- Email: [email protected]
Autism and macrocephaly
THE LANCET
the plasma concentration of angiotensin II, losartan increases it, which may then lead to overstimulation of AT2 receptors. The function of AT2 receptors is unclear, but their expression in fetal and injured tissues suggests a role in growth and proliferation. Although rat heart expresses mainly AT1 receptors, the human myocardium seems to express mainly AT2 receptors.5 This small study cannot exclude the possibility that longterm treatment with an angiotensin II antagonist may have a beneficial effect on left-ventricular hypertrophy, but it would be difficult ethically to justify a placebo-controlled study of longer duration or the selection of patients with known left-ventricular hypertrophy. Nevertheless, it would be disconcerting if losartan does have the unexpected effect of increasing LVM. As with calcium-channel blockers, it may be prudent to have long-term data before it is used as a first-line agent in the treatment of hypertension.
Change in diastolic blood pressure (mm Hg)
25 20 15 10 5 0 –5 –10 –15
1
Change in left-ventricular-mass index (g/m2)
50
2
40
3
30 4
20 5
10
Caskey FJ, Thacker EJ, Johnston PA, Barnes JN. Failure of losartan to control blood pressure in scleroderma renal crisis. Lancet 1997; 349: 620. Lievre M, Gueret P, Gayet C, et al. Ramipril-induced regression of left ventricular hypertrophy in treated hypertensive individuals. Hypertension 1995; 25: 92–97. Cheung BMY, Lau CP. Fosinopril reduces left ventricular mass in patients with essential hypertension. Presented at the 5th International Symposium on ACE inhibition and other inhibitors of the renin-angiotensin system. Hong Kong, April, 1997. Linz W, Wiemer G, Gohlke P, Unger T, Scholkens BA. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev 1995; 47: 25–49. Nozawa Y, Haruno A, Oda N, et al. Angiotenin II receptor subtypes in bovine and human ventricular myocardium. J Pharmacol Exp Ther 1994; 270: 566–71.
Department of Medicine, Queen Mary Hospital, Pokfulam, Hong Kong (B Cheung)
0
–10
Autism and macrocephaly
–20 Placebo
Losartan
Change in diastolic blood pressure and left-ventricular-mass index after 12 weeks of treatment with losartan or placebo
increase in LVM index in the placebo group (107·8 [17·5] g/m2 at baseline; 108·9 [4·2] g/m2 at 12 weeks; figure). The changes in LVM index with time, the primary endpoint, were significantly different between the losartan group and the placebo group (p=0·03, repeated measures ANOVA). Use of non-parametric tests did not alter the results. There were were no adverse events in the losartan-treated patients and no striking changes in plasma potassium, urea, creatinine or 24-h creatinine clearance. Although losartan decreased blood pressure in all the treated patients, the effect was not significantly different from placebo. This result was expected because losartan monotherapy might not control the blood pressure in all patients, although a proportion would be expected to respond to placebo. However, the effect on LVM was surprising. Previous randomised placebo-controlled studies have shown that ACE inhibitors may cause left-ventricular hypertrophy to regress, even at a low dose which does not affect blood pressure. 2,3 Regression of left-ventricular hypertrophy may be desirable since this condition is associated with increased cardiovascular events and mortality. ACE-inhibitor-induced regression of leftventricular hypertrophy might be mediated partly through potentiation of kinins,4 a pathway that is not directly affected by losartan. Also, although ACE inhibitors reduce
1744
Roger E Stevenson, Richard J Schroer, Cindy Skinner, Don Fender, Richard J Simensen
Aberrations of brain growth are often associated with impairments in central-nervous-system function. 1 Severe undergrowth of the brain carries a high risk of impaired cognitive function. Brain overgrowth may be associated with cognitive impairment, but in general has a less ominous prognosis than undergrowth. Several external measurements have been used to assess brain size. Occipitofrontal head circumference is the measure most widely accepted in clinical practice. Microcephaly (head circumference 2 SD or more below the mean) is correlated with clinically significant undergrowth of the brain, and macrocephaly (head circumference 2 SD or more above the mean) with overgrowth of the brain. Brain size may also be determined indirectly with cranial imaging techniques or by direct measurement at necropsy. Macrocephaly has been reported in retrospective and prospective surveys of individuals with autism. 2–4 Bailey and colleagues2 reported macrocephaly (head circumference >97th centile) in 42% (nine of 19) twins with autism under 16 years of age. They also found macrocephaly in 37% of singletons with autism under 16 years of age. In a retrospective review, Davidovitch et al3 found macrocephaly in 18·2% (27 of 148) individuals with autism. Increased height and weight frequently accompanied the macrocephaly. Lainhart and colleagues4 found 14% of 91 individuals (60 children and 31 adults) with autism to have head circumferences above the 97th percentile. Excess brain weights have been noted
Vol 349 • June 14, 1997
THE LANCET
62 Head circumference (cm)
98th 75th 50th 25th 2nd
58 56 54
Centile
4
60
50
46 0
2
4
6
8
10
12
14
16
18
Age (years) Head circumference by age Head circumference at birth by centile
Macrocephaly at birth and by age in 18 individuals with autism
in four of eight cases with autism at necropsy (ages 4–33 years).2 Enlarged brains have also been documented in individuals with autism studied by magnetic resonance imaging.5 We studied the association between macrocephaly and autism in South Carolina. Families of all individuals younger than 21 years who receive services for autism from South Carolina were eligible to participate in this study. Enrolment was voluntary. Other characteristics of the study population included: mean age 8 years, 12% with height above 97th centile, 20% with weight above 97th centile, 5:1 male/female ratio, mean maternal age 28 years (range 15–44), mean paternal age 29 years (range 19–53), and mean birth order 2·2. A specific genetic diagnosis was found in 8% of cases. Cognitive function was similar in the macrocephalic and non-macrocephalic individuals (means for IQ 51 and 50, respectively), but adaptive function was lower in macrocephalic individuals (means for Vineland Scale 40 and 49, respectively). Autism was confirmed by the Autism Diagnostic Interview, Revised, or the Childhood Autism Rating Scale in all participants with macrocephaly. Macrocephaly appears to be the single most consistent physical characteristic of children with autism. The head circumference was greater than 2 SD above the mean for age and sex in 24% of the first 100 individuals under 21 years enrolled in the South Carolina (USA) Autism Study. By contrast, only 3% had microcephaly (head circumference less than 2 SD below the mean). 80% of the study participants had head circumferences above the mean. Birth head circumferences were available for 18 of the 24 individuals with macrocephaly. The head size at birth was normal in all except one of these 18 individuals (figure). One or both parents of 62% of the individuals with macrocephaly also had macrocephaly. Magnetic resonance imaging in four cases showed no evidence of structural anomalies or ventricular enlargement. Macrocephaly may represent a clinical marker for grouping individuals with autism into more homogeneous subgroups. Such subgroups may be useful for genetic linkage analysis and in the search for candidate genes which cause or predispose to autism.
2 3
J C Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA (R E Stevenson) ; and South Carolina Department of Disabilities and Special Needs, Columbia
52
48
1
5
measurements in children with autism. J Child Neurol 1996; 11: 389–93. Lainhart JE, Piven J, Wzorek M, et al. Macrocephaly in children and adults with autism. J Am Acad Child Adolesc Psychiatry 1997; 36: 282–90. Piven J, Arndt S, Bailey J, et al. An MRI study of brain in autism. Am J Psychiatry 1995; 152: 1145–49.
Stevenson RE, Massey PS, Schroer RJ, et al. Preventable fraction of mental retardation: analysis based on individuals with severe mental retardation. Ment Retard 1996; 34: 182–88. Bailey A, Luthert P, Bolton P, et al. Autism and megalencephaly. Lancet 1993; 341: 1225–26. Davidovitch M, Patterson B, Gartside P. Head circumference
Vol 349 • June 14, 1997
Pancreatorenal syndrome associated with combination antiretroviral therapy in HIV infection Raphael B Stricker, Kevin M Man, Denis B Bouvier, David A Goldberg, Aristotle E Mendiola
Acute renal failure is an unusual complication of acute pancreatitis, occurring as an isolated event in only 2–4% of cases.1,2 Unlike the well-known hepatorenal syndrome, pancreatorenal syndrome is poorly characterised, and the mortality rate is as high as 75–80%.1 We describe two cases of pancreatorenal syndrome associated with combination antiretroviral therapy for HIV infection. A 47-year-old man was admitted to hospital with fever and increasing abdominal pain. He had been HIV-positive for 6 years with a recent CD4 T-cell count of 31 cells/L and a viral load of 121 000 copies/mL. He had been treated with combinations of zidovudine, lamivudine, saquinavir, and indinavir until 2 months before admission, when he discontinued antiretroviral therapy. 3 weeks before admission he restarted combination therapy with stavudine (80 mg daily), lamivudine (300 mg daily), and incremental ritonavir. His blood urea nitrogen (BUN) and creatinine were normal. His other medications were azithromycin, ethambutol, dapsone, fluconazole, acyclovir, mexiletene, erythropoietin, and testosterone. The symptoms that prompted admission occurred when he began taking fulldose ritonavir (1200 mg daily). He weighed 66 kg. Tests showed amylase 843 U/L (normal 45–130), lipase 200 U/L (normal 5–30), and triglycerides 20·9 mmol/L (normal 0·5–1·8). The BUN was 20·7 mmol/L (normal 1·8–8·9) and creatinine 344·8 mol/L (normal 26·5–123·8). Computed tomography (CT) scan of the abdomen revealed phlegmonous pancreatitis without gallstones or renal calculi. Multiple cultures for bacteria, fungi, and acid-fast bacilli were negative, and stool examination was unremarkable. Antiretroviral drugs were discontinued. Subsequently the patient developed nausea and vomiting, and the BUN and creatinine rose to 41·8 mmol/L and 760·2 mol/L over the next 4 days. Urinalysis showed a specific gravity of 1·025 (normal 1·005–1·025) with trace proteinuria and coarse granular casts. A repeat CT scan showed persistent pancreatic inflammation. Dialysis was initiated, but the BUN and creatinine rose to 68·5 mmol/L and 1096·2 mol/L and the patient developed severe metabolic acidosis with a serum carbon dioxide of 12·5 mmol/L (normal 24–31). Dialysis was continued during the next 16 days, and he gradually improved. He was discharged after 6 weeks with a normal amylase and normal renal function. A 40-year-old man was admitted to hospital with fever, abdominal pain, and increasing abdominal girth. He had been HIV-positive for 12 years and had taken zidovudine, didanosine, and zalcitabine sequentially. 10 months before admission his CD4 count was 12 cells/L and his plasma viral load was 1·1 million copies/mL, and he began combination antiretroviral therapy with lamivudine (300 mg
1745
the plasma concentration of angiotensin II, losartan increases it, which may then lead to overstimulation of AT2 receptors. The function of AT2 receptors is unclear, but their expression in fetal and injured tissues suggests a role in growth and proliferation. Although rat heart expresses mainly AT1 receptors, the human myocardium seems to express mainly AT2 receptors.5 This small study cannot exclude the possibility that longterm treatment with an angiotensin II antagonist may have a beneficial effect on left-ventricular hypertrophy, but it would be difficult ethically to justify a placebo-controlled study of longer duration or the selection of patients with known left-ventricular hypertrophy. Nevertheless, it would be disconcerting if losartan does have the unexpected effect of increasing LVM. As with calcium-channel blockers, it may be prudent to have long-term data before it is used as a first-line agent in the treatment of hypertension.
Change in diastolic blood pressure (mm Hg)
25 20 15 10 5 0 –5 –10 –15
1
Change in left-ventricular-mass index (g/m2)
50
2
40
3
30 4
20 5
10
Caskey FJ, Thacker EJ, Johnston PA, Barnes JN. Failure of losartan to control blood pressure in scleroderma renal crisis. Lancet 1997; 349: 620. Lievre M, Gueret P, Gayet C, et al. Ramipril-induced regression of left ventricular hypertrophy in treated hypertensive individuals. Hypertension 1995; 25: 92–97. Cheung BMY, Lau CP. Fosinopril reduces left ventricular mass in patients with essential hypertension. Presented at the 5th International Symposium on ACE inhibition and other inhibitors of the renin-angiotensin system. Hong Kong, April, 1997. Linz W, Wiemer G, Gohlke P, Unger T, Scholkens BA. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev 1995; 47: 25–49. Nozawa Y, Haruno A, Oda N, et al. Angiotenin II receptor subtypes in bovine and human ventricular myocardium. J Pharmacol Exp Ther 1994; 270: 566–71.
Department of Medicine, Queen Mary Hospital, Pokfulam, Hong Kong (B Cheung)
0
–10
Autism and macrocephaly
–20 Placebo
Losartan
Change in diastolic blood pressure and left-ventricular-mass index after 12 weeks of treatment with losartan or placebo
increase in LVM index in the placebo group (107·8 [17·5] g/m2 at baseline; 108·9 [4·2] g/m2 at 12 weeks; figure). The changes in LVM index with time, the primary endpoint, were significantly different between the losartan group and the placebo group (p=0·03, repeated measures ANOVA). Use of non-parametric tests did not alter the results. There were were no adverse events in the losartan-treated patients and no striking changes in plasma potassium, urea, creatinine or 24-h creatinine clearance. Although losartan decreased blood pressure in all the treated patients, the effect was not significantly different from placebo. This result was expected because losartan monotherapy might not control the blood pressure in all patients, although a proportion would be expected to respond to placebo. However, the effect on LVM was surprising. Previous randomised placebo-controlled studies have shown that ACE inhibitors may cause left-ventricular hypertrophy to regress, even at a low dose which does not affect blood pressure. 2,3 Regression of left-ventricular hypertrophy may be desirable since this condition is associated with increased cardiovascular events and mortality. ACE-inhibitor-induced regression of leftventricular hypertrophy might be mediated partly through potentiation of kinins,4 a pathway that is not directly affected by losartan. Also, although ACE inhibitors reduce
1744
Roger E Stevenson, Richard J Schroer, Cindy Skinner, Don Fender, Richard J Simensen
Aberrations of brain growth are often associated with impairments in central-nervous-system function. 1 Severe undergrowth of the brain carries a high risk of impaired cognitive function. Brain overgrowth may be associated with cognitive impairment, but in general has a less ominous prognosis than undergrowth. Several external measurements have been used to assess brain size. Occipitofrontal head circumference is the measure most widely accepted in clinical practice. Microcephaly (head circumference 2 SD or more below the mean) is correlated with clinically significant undergrowth of the brain, and macrocephaly (head circumference 2 SD or more above the mean) with overgrowth of the brain. Brain size may also be determined indirectly with cranial imaging techniques or by direct measurement at necropsy. Macrocephaly has been reported in retrospective and prospective surveys of individuals with autism. 2–4 Bailey and colleagues2 reported macrocephaly (head circumference >97th centile) in 42% (nine of 19) twins with autism under 16 years of age. They also found macrocephaly in 37% of singletons with autism under 16 years of age. In a retrospective review, Davidovitch et al3 found macrocephaly in 18·2% (27 of 148) individuals with autism. Increased height and weight frequently accompanied the macrocephaly. Lainhart and colleagues4 found 14% of 91 individuals (60 children and 31 adults) with autism to have head circumferences above the 97th percentile. Excess brain weights have been noted
Vol 349 • June 14, 1997
THE LANCET
62 Head circumference (cm)
98th 75th 50th 25th 2nd
58 56 54
Centile
4
60
50
46 0
2
4
6
8
10
12
14
16
18
Age (years) Head circumference by age Head circumference at birth by centile
Macrocephaly at birth and by age in 18 individuals with autism
in four of eight cases with autism at necropsy (ages 4–33 years).2 Enlarged brains have also been documented in individuals with autism studied by magnetic resonance imaging.5 We studied the association between macrocephaly and autism in South Carolina. Families of all individuals younger than 21 years who receive services for autism from South Carolina were eligible to participate in this study. Enrolment was voluntary. Other characteristics of the study population included: mean age 8 years, 12% with height above 97th centile, 20% with weight above 97th centile, 5:1 male/female ratio, mean maternal age 28 years (range 15–44), mean paternal age 29 years (range 19–53), and mean birth order 2·2. A specific genetic diagnosis was found in 8% of cases. Cognitive function was similar in the macrocephalic and non-macrocephalic individuals (means for IQ 51 and 50, respectively), but adaptive function was lower in macrocephalic individuals (means for Vineland Scale 40 and 49, respectively). Autism was confirmed by the Autism Diagnostic Interview, Revised, or the Childhood Autism Rating Scale in all participants with macrocephaly. Macrocephaly appears to be the single most consistent physical characteristic of children with autism. The head circumference was greater than 2 SD above the mean for age and sex in 24% of the first 100 individuals under 21 years enrolled in the South Carolina (USA) Autism Study. By contrast, only 3% had microcephaly (head circumference less than 2 SD below the mean). 80% of the study participants had head circumferences above the mean. Birth head circumferences were available for 18 of the 24 individuals with macrocephaly. The head size at birth was normal in all except one of these 18 individuals (figure). One or both parents of 62% of the individuals with macrocephaly also had macrocephaly. Magnetic resonance imaging in four cases showed no evidence of structural anomalies or ventricular enlargement. Macrocephaly may represent a clinical marker for grouping individuals with autism into more homogeneous subgroups. Such subgroups may be useful for genetic linkage analysis and in the search for candidate genes which cause or predispose to autism.
2 3
J C Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA (R E Stevenson) ; and South Carolina Department of Disabilities and Special Needs, Columbia
52
48
1
5
measurements in children with autism. J Child Neurol 1996; 11: 389–93. Lainhart JE, Piven J, Wzorek M, et al. Macrocephaly in children and adults with autism. J Am Acad Child Adolesc Psychiatry 1997; 36: 282–90. Piven J, Arndt S, Bailey J, et al. An MRI study of brain in autism. Am J Psychiatry 1995; 152: 1145–49.
Stevenson RE, Massey PS, Schroer RJ, et al. Preventable fraction of mental retardation: analysis based on individuals with severe mental retardation. Ment Retard 1996; 34: 182–88. Bailey A, Luthert P, Bolton P, et al. Autism and megalencephaly. Lancet 1993; 341: 1225–26. Davidovitch M, Patterson B, Gartside P. Head circumference
Vol 349 • June 14, 1997
Pancreatorenal syndrome associated with combination antiretroviral therapy in HIV infection Raphael B Stricker, Kevin M Man, Denis B Bouvier, David A Goldberg, Aristotle E Mendiola
Acute renal failure is an unusual complication of acute pancreatitis, occurring as an isolated event in only 2–4% of cases.1,2 Unlike the well-known hepatorenal syndrome, pancreatorenal syndrome is poorly characterised, and the mortality rate is as high as 75–80%.1 We describe two cases of pancreatorenal syndrome associated with combination antiretroviral therapy for HIV infection. A 47-year-old man was admitted to hospital with fever and increasing abdominal pain. He had been HIV-positive for 6 years with a recent CD4 T-cell count of 31 cells/L and a viral load of 121 000 copies/mL. He had been treated with combinations of zidovudine, lamivudine, saquinavir, and indinavir until 2 months before admission, when he discontinued antiretroviral therapy. 3 weeks before admission he restarted combination therapy with stavudine (80 mg daily), lamivudine (300 mg daily), and incremental ritonavir. His blood urea nitrogen (BUN) and creatinine were normal. His other medications were azithromycin, ethambutol, dapsone, fluconazole, acyclovir, mexiletene, erythropoietin, and testosterone. The symptoms that prompted admission occurred when he began taking fulldose ritonavir (1200 mg daily). He weighed 66 kg. Tests showed amylase 843 U/L (normal 45–130), lipase 200 U/L (normal 5–30), and triglycerides 20·9 mmol/L (normal 0·5–1·8). The BUN was 20·7 mmol/L (normal 1·8–8·9) and creatinine 344·8 mol/L (normal 26·5–123·8). Computed tomography (CT) scan of the abdomen revealed phlegmonous pancreatitis without gallstones or renal calculi. Multiple cultures for bacteria, fungi, and acid-fast bacilli were negative, and stool examination was unremarkable. Antiretroviral drugs were discontinued. Subsequently the patient developed nausea and vomiting, and the BUN and creatinine rose to 41·8 mmol/L and 760·2 mol/L over the next 4 days. Urinalysis showed a specific gravity of 1·025 (normal 1·005–1·025) with trace proteinuria and coarse granular casts. A repeat CT scan showed persistent pancreatic inflammation. Dialysis was initiated, but the BUN and creatinine rose to 68·5 mmol/L and 1096·2 mol/L and the patient developed severe metabolic acidosis with a serum carbon dioxide of 12·5 mmol/L (normal 24–31). Dialysis was continued during the next 16 days, and he gradually improved. He was discharged after 6 weeks with a normal amylase and normal renal function. A 40-year-old man was admitted to hospital with fever, abdominal pain, and increasing abdominal girth. He had been HIV-positive for 12 years and had taken zidovudine, didanosine, and zalcitabine sequentially. 10 months before admission his CD4 count was 12 cells/L and his plasma viral load was 1·1 million copies/mL, and he began combination antiretroviral therapy with lamivudine (300 mg
1745