Childhood Autism Cerebrospinal Fluid Examination and Immunoglobulin Levels
J.
Gemld Young, M.D., Barbam K. Caparulo, B.S., Bennett A. Shaywitz, M.D., Warren T. Johnson, B.A., and Donald J. Cohen, M.D.
Abstract. The cerebrospinal fluid (CSF) of 15 children afflicted with primary childhood au-
tism was examined. There were no abnormalities of glucose, protein, cells, or folate. There is evidence that slow virus infections may underlie a variety of chronic neurological diseases and it has been hypothesized that slow viruses may playa role in the etiology of adult schizophrenia. We have evaluated this viewpoint in relation to childhood autism. Preliminary studies of CSF immunoglobulin levels in children with autism offer no support to the hypothesis.
Primary childhood autism is a profound, usually lifelong syndrome which appears before age 2 years and includes social inaccessibility, major disturbance in language development, and motility abnormalities (e.g., posturing, stereotypies, and hyperactivity) in the absence of specific neurological disease (Kanner, 1973; Rimland, 1964; Rutter, 1968; Cohen and Caparulo, 1975). Biological studies have utilized a range of methods, including physical and neurological examinations, perceptual testing, and neurophysiological and biochemical techniques, but no consistent correlates have been uncovered (Rutter, 1968, 1974; Goldfarb, 1970; Coleman, 1973; Hutt et aI., 1965; Ornitz, 1973; Guthrie et aI., 1975). There have been few reports of cerebrospinal fluid (CSF) findings (Cohen et aI., 1974). From the Yale Unipenil)' School a/Medicine and the Child Study Center, where Dr. Yaung is Assistant Professor 0/ Pediatrics and Psychiah),: Ms. Caparulo is Associate in Research: Dr. Slwywitz is Assistanl Professor 0/ Pediatrics and Neurology: MI'. Johnson is Associate in Research: and Dr. Cohen is Associate Professor 0/ Pediatrics, P.\~vchiat,..y, and Psychology. This im'estigation was supporled in pori by the Granl Fowuiatial/: Public Health Sen'ice Research Granl HD-03008: Childrell's Clinical Research Center Granl RROU 125, General Clinical Research Centns Pro/S'wn, Dipisi(JII 0/ Research Resources, Natianal fnstitute.< of Health; and MI'. Lealwrd Berger. Suppart 0/ the Children's Clinical Research Center wuier the directiOlI 0/ Myron Genel, M.D., and Mw)' Carey. R.N., made the studies possible. Reprints may be requested from Dr. Cohen. Yale Uniz'enit)' Child Study Center. 333 Cedar Street. New Hal'ell, CT 065/0.
174
175
Childhood Autism
The lifelong and characteristic natural history of childhood autism, and such observations as the high incidence of epileptic seizures during later childhood, have suggested that autism may represent a chronic neurological dysfunction. Recently, attention has been focused on the possibility that some previously enigmatic, chronic disorders may be caused by slow virus infections. This hypothesis has been explored in relation to adult schizophrenia (Torrey and Peterson, 1973), and slow viruses have been clearly implicated in several diseases of humans and animals, e.g., kuru, Creutzfeldt-J akob disease, and subacute sclerosing panencephalitis (SSPE) (Holland, 1974; Horta-Barbosa et al., 1971). The purpose of this report is to raise the possibility of a relationship between slow viruses and developmental problems of early childhood (such as childhood autism) and to present preliminary data. POPULATION AND METHODS
Eleven boys and 4 girls who satisfied the usual criteria for the diagnosis of childhood autism were biologically and psychiatrically evaluated after consent was obtained from both parents (ages 3.8 to 9.11 years, mean 7.5 years). (See Cohen et al. [1974, 1976] and Cohen and Caparulo [1975] for details.) None had evidence of specific neurological or metabolic disease which could explain the developmental disturbance, nor was any child on medication other than probenecid (administered for determination of biogenic amine metabolites) (Cohen et al., 1974). Lumbar puncture was performed using standard technique and CSF was examined for glucose, protein, and cells. Immunoglobulin levels (5 children), folate (12 children), and colloidal gold (4 children) were measured using standard methods (Mancini et al., 1965; Herbert, 1966). Biogenic amine metabolites, reported elsewhere (Cohen et al., 1974), were obtained for all children. The unequal and limited numbers of determinations for various parameters were the result of the need to conserve valuable CSF for various studies.
RESULTS
Cerebrospinal fluid protein, glucose, cells, and folate were within normal limits (table 1). There was no evidence of cellular response; red cells were considered secondary to the procedure. Normal CSF folate is between 12-70 nanograms per ml. (Wells and Casey,
j. Gerald Young
176
el al.
1967; Reynolds et al., 1972) and all children in this population had folate above 25 ng/ml. One child had normal folate on his first examination; when reexamined months later after a period of institutionalization and reduced dietary intake, blood and CSF folate were reduced. one of the children demonstrated elevation of CSF immunoglogulins (table 2) (Hartley et al., 1966; Link and Miiller, 1971). Table I Cerebrospinal Fluid Findings in Childhood AUlism PI. No.
Total WBC
Age
Sex
2 3
3.8 3.9 5.3
F M M
4
5.3
M
5 6 7 7
6.6 7.0 7.6 8.6
M F M M
0 0 10 0
0 0
8 9 10 II 12 13 14
7.11 8.6 8.8 8.10 8.10 9.1 9.3
M F M M F M M
2 0 10 0 0 0 0
0 0 9 0 0 0 0
15
9.11
M
I
2 0 2
Polys
Lymphs
0 0 I
0
2 I
0 0 0 8 0
2 0
2 0 I
0 0 0 0
0
Glucose mg. %
Protein mg.S7c
0 162 102
56 53 64
7 5 9
0
60
9
7 2073 0
60 67 56 61
14 15 8 8
0 4 4500 433 0 0 2000
52 51 55 55 49 62
0
50
RBC
I
* Colloidal Gold
CSF Folale ng.lml. >25 >25
0110000000 0000000000
>25 >25 27 II
0000000000
10 8
28
II
28 43 >25 >25 >25
15 II
12
0111100000
>25
17
* All CSF was clear and the pressure normal. Cell counts were measured in cellslcc. Child #7 was studied on two occasions. Table 2 Cerebrospinal Fluid Immunoglobulins in Childhood AUlism Normal Values
IgA mg. o/c
IgM mg. o/c
IgG mg. %
Total Protein mg. o/c
% TOlal Protein
Palienl No.
J.
Gemld Young, M.D., Barbam K. Caparulo, B.S., Bennett A. Shaywitz, M.D., Warren T. Johnson, B.A., and Donald J. Cohen, M.D.
Abstract. The cerebrospinal fluid (CSF) of 15 children afflicted with primary childhood au-
tism was examined. There were no abnormalities of glucose, protein, cells, or folate. There is evidence that slow virus infections may underlie a variety of chronic neurological diseases and it has been hypothesized that slow viruses may playa role in the etiology of adult schizophrenia. We have evaluated this viewpoint in relation to childhood autism. Preliminary studies of CSF immunoglobulin levels in children with autism offer no support to the hypothesis.
Primary childhood autism is a profound, usually lifelong syndrome which appears before age 2 years and includes social inaccessibility, major disturbance in language development, and motility abnormalities (e.g., posturing, stereotypies, and hyperactivity) in the absence of specific neurological disease (Kanner, 1973; Rimland, 1964; Rutter, 1968; Cohen and Caparulo, 1975). Biological studies have utilized a range of methods, including physical and neurological examinations, perceptual testing, and neurophysiological and biochemical techniques, but no consistent correlates have been uncovered (Rutter, 1968, 1974; Goldfarb, 1970; Coleman, 1973; Hutt et aI., 1965; Ornitz, 1973; Guthrie et aI., 1975). There have been few reports of cerebrospinal fluid (CSF) findings (Cohen et aI., 1974). From the Yale Unipenil)' School a/Medicine and the Child Study Center, where Dr. Yaung is Assistant Professor 0/ Pediatrics and Psychiah),: Ms. Caparulo is Associate in Research: Dr. Slwywitz is Assistanl Professor 0/ Pediatrics and Neurology: MI'. Johnson is Associate in Research: and Dr. Cohen is Associate Professor 0/ Pediatrics, P.\~vchiat,..y, and Psychology. This im'estigation was supporled in pori by the Granl Fowuiatial/: Public Health Sen'ice Research Granl HD-03008: Childrell's Clinical Research Center Granl RROU 125, General Clinical Research Centns Pro/S'wn, Dipisi(JII 0/ Research Resources, Natianal fnstitute.< of Health; and MI'. Lealwrd Berger. Suppart 0/ the Children's Clinical Research Center wuier the directiOlI 0/ Myron Genel, M.D., and Mw)' Carey. R.N., made the studies possible. Reprints may be requested from Dr. Cohen. Yale Uniz'enit)' Child Study Center. 333 Cedar Street. New Hal'ell, CT 065/0.
174
175
Childhood Autism
The lifelong and characteristic natural history of childhood autism, and such observations as the high incidence of epileptic seizures during later childhood, have suggested that autism may represent a chronic neurological dysfunction. Recently, attention has been focused on the possibility that some previously enigmatic, chronic disorders may be caused by slow virus infections. This hypothesis has been explored in relation to adult schizophrenia (Torrey and Peterson, 1973), and slow viruses have been clearly implicated in several diseases of humans and animals, e.g., kuru, Creutzfeldt-J akob disease, and subacute sclerosing panencephalitis (SSPE) (Holland, 1974; Horta-Barbosa et al., 1971). The purpose of this report is to raise the possibility of a relationship between slow viruses and developmental problems of early childhood (such as childhood autism) and to present preliminary data. POPULATION AND METHODS
Eleven boys and 4 girls who satisfied the usual criteria for the diagnosis of childhood autism were biologically and psychiatrically evaluated after consent was obtained from both parents (ages 3.8 to 9.11 years, mean 7.5 years). (See Cohen et al. [1974, 1976] and Cohen and Caparulo [1975] for details.) None had evidence of specific neurological or metabolic disease which could explain the developmental disturbance, nor was any child on medication other than probenecid (administered for determination of biogenic amine metabolites) (Cohen et al., 1974). Lumbar puncture was performed using standard technique and CSF was examined for glucose, protein, and cells. Immunoglobulin levels (5 children), folate (12 children), and colloidal gold (4 children) were measured using standard methods (Mancini et al., 1965; Herbert, 1966). Biogenic amine metabolites, reported elsewhere (Cohen et al., 1974), were obtained for all children. The unequal and limited numbers of determinations for various parameters were the result of the need to conserve valuable CSF for various studies.
RESULTS
Cerebrospinal fluid protein, glucose, cells, and folate were within normal limits (table 1). There was no evidence of cellular response; red cells were considered secondary to the procedure. Normal CSF folate is between 12-70 nanograms per ml. (Wells and Casey,
j. Gerald Young
176
el al.
1967; Reynolds et al., 1972) and all children in this population had folate above 25 ng/ml. One child had normal folate on his first examination; when reexamined months later after a period of institutionalization and reduced dietary intake, blood and CSF folate were reduced. one of the children demonstrated elevation of CSF immunoglogulins (table 2) (Hartley et al., 1966; Link and Miiller, 1971). Table I Cerebrospinal Fluid Findings in Childhood AUlism PI. No.
Total WBC
Age
Sex
2 3
3.8 3.9 5.3
F M M
4
5.3
M
5 6 7 7
6.6 7.0 7.6 8.6
M F M M
0 0 10 0
0 0
8 9 10 II 12 13 14
7.11 8.6 8.8 8.10 8.10 9.1 9.3
M F M M F M M
2 0 10 0 0 0 0
0 0 9 0 0 0 0
15
9.11
M
I
2 0 2
Polys
Lymphs
0 0 I
0
2 I
0 0 0 8 0
2 0
2 0 I
0 0 0 0
0
Glucose mg. %
Protein mg.S7c
0 162 102
56 53 64
7 5 9
0
60
9
7 2073 0
60 67 56 61
14 15 8 8
0 4 4500 433 0 0 2000
52 51 55 55 49 62
0
50
RBC
I
* Colloidal Gold
CSF Folale ng.lml. >25 >25
0110000000 0000000000
>25 >25 27 II
0000000000
10 8
28
II
28 43 >25 >25 >25
15 II
12
0111100000
>25
17
* All CSF was clear and the pressure normal. Cell counts were measured in cellslcc. Child #7 was studied on two occasions. Table 2 Cerebrospinal Fluid Immunoglobulins in Childhood AUlism Normal Values
IgA mg. o/c
IgM mg. o/c
IgG mg. %
Total Protein mg. o/c
% TOlal Protein
Palienl No.
