeman, W., Donahue, S., Dyken, P. and Green, J.: The neuronal ceroid-lipofuscinoses (Batten-Vogt syndrome). Ed. by P. J. Vinken and G. W. Bruyn. Chapter 25. Handbook of Clinical Neurology. Vol. 10. Leucodystrophies and Poliodystropies. Ch. 25. North Holland Publishing Co. Amsterdam 1970, p. 617. 9. Zeman, W.: Presidential Address. "Studies
in the neuronal ceroidlipofuscinosis". Neuropath & Exper. Neurol. 33: 1 (1974). Downloaded by: University of British Columbia. Copyrighted material.
Santavuori and Moren
Santavuori, P. and Moren, R.: Experience of antioxidant treatment in neuronal ceroid-lipofuscinosis of Spielmeyer-Sjogren type. Neuropadiatrie 8: 333—344 (1977). A therapeutic trial with antioxidants in neuronal ceroid lipofuscinonis (NCL) of Spielmeyer-Sjogren type is presented. The series consisted of 46 patients, 23 of whom received antioxidants while 23 served as controls. At the start of the trial the patients were classified into two groups on the basis of their IQs. Eleven children, aged 6V2 to 12 years, were of low normal or subnormal intelligence (treatment group I). After an observation period of 5 to 6 years a significant change in IQ was seen in 6 children; an improvement was noticed in 2 boys and a deterioration in 4 patients. The IQs were higher, the neurological signs less marked and epilepsy less frequent among the patients receiving antioxidants than among the controls. The therapy did not benefit vision and it was unsuccessful in advanced cases. The results are discussed and compared with those reported by other authors. NCL
Spielmeyer-Sjogren's disease
antioxidants
The slowly progressive type of neuronal ceroid-lipofuscinosis (NCL) called Spielmeyer-Sjogren's disease (Zeman and Dyken 1969) is characterized by gradual loss of vision, beginning at the age of 4 to 8 years, accompanied by progressive dementia and impairment of speech and motor functions and usually leading to death by the age of 18 years. Only a few therapeutic attempts have been published. Trials with cholestyramine resin, centrophenoxine and synthetic and vitamin antioxidants have been reported (von Crevald et al. Received: March 16, 1977
1967, Zeman et al. 1970> Melchior et al. 1972, Koppang 1975). Zeman et al. (1970) put forward the hypothesis that NCL is due to the peroxidation of polyunsaturated fatty acids and that this reaction could be counteracted by antioxidant therapy. This hypothesis encouraged us to carry out a clinical trial with antioxidant treatment in Spielmeyer-Sjogren's disease. Material and methods The total series consisted of 46 patients, 23 of whom were subjected to
Accepted: March 29, 1977
Address: P. S., Children's Hospital, University of Helsinki, Stenbackink. 11, 00290 Helsinki 29, Finland Acknowledgements: We are indebted to Prof. W. Zeman and Prof. E. Kivalo, who encouraged us to start antioxidant treatment in Spielmeyer-Sjogren's disease, and to Messrs. Orion Oy, Drug Manufacturers for supplying us with the drugs. We are also indebted to Associate Professor Jaakko Perheentupa for valuable discussions and to the personnel of the Finnish Blind Schools and Institutes for the Mentally Retarded. 1 This work was supported by grants from Paulo Foundation, Foundation for Pediatric Research and The Research Department Rinnekoti Institution for Mentally Retarded.
333
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Children's Hospital, University of Helsinki, Finland
Vol. 8, No. 4, 1977
treatment. They were divided into two groups, I and 11, on the basis of their intelligence quotients (by WHO'S classification) at the institution of therapy. Treatment group I consisted of 11 children, 7 male and 5 female, aged 6l/2 to 12 years. Six had a low normal intelligence and 5 were mentally subnormal (Table I). The children were neurologically and psychologically tested at the Children's Hospital, University of Helsinki, before the institution of treatment and subsequently once a year. The verbal Wechsler Intelligence Scale for Children was used because in our experience this test is reliable in repeat, without bias from school training or visual failure. During the last two years some of the children were tested by a psychologist working at the Blind School of Jyvaskyla. The patients have been followed up for 5 to 6 years. Table I Intelligence quotients a t the start of therapy in treatment groups (WHO'S classification) -
Intelligence Levels Average Low normal 85-95 Subnormal 68-85 Mental retardation Mild 52-67 Moderate 36-51 Severe 35-20 Profound 20
Treatment Treatment group I group I1
1
Neuropidiatrie
Treatment group 11 consisted of 12 mentally retarded patients, six male and six female, at the institution of therapy aged 10'12 to 20 years (Table I). These patients were examined at the Rinnekoti Institute (an institute for the mentally retarded) or occasionally at the Children's Hospital, University of Helsinki. Seven patients have been followed up for 6 years. Because of the death of the patients the observation time in the remaining 5 cases has been 6 months, 3 years, 4l/s years, 5 years and 5l/z years, respectively. I t soon became evident that it would be difficult to evaluate the treatment without a control group. All Finnish schools for blind children and all institutes for the mentally retarded were searched for suitable candidates. Children of about the same age, with the same duration of illness and with about the same IQ at the onset of the disease were chosen as controls. In some cases psychological tests were not performed, but the children were considered normal. Control group I consisted of 4 boys and 7 girls. At the beginning of the observation time 8 children were inmates at schools for the blind, one girl visited a school for mentally subnormal children and 2 were inmates at an institute for the mentally retarded. The patients were subjected to neurological and psychological tests once a year. The observation time ranged from 2 to 4 years. Control group I I consisted of 12 mentally retarded patients, 8 male and 4 female. The patients were examined
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Santavuori and Moren
Antioxidant treatment in ceroid-lipofuscinosis
Intelligence
An additional control group, group ZZZ, consisted of 20 patients born in 1940-1956. Fourteen of them had died before this study was started, but their hospital records were available. These patients were examined only once or twice.
A significant (9-10 points) change in the intelligence quotient was observed in 6 patients (Table 11). An improvementwas noticed in 2 boys (cases 5 and 6) and a deterioration in 4 children (cases 3, 7, 8 and 9). The deterioration was marked in 3 patients (cases 7, 8, 9). (See Tables I1 and 111).
All patients of both the treatment and control groups showed vacuolated lymphocytes in the peripheral blood. The lymphocytes were also studied electronmicroscopically in 10 cases. Electron-dense lamellary particles, with regard to structure and dimension identical with the so-called fingerprint bodies (Aula et a1 1975) were observed in all cases. All patients in treatment group I and in control group I had an abolished electroretinogram (ERG). A typical clinical course with tapetoretinal degeneration was seen in all cases in treatment group I1 and control groups I1 and 111. Patients who died during the observation period were examined neuropathologically (Haltia). The therapy consisted of butulated hydroxy toluene (BHT) in a daily dose of 0.5 mg/kg (the highest dose allowed in Finland), 1.0 g vitamin E, 0.5 g vitamin C and 1.0 g methionine. In four patients (cases 1, 2, 6, 7) the vitamin E dose was increased to 1.5 g after one year of treatment.
Results The results are summarized in Tables 11, 111, IV, V and VI.
Neurological signs (Table IV)
The neurological signs were classified as slight in 4 children. In these, only a slight aggravation of the abnormalities was noted during the observation time (cases 3, 5, 10 and 11). One boy (case 10) showed slight speech impairment, but his motoric clumsiness nearly disappeared. Definite, though not marked, deterioration was obvious in 5 cases (cases 1, 2, 4, 6 and 7). In these, the neurological signs were classified as significant. A marked increase in neurological signs was noticed in one boy (case 8) and one girl (case 9). None of the patients was severely affected. Vision
Two patients (cases 2 and 3) had a vision of finger count 50 cm; the remainder were blind. Epilepsy
During the observation period 5 children (cases 3, 4, 7, 9 and 11) developed epileptic fits. In most cases the seizures were occasional. One boy (case 8) had convulsions before the institution of treatment.
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Treatment group I
once a year or every 2 years. The observation period is 4 years.
Vol. 8, No. 4, 1977
Santavuori and Moren
Table I I IQs at the end of the observation time in treatment group I and control group I Treatment Control group I group I 1 3
1
Subnormal
5
5
Mentally retarded
2
5
Table I l l
Treatment group I1 One boy aged 15.9 years showed definite, though not marked, aggravation of the neurological signs, but no significant change in IQ. One girl aged 15.11 years definite thought not marked, deterioration in both IQ and neurologically. These two patients are relatively independent in their daily life.
IQs in treatment group I
Case
Present
IQ
I Q during the observation period
number
age
Initial
1 yr
2 yrs
3 yrs
11.0 yrs
85
89
90
11.3 yrs
90
92
11.11 yrs
90
87
12.6 yrs
72
4 yrs
5 yrs
91
85
81
96
89
85
85
81
85
81
81
69
67
66
76
72
13.7 yrs
85
96
85
99
100
100
14.7 yrs
72
71
77
86
80
85
14.8 yrs
94
89
96
90
87
84
15.10 yrs
79
74
79
62
69
67
60
15.11 yrs
69
74
74
70
57
55
47
16.1 yrs
70
71
77
75
70
72
74
17.3 yrs
90
96
90
86
90
91
3 yrs
4 yrs
95
Table IV Table V Case number
Neuropidiatrie
Present age
1
9.6 yrs
85
10.9 yrs
75
3
11.5 yrs
80
4
13.4 yrs
75
5
13.4 yrs
80
6
13.5 yrs
89
7
14.2 yrs
73
8
(15.0 yrs :>)
79
9
15.10 yrs
81
10
(15.6 yrs :>)
70 "
11
16.6 yrs
89
'" According hospital records
104 72
see pages 337 and 338
Intelligence quotients in control group I
IQs at the start of the observation time
2
6 yrs
Observation time 1 yr 2 yrs
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Average Low normal
1
Duration of therapy
5 yrs
4 yrs
5 yrs
5 yrs
6 yrs
5 yrs
6 yrs
6 yrs
6 yrs
5 yrs
5 yrs
Present age
10.0 yrs
10.3 yrs
10.11 yrs
11.6 yrs
12.7 yrs
13.7 yrs
13.8 yrs
14.10 yrs
14.11 yrs
15.1 yrs
16.1 yrs
Normal
light perception
blind
blind
blind
0.2 0.a.
Slight dysdiadochocinesis
Slight motor clumsiness
blind
light perception
Slight hypotonia
blind
blind
0.1 0.a.
f.c. 1'12 m
blind
Slight dysdiadochocinesis clumsy finger movements Brisk patellar yerks
Within normal limits
Normal
f. c. 'In m
0.110.1
1.011.0
Brisk tendon jerks
f. c. 'In m
blind
0.210.2
Within normal limits
blind
Vision
perception light
f.c. 3 m
Within normal limits
Within normal limits
Vision
Neurological signs
Slight occasional tremor
Slight dysarthria
Dysarthris speech. Slight rigidity. Unable to stand or jump on one foot. Dysdiadochocinesis
Severe dysarthria. Rigidity. Tremor. N o t able t o jump or stand on one foot. Walks with short steps. Straight stature.
Slight dysdiadochocinesis, dysarthria Tremor. Difficulties to stand and jump on one foot
Dysdiadochocinesis Brisk tendon jerks
Slight dysdiadochocinesis Brisk patellar jerks
Brisk tendon jerks, ancle clonus o n the right Difficulty in standing on one foot. Slight tremor
Slight rigidity and spasticity. Difficulty in standing or jumping on one foot. Brisk tendon jerks
Slight dysdiadochocinesis difficulty in standing on one foot
Neurological signs
Examinations in spring 1976 Tests
Neurological signs in treatment group I
Examinations before the start of medication
Tuble IV
15 yrs
-
-
8,6 yrs
11.8 yrs
-
-
9.6 yrs
10.9 yrs
-
-
Age at onset of epilepsy
8
00
13.4 yrs
13.4 yrs
4
5
(3 ~ r s )
4 yrs 'i
Brisk tendon jerks :>
Normal "
Slight motor clumsiness
4 yrs
11.5 yrs
3
6 yrs
Normal ::.
4 yrs" (2 yrs)
10.9 yrs
2
Brisk tendon jerks
4 yrs
9.6 yrs
Observation Neurological signs time
1
Case Present num- age ber
Test in spring 1976
light perception
blind
blind
0.110.1
light perception
0.110.1 blind
blind
f. c. l12 m
f. c. 112 m
Vision
Vision
Initial tests
7.6 yrs
7.1 1 yrs
7.5 yrs
Onset of epilepsy
Unable to stand on one foot, difficulty in jumping on one foot. Short steps. Dysdiadochocinesis. Slight spasticity. Brisk tendon jerks.
10.8 yrs
Dysarthric speech. Forewardbent stature and bent knees when walking. Tremor. Rigidity. Dysdiadochocinesis.
Dysarthric speech. Bent knees when walking. Unable to stand or jump on one foot. Muscular h~pertonia. Brisk tendon jerks.
Unable to jump on one foot. Slight rigidity. Week tendon jerks.
Slightly bent stature. Unable t o stand and jump on one foot. Dysdiadochocinesis. Slight muscular hypertonia. Brisk tendon jerks.
Neurological signs
Table VZ Neurological signs in control group I
10 yrs "o'rma1 (2.5 yrs)
4 y r s ' m i t h i n normal limits (4 months) except for sensorineural hearing loss (Diagnosed at 2 yrs)
10 yrs
15.10 yrs
12.10 yrs (16.6 yrs)
16.6 yrs
9
10
11
a According hospital records
2.2 yrs
13.7 yrs (15.0 yrs)
S
Normal "
" Behavioural disturbances
Motor clumsiness
Slightly forward-bent stature. Unable to stand or jump on one foot. Rigidity
4 yrs
14.2 yrs
Slight dysdiadochocinesis
7
4 yrs
13.5 yrs
Observation Neurological signs time
6
Case Present num- age ber
Test in spring 1976
light perception
light perception
Vision
9.6 yrs
13.6 yrs
Aged 12.6: Marked cervical scoliosis. Rigidity of upper extremities. Brisk tendon jerks in lower limbs. Slightly bent knees when walking. Dysdiadochocinesis. Brisk tendon jerks. Slight muscular hypertonia.
blind
blind
9.0 yrs
Aged 13: Unable to walk and sit. Died after an epileptic fit.
light perception
13.6 yrs
10.6 yrs
Anarthria. Unable to walk or sit. Marked rigidity and spasticity.
blind
Dysarthric speech. Unable to stand or jump on one foot. Tremor. Slight muscular hypertonia. Brisk tendon jerks.
9.0 yrs
Slight dysarthria. Unable to jump on one foot and difficulty in standing on one foot. Slight tremor and rigidity.
light perception
blind
Onset of epilepsy
Neurological signs
Vision
Initial tests
Table VI Cont.
In the remaining cases marked impairment of all skills was observed during the observation period. All these patients showed severe dysarthria and none of them was able to walk. Five patients died. Their ages at death were 15.10, 17.0, 17.11, 20.0, and 21.4 years, respectively. Control group I Intelligence (Table V)
One girl had a low normal IQ, 5 patients had subnormal IQs and 5 patients were mentally retarded. A significant deterioration was noticed in 8 patients (cases 1, 3, 4, 6, 7, 8, 9 and 10) during the observation period. The impairment was very marked in four patients (cases 6, 7, 8 and 10). One boy (case 2) was discharged from a school for the blind because of behavioural disturbances. Neurological signs (Table VI)
One girl (case 11) showed only slight aggravation of her neurological signs, which were classified as significant. In the remaining cases moderate or marked neurological impairment occurred. The neurological signs were considered marked in 7 children (1, 2, 3, 4, 5, 6 and 9) and severe in 3 (cases 7, 8 and 9). Two of the latter (cases 8 and 10) died during the observation time. Vision
Three patients still had some light perception, although of no significance in their daily life. The remainder were completely blind. Epilepsy
Nine children had epileptic fits, which were relatively frequent (several per
Vol. 8, No. 4, 1977
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NeuropZdiatrie
month or week) in three cases (nos. 2, 3Y6). Control group I1 All patients showed a definite deterioration of all skills during the observation period. Five patients died at the age of 16.0, 16.4, 17.4 and 23.6 years, respectively. Only two patients were able to walk with support; the remainder were severely affected and unable to move about. Control group I11 In one girl of this group progression of the disease was slower than usual. At the age of 14 she still had an I Q of 89, and she was not considered mentally retarded until she was 18. Since the age of 28 she has been entirely helpless. In the remainder of cases the course of the disease was typical. Discussion Sjogren described Spielmeyer-Sjogren's disease in detail in an extensive report (1931). The children of his large series (1 15 patients) showed normal development until the age of 5 to 8 years, when visual failure was noticed. Mental retardation was observed some years later, and at that time a typical impairment of speech appeared. The first epileptic seizure occurred at an average age of 11.0 years. By that time the patients were already mentally retarded. Mental retardation was noticed before the visual symptoms in 10 cases only. . However, in some of Sjogren's patients the onset of mental impairment occurred at a later age. Owing to this varia-
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Santavuori and Moren
Antioxidant treatment in ceroid-lipofuscinosis
Starting our trial we felt that a double blind test in a progressive encephalopathy was not justified. For this reason all patients with Spielmeyeu-Sjogren's disease admitted to the Children's Hospital, University of Helsinki, were treated (9 cases with an observation time ranging from only 3 months to 2 years are not included in this report). Later, it became evident that a reliable evaluation of the results of our therapeutic trial would not be possible without a control group. Sjogren's material seemed somewhat out-of-date for comparison. It is unfortunate that the controls were not as thoroughly examined at the onset of illness as the children of treatment group I. However, according to the records of the local hospitals, where the first examinations were performed, all these patients were mentally quite normal at the onset of visual impairment. We tried to discover a possible correlation between the initial test results (non-treated patients) and the clinical course, which might be of significance in evaluating the therapy given, but none was observed. Several factors may be assumed to influence the I Q of patients with Spielmeyer-Sjogren's disease. When a child rather suddenly finds that his vision is impaired, the situation is alarming to both the child and his family. Therefore, the patients are usually anxious when first seen, and the scores on psychological tests may be falsely low. La-
ter, when the children have got used to their handicap, they are capable of better achievements. Stimulation of various kinds, regular attendance at school and an independent, normal life without overprotection from the family keep the patients more alert. It is clear that the situation varies in different families with children suffering from Spielmeyer-Sjogren's disease, but such differences can hardly explain the present results. A significant difference was observed between treatment group I and control group I. The IQs in treatment group I were higher, the neurological signs were less marked and epilepsy was less common than in control group I. As these groups were rather small, it is of course possible that children with an unusually show progression of the disease were overrepresented by change in treatment group I., However, control groups I1 and I11 consisted of a total of 42 patients, and only one of these showed an atypical clinical course. After an observation time of 5 and 6 years, respectively, two patients (cases 5 and 6) in treatment group I had significantly higher IQs than at the institution of antioxidant treatment. In control group I only three patients did not show significant decreases of their IQs, and an increased I Q was observed in none. It may be presumed that the antioxidant medication had at least some favourable effect on the course of the disease in the patients of treatment group I. Visual impairment in the children of treatment group I increased significantly during the observation period.
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tion in the course of Spielmeyer-Sjogren's disease a clinical trial is difficult.
As regards this defect antioxidant therapy thus proved ineffective. The difference between treatment group I1 and control group I1 was very slight. Consequently, no benefit seemed to be derived from antioxidants in advanced cases. The neuropathological findings were typical in all examined cases (Haltia, personal communication). The difference between the present results, except in treatment group I, and those of Sjogren is not great. It is amazing that, in spite of all modern therapeutic resources, the mean age at death in Spielmeyer-Sjogren's disease is today about the same (18.8 years in the present series) as 40 years age (17.818.2 years in Sjogren's series), Melchior et al. (1972) have published a pilotstudy on the treatment of patients with Spielmeyer-Sjogren's disease a. m. Zeman. They described three patients who received vitamin E, vitamin C and methionine intermittently for 26, 24 and 14 months, but no BHT. The doses were the same as in the present trial. The patient who was treated longest seemed to make some progress during the therapy, whereas the other two were uncertain. One boy had an episode of nausea, vomiting and anorexia, which disappeared when methionine was reduced. In the present trial no side-effects or complications from the treatment occurred. Zeman treated 7 patients (1974) with antioxidants. The daily dose consisted of BHT 0.2 mg or Santoquin 100 mg, vitamin E 2.0 g, vitamin C 0.5 g and methionine 1.0 g. Zeman's series contained 3 girls aged 7 to 8 years, who
Vol. 8, No. 4, 1977
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NeuropZdirtrie
were in the process of being discharged from their public schools, but were able to continue at school after the institution of treatment. Their behaviour was normalized. Zeman noticed improvement even in severely affected patients. In this respect the results of the present trial are not compatible with those of Zeman. We found no significant difference in behaviour between treatment group I and control group I. No difference was observed between the patients who received 1.5 g of vitamin E and those given a daily dose of 1.0 g. Trials with cholestyramine resin and centrophenoxine have been unsuccessful (von Crevald et al. 1967). Koppang performed a therapeutic trial on English Setters with autosomal recessive disease, in which homozygous animals exhibit a clinical and morphological picture similar to that seen in Spielmeyer-Sjogren's disease (Koppang 1973, 1975). In serial brain biopsies Koppang noticed that pigment was stored in the neurons, already at birth and increased linearly in amount with age. The first clinical signs appeared wheqthe intracellular storage had reached an advanced stage, usually during the second year of life. Treatment was instituted at the age of 2 to 3 months. Untreated litters showed clinical signs 2 to 3 months earlier than treated litters. Koppang used three different therapeutic combinations: I) tocopherol 1.0 IE daily, 2) tocopherol 1.0 IE vitamin C 0.5 g methionine 1.0 g BHT 0.2 g daily, 3) parenteral tocopherol 1.0 g twice a week. There were no differences in results with the va-
+
+ +
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Santavuori and Moren
rious therapies. In the present trial no difference was noticed between the patients present receiving an additional dose of vitamin E and the other patients of treatment group I. Sjogren (1931) and Zeman (1974) assumed that mental impairment in Spielmeyer-Sjogren's disease sets in some years later than the visual failure. However, none of the children of the present study had an average intelligence quotient when first tested. The parents and siblings of these children are of average, bright normal or superior in intelligence. Perhaps the mental retardation sets in early, but the progress is in most cases slow during the first few years. The frequent school problems as well as the behavioural disturbances of patients with Spielmeyer-Sjogren's disease may at least partly be attributed to early mental impairment, which is hardly noticeable without careful psychological testing. On the basis of previous reports (Melchior et al. 1972, Zeman 1974, Koppang 1975) and the present results, antioxidant therapy in Spielmeyer-Sjogren's disease seems to be indicated. However, the medication used so far is unfortunately only able to retard the progress of the disease, they do not cure the patients. Therefore, the patients and their families are in need of support to be able to lead a happy life as long as possible. Furthermore, trials with other antioxidants are required. Zusammenf assung Ein Versuch der therapeutischen Wirkung der Antioxydantien in der neuro-
nalen Ceroidlipofuscinose (NCL) vom Spielmeyer-Sjogren-Typus wird dargestellt. Die Serien urnfafiten 46 Patienten, von denen 23 Antioxydantien erhielten, wahrend die anderen 23 zur Kontrollgruppe gehorten. Zu Beginn des Versuchs wurden die Patienten in zwei Gruppen aufgrund ihrer I Q eingeteilt. Der Intelligenz nach gehorten elf Kinder im Alter von 6 l / 2 bis 12 Jahren zu den Minderbegabten oder zu den Grenzfallen in Richtung Schwachsinn (Therapiegruppe I). Nach einer Observationszeit von 5 bis 6 Jahren war eine signifikante Veranderuq des IQ bei 6 Kindern zu beobachten; eine Verbesserung wurde bei 2 Jungen und eine Verschlechterung bei 4 Patienten gesehen. Die I Q waren hoher, die neurologischen Befunde weniger auffallig, und epileptische Anfalle waren weniger haufig unter den Patienten zu beobachten, die Antioxydantien erhielten, als in der Kontrollgruppe. Von der Therapie war kein Vorteil fur das Sehvermogen zu erzielen, und in den vorgeruckten Fallen war sie nutzlos. Es werden die Resultate diskutiert sowie mit denen der anderen Autoren verglichen. References Aula, P., Rapola, J. and Anderson, L. J.: Distribution of cytoplasmic vacuoles in blood T and B lymphocytes in two lysosomal disorders. Virchows Arch. & Cell Path. 1 8 : 263 (1975). Von Crevald, S. and Hooghwinkel, G . J. M.: Lipids in blood plasma and erythrocytes in juvenile amaurotic idiocy. Arch. Neurol. 17: 225 (1967). Koppang, N. : Canine ceroid-lipofuscinosis - A model for human neuronal ceroidlipofuscinosis and aging. Mechan. Aging Dev. 74: 421 (1973). - -
~
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Antioxidant treatment in ceroid-lipofuscinosis
4. Koppang,
N.: Ceroid-lipofuscinosis hos engelsk setter. Terapiforsok. Syndr. Spielmeyer-vogt. Symp. Dianalund, Danmark 1975. 5. MelQior, J. C., Clausen, J., Konat, C. and Brandt, S.: Are there abnormalities in the fatty acid metabolism in cerioid lipofuscinosis (Spielmeyer-Vogt's syndrome)? Psykiskt utveddingsstorda. Symp. Lidingo, Sweden 1071 171L.
6. Sjogren, T.: Die juvenile amaurotische Idiotie. Hereditas. 14: 197 (1931). 7. Zeman, W. and Dyken, P.: "Neuronal ceroid-lipofuscinosis (Batten's disease). Re-
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Neuropddiatrie
lationship to amaurotic family idiocy." Pediatrics. 44: 570 (1969). 8. Zeman, W., Donahue, S., Dyken, P. and Green, J.: The neuronal ceroid-lipofuscinoses (Batten-Vogt syndrome). Ed. by P. J. Vinken and G. W. Bruyn. Chapter 25. Handbook of Clinical Neurology. Vol. 10. Leucodystrophies and Poliodystropies. Ch. 25. North Holland Publishing Co. Amsterdam 1970, p. 617. 9. Zeman, W.: Presidential Address. "Studies
in the neuronal ceroidlipofuscinosis". Neuropath & Exper. Neurol. 33: 1 (1974). Downloaded by: University of British Columbia. Copyrighted material.
Santavuori and Moren
