8
7. Imrie CW, Benjamin IS, Ferguson JC, et al. A single centre double-blind trial of trasylol therapy in primary acute pancreatitis. Br J Surg 1978; 65: 337-41. 8. Osborne DH, Imrie CW, Carter DC. Biliary surgery in the same admission for gallstone associated acute pancreatitis. Br J Surg 1981; 68: 75-61. 9. Corfield AP, Cooper MJ, Williamson RCN, et al. Prediction of severity in acute pancreatitis: prospective comparison of three prognostic indices. Lancet 1985; ii: 403-06. 10. McMahon MJ, Playforth MJ, Pickford IR. A comparative study of the methods for prediction of severity of attacks of acute pancreatitis. Br J Surg 1980; 67: 22-25. 11. Mayer AD, McMahon MJ, Bowen M, Cooper EH. C-reactive protein: an aid to assessment and monitoring of acute pancreatitis. J Clin Pathol 1984; 37: 207-11.
C, Heads A, Shenkin A, Imrie CW. C-reactive protein, antiproteases and complement factors as objective markers of severity in acute pancreatitis. Br J Surg 1989; 76: 177-81. 13. Gudgeon AM, Jehanli A, Patel G, Hurley P, Austen BM, HermonTaylor J. Immunoassay for free prophospholipase A2 activation peptides (PLAP) reporting phospholipase activation. Pancreas 1988; 3:
12. Wilson
599.
Hermon-Taylor J, Magee AI, Grant DAW, Jones PA, Marshall CE, Dunham J. Cleavage of peptide hormones by &agr;2-macroglobulin trypsin complex and its relation to the pathogenesis and chemotherapy of acute pancreatitis. Clin Chim Acta 1981; 109: 203-09. 15. Steinberg WM, Schlesselman SE. Treatment of acute pancreatitis: comparison of animal and human studies. Gastroenterology 1987; 93:
14.
1420-27.
Focal cerebral dysfunction in developmental learning disabilities
24 children with developmental learning disabilities and 15 age-matched controls regional cerebral activity was studied with xenon-133 single photon emission tomography. In the 9 children with pure attention deficit and hyperactivity disorder (ADHD), the distribution of regional cerebral activity was abnormal—low in striatal and posterior periventricular regions and In
high in occipital regions. Low activity in striatal and posterior periventricular areas was also seen in
where inhaled 133Xe gives a quantitative measure of three-dimensional regional cerebral blood flow (rCBF), and, by inference, metabolic and functional activity.5,6 We used SPET to study regional cerebral blood flow in children with various learning disorders. The hypotheses to be tested were in particular: (a) that attention deficit and hyperactivity disorder (ADHD) is associated with hypoperfusion in the prefrontal lobe or striatal regions, and (b) that cerebral blood flow is low in the left temporal lobe in decoding or lexical-semantic dysphasia, and in the left frontal lobe in
the 8 children with ADHD in combination with phonologic-syntactic dysphasia. 7 children with dysphasia, but without hyperactive behaviour, had low cerebral activity in left temporofrontal
phonologic-syntactic dysphasia.
regions.
Patient groups and controls Lancet 1 990; 335: 8-11 .
Introduction
Developmental learning disabilities are a common and serious obstacle to scholastic and professional achievement. The delineation of these disorders from normal variants is vague: no biological marker has yet been identified. The likely prevalence is 2-10%. The aetiology is poorly understood, but undoubtedly involves genetic as well as environmental factors.2 Even less is known about the pathogenesis: in adult neurology reports relate cognitive syndromes to focal brain but a similar correlation has not been established in lesions, developmental paediatrics. The application of imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) has not been very illuminating so far. However, refined methods of morphometry seem to be promising.3 Physiological approaches, such as computed electroencephalographic analysis,4hold some promise but the spatial resolution is poor and these techniques mainly reflect cortical function. Subcortical dysfunction may be more important in the pathogenesis of some learning disorders. The use of positron emission tomography has been hampered in the study of children by the radiation dose and the rather invasive and cumbersome procedure. Much smaller doses of radiation are given with single photon emission tomography (SPET),
numerous
Patients and methods
24 patients (median age 10 yr, range 6-15) were selected from the department of child psychiatry, Rigshospitalet, the Copenhagen County Speech Institute, and Ringstedcentret (a special school for children with neurological and neuropsychological handicaps). In retrospect, 11 of the children had a history of adverse, but mostly poorly described, antenatal and perinatal events such as vaginal haemorrhage, pre-eclampsia, weak prenatal cardiac sounds, prolonged labour, and perinatal asphyxia. In 2 cases the probable cause of brain dysfunction was head trauma and measles encephalitis at 1-5 and 2-5 yr respectively. 2 of the boys with pure attention deficit and hyperactivity disorder were brothers. The children were neurologically nomial except for minor motor dysfunction in 5 (mild dyspraxia and/or choreoathetosis). CT scans were normal apart from slightly widened frontal sulci in 1 child. The children were investigated with a battery of neuropsychological tests, observations, and interviews.7 Visual perception was tested
with Bender Visual Motor Gestalt Test and Goodenough Draw-aTest; verbal auditory comprehension with the Token Test and the Peabody Picture Vocabulary Test. The following junctions were also tested: repetition (Spreen and Benton Sentence Repetition), digit span, word finding (naming of common objects), articulation, and spontaneous speech production (including fluency, grammar, and syntax). Ability to sustain attention was assessed with the Visual
man
ADDRESSES. John F. Kennedy Institute, Glostrup (H. C. Lou, MD) and Department of Neurology, Rigshospitalet, Copenhagen, Denmark (L. Henriksen, MD, P. Bruhn, Cand Psych). Correspondence to Dr H. C. Lou, John F. Kennedy Institute, DK-2600 Glostrup, Denmark
9
Fig 2-Flow distribution
Fig 1-Definition of cerebral regions. A prefrontal, B anterior, C central, D posterior perisylvian, E occipital, F striatal, and G posterior periventricular regions. (Redrawn from S-M Aquilonius. A colour atlas of the human brain. Esselte: Sweden, 1980.) Reaction Time (RT) Test. The RT variability is a measure of attention lapses or reduced vigilance. The RT latency is much more variable in patients with brain damage and attention deficit than in normal subjects. From the results of these tests and interviews with parents and teachers, the learning disabled children were allocated to the following groupS.8 1. 7 boys and 2 girls with attention deficit and hyperactivity disorder (ADHD) as defined by the DSM III criteria (revised edition). None were left-handed. 2. 8 boys with ADHD and phonologic-syntactic dysphasia, but without significant decoding or semantic difficulties. 2 of these patients had, in addition, visuospatial difficulties. 4 were left-handed. 3. 1 boy and 2 girls with severe phonologic-syntactic dysphasia, without decoding/semantic difficulties and without ADHD. 2 had slight visuospatial difficulties. None were left-handed. 4. 3 boys with severe verbal decoding difficulties, and 1 boy with severe lexical-semantic deficit. 2 of these patients also had phonologic-syntactic deficits (both were left-handed), and 1 had slight visuospatial deficit. The control group was 15 normal children (median age 11yr, range 6-17), 8 boys and 7 girls, mostly sons or daughters of medical personnel. 4 were siblings of learning disabled children.
Single photon emission tomography For this examination all children were at rest with open eyes. Three-dimensional regional cerebral blood flow (CBF) and flow
in
a
normal 12-year-old boy.
distribution were determined.6,7,9Rebreathing 133Xe 10 mCi/1 for 1 minute gives lung doses of 0,00 to 0-002 Gy.5 3 slices were recorded simultaneously with a resolution of about 15 mm. We used the middle slice-5 cm above the orbito-meatal line and including prefrontal cortex, perisylvian regions, stratium, diencephalon, and occipital cortex (fig 1). CT scans were used for defining the cerebral outline and identifying cerebral structures. Care was taken over positioning the child’s head, which was held by an inflatable cuff. The test-retest variability was small. In 30 unselected patients from our clinic the variability of the mean CBF at rest was 6-4%. The mean regional test-retest variability was 7%.9 The distribution of cerebral blood flow to each of 14 predefined regions (fig 1) was calculated for each child. The flow distribution was expressed as a discontinuous colour scale in which total cerebral blood flow was 100% and each 7-8% increment was represented by a different colour.
Results TablesI and II show flow distribution for each region in the different patient groups and controls. Theflow to stratial and posterior periventricular regions was lower in the ADHD and ADHD/phonologic-syntactic deficit groups than the control group (table I, figs 2, 3, and 4). The greatest reduction (10 7%) was seen in the striatal regions. The flow to occipital regions in pure ADHD was much higher than in controls; however, this difference was not found in ADHD with phonologic-syntactic deficit. Language deficit disorders were accompanied by less conspicuous abnormalities in the regional distribution of brain activity. In the group of 4 patients with decoding or lexical-semantic deficit, flow was lower in the left central perisylvian region than the right (table II, fig 5), median
TABLE I-REGIONAL DISTRIBUTION OF CEREBRAL BLOOD FLOW IN ADHD
Cerebral blood flow (CBF) to each region: mean % total blood flow (standard deviation). Difference between right and left region not significant for any region. ’Significantly different from control group (p < 05, Student Newmann-Keul).
10
TABLE II-DISTRIBUTION OF CEREBRAL BLOOD FLOW TO TEMPOROFRONTALREGIONS IN PURE DYSPHASIA
I
I
I
I
I
Cerebral blood flow (CBF) to each region: median % total blood flow (range). Difference between right and left (per cent) significantly greater than in control group (Mann Whitney): *p
7. Imrie CW, Benjamin IS, Ferguson JC, et al. A single centre double-blind trial of trasylol therapy in primary acute pancreatitis. Br J Surg 1978; 65: 337-41. 8. Osborne DH, Imrie CW, Carter DC. Biliary surgery in the same admission for gallstone associated acute pancreatitis. Br J Surg 1981; 68: 75-61. 9. Corfield AP, Cooper MJ, Williamson RCN, et al. Prediction of severity in acute pancreatitis: prospective comparison of three prognostic indices. Lancet 1985; ii: 403-06. 10. McMahon MJ, Playforth MJ, Pickford IR. A comparative study of the methods for prediction of severity of attacks of acute pancreatitis. Br J Surg 1980; 67: 22-25. 11. Mayer AD, McMahon MJ, Bowen M, Cooper EH. C-reactive protein: an aid to assessment and monitoring of acute pancreatitis. J Clin Pathol 1984; 37: 207-11.
C, Heads A, Shenkin A, Imrie CW. C-reactive protein, antiproteases and complement factors as objective markers of severity in acute pancreatitis. Br J Surg 1989; 76: 177-81. 13. Gudgeon AM, Jehanli A, Patel G, Hurley P, Austen BM, HermonTaylor J. Immunoassay for free prophospholipase A2 activation peptides (PLAP) reporting phospholipase activation. Pancreas 1988; 3:
12. Wilson
599.
Hermon-Taylor J, Magee AI, Grant DAW, Jones PA, Marshall CE, Dunham J. Cleavage of peptide hormones by &agr;2-macroglobulin trypsin complex and its relation to the pathogenesis and chemotherapy of acute pancreatitis. Clin Chim Acta 1981; 109: 203-09. 15. Steinberg WM, Schlesselman SE. Treatment of acute pancreatitis: comparison of animal and human studies. Gastroenterology 1987; 93:
14.
1420-27.
Focal cerebral dysfunction in developmental learning disabilities
24 children with developmental learning disabilities and 15 age-matched controls regional cerebral activity was studied with xenon-133 single photon emission tomography. In the 9 children with pure attention deficit and hyperactivity disorder (ADHD), the distribution of regional cerebral activity was abnormal—low in striatal and posterior periventricular regions and In
high in occipital regions. Low activity in striatal and posterior periventricular areas was also seen in
where inhaled 133Xe gives a quantitative measure of three-dimensional regional cerebral blood flow (rCBF), and, by inference, metabolic and functional activity.5,6 We used SPET to study regional cerebral blood flow in children with various learning disorders. The hypotheses to be tested were in particular: (a) that attention deficit and hyperactivity disorder (ADHD) is associated with hypoperfusion in the prefrontal lobe or striatal regions, and (b) that cerebral blood flow is low in the left temporal lobe in decoding or lexical-semantic dysphasia, and in the left frontal lobe in
the 8 children with ADHD in combination with phonologic-syntactic dysphasia. 7 children with dysphasia, but without hyperactive behaviour, had low cerebral activity in left temporofrontal
phonologic-syntactic dysphasia.
regions.
Patient groups and controls Lancet 1 990; 335: 8-11 .
Introduction
Developmental learning disabilities are a common and serious obstacle to scholastic and professional achievement. The delineation of these disorders from normal variants is vague: no biological marker has yet been identified. The likely prevalence is 2-10%. The aetiology is poorly understood, but undoubtedly involves genetic as well as environmental factors.2 Even less is known about the pathogenesis: in adult neurology reports relate cognitive syndromes to focal brain but a similar correlation has not been established in lesions, developmental paediatrics. The application of imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) has not been very illuminating so far. However, refined methods of morphometry seem to be promising.3 Physiological approaches, such as computed electroencephalographic analysis,4hold some promise but the spatial resolution is poor and these techniques mainly reflect cortical function. Subcortical dysfunction may be more important in the pathogenesis of some learning disorders. The use of positron emission tomography has been hampered in the study of children by the radiation dose and the rather invasive and cumbersome procedure. Much smaller doses of radiation are given with single photon emission tomography (SPET),
numerous
Patients and methods
24 patients (median age 10 yr, range 6-15) were selected from the department of child psychiatry, Rigshospitalet, the Copenhagen County Speech Institute, and Ringstedcentret (a special school for children with neurological and neuropsychological handicaps). In retrospect, 11 of the children had a history of adverse, but mostly poorly described, antenatal and perinatal events such as vaginal haemorrhage, pre-eclampsia, weak prenatal cardiac sounds, prolonged labour, and perinatal asphyxia. In 2 cases the probable cause of brain dysfunction was head trauma and measles encephalitis at 1-5 and 2-5 yr respectively. 2 of the boys with pure attention deficit and hyperactivity disorder were brothers. The children were neurologically nomial except for minor motor dysfunction in 5 (mild dyspraxia and/or choreoathetosis). CT scans were normal apart from slightly widened frontal sulci in 1 child. The children were investigated with a battery of neuropsychological tests, observations, and interviews.7 Visual perception was tested
with Bender Visual Motor Gestalt Test and Goodenough Draw-aTest; verbal auditory comprehension with the Token Test and the Peabody Picture Vocabulary Test. The following junctions were also tested: repetition (Spreen and Benton Sentence Repetition), digit span, word finding (naming of common objects), articulation, and spontaneous speech production (including fluency, grammar, and syntax). Ability to sustain attention was assessed with the Visual
man
ADDRESSES. John F. Kennedy Institute, Glostrup (H. C. Lou, MD) and Department of Neurology, Rigshospitalet, Copenhagen, Denmark (L. Henriksen, MD, P. Bruhn, Cand Psych). Correspondence to Dr H. C. Lou, John F. Kennedy Institute, DK-2600 Glostrup, Denmark
9
Fig 2-Flow distribution
Fig 1-Definition of cerebral regions. A prefrontal, B anterior, C central, D posterior perisylvian, E occipital, F striatal, and G posterior periventricular regions. (Redrawn from S-M Aquilonius. A colour atlas of the human brain. Esselte: Sweden, 1980.) Reaction Time (RT) Test. The RT variability is a measure of attention lapses or reduced vigilance. The RT latency is much more variable in patients with brain damage and attention deficit than in normal subjects. From the results of these tests and interviews with parents and teachers, the learning disabled children were allocated to the following groupS.8 1. 7 boys and 2 girls with attention deficit and hyperactivity disorder (ADHD) as defined by the DSM III criteria (revised edition). None were left-handed. 2. 8 boys with ADHD and phonologic-syntactic dysphasia, but without significant decoding or semantic difficulties. 2 of these patients had, in addition, visuospatial difficulties. 4 were left-handed. 3. 1 boy and 2 girls with severe phonologic-syntactic dysphasia, without decoding/semantic difficulties and without ADHD. 2 had slight visuospatial difficulties. None were left-handed. 4. 3 boys with severe verbal decoding difficulties, and 1 boy with severe lexical-semantic deficit. 2 of these patients also had phonologic-syntactic deficits (both were left-handed), and 1 had slight visuospatial deficit. The control group was 15 normal children (median age 11yr, range 6-17), 8 boys and 7 girls, mostly sons or daughters of medical personnel. 4 were siblings of learning disabled children.
Single photon emission tomography For this examination all children were at rest with open eyes. Three-dimensional regional cerebral blood flow (CBF) and flow
in
a
normal 12-year-old boy.
distribution were determined.6,7,9Rebreathing 133Xe 10 mCi/1 for 1 minute gives lung doses of 0,00 to 0-002 Gy.5 3 slices were recorded simultaneously with a resolution of about 15 mm. We used the middle slice-5 cm above the orbito-meatal line and including prefrontal cortex, perisylvian regions, stratium, diencephalon, and occipital cortex (fig 1). CT scans were used for defining the cerebral outline and identifying cerebral structures. Care was taken over positioning the child’s head, which was held by an inflatable cuff. The test-retest variability was small. In 30 unselected patients from our clinic the variability of the mean CBF at rest was 6-4%. The mean regional test-retest variability was 7%.9 The distribution of cerebral blood flow to each of 14 predefined regions (fig 1) was calculated for each child. The flow distribution was expressed as a discontinuous colour scale in which total cerebral blood flow was 100% and each 7-8% increment was represented by a different colour.
Results TablesI and II show flow distribution for each region in the different patient groups and controls. Theflow to stratial and posterior periventricular regions was lower in the ADHD and ADHD/phonologic-syntactic deficit groups than the control group (table I, figs 2, 3, and 4). The greatest reduction (10 7%) was seen in the striatal regions. The flow to occipital regions in pure ADHD was much higher than in controls; however, this difference was not found in ADHD with phonologic-syntactic deficit. Language deficit disorders were accompanied by less conspicuous abnormalities in the regional distribution of brain activity. In the group of 4 patients with decoding or lexical-semantic deficit, flow was lower in the left central perisylvian region than the right (table II, fig 5), median
TABLE I-REGIONAL DISTRIBUTION OF CEREBRAL BLOOD FLOW IN ADHD
Cerebral blood flow (CBF) to each region: mean % total blood flow (standard deviation). Difference between right and left region not significant for any region. ’Significantly different from control group (p < 05, Student Newmann-Keul).
10
TABLE II-DISTRIBUTION OF CEREBRAL BLOOD FLOW TO TEMPOROFRONTALREGIONS IN PURE DYSPHASIA
I
I
I
I
I
Cerebral blood flow (CBF) to each region: median % total blood flow (range). Difference between right and left (per cent) significantly greater than in control group (Mann Whitney): *p
