- Email: [email protected]
Vaccination and Dravet syndrome
Correspondence
therapy with ciclosporin A or placebo (adjusted group difference estimate, ciclosporin A compared with placebo –2·2, 95% CI –7·1 to 2·7; p=0·38) or after an additional 12 months (month 15) of combined treatment with intermittent prednisone (2·8, –2·6 to 8·1; p=0·30). We believe that we have used appropriate and clinically meaningful methods to assess and analyse the effect of ciclosporin A on muscle strength in ambulant patients with Duchenne muscular dystrophy.1 We declare that we have no conflicts of interest.
Janbernd Kirschner, Gabriele Ihorst, Rudolf Korinthenberg janbernd.kirschner@uniklinik-freiburg. de Division of Neuropaediatrics and Muscle Disorders (JK, RK), and Clinical Trials Centre (GI), University Medical Centre, Freiburg, Germany 1
2
3
4
5
Kirschner J, Schessl J, Schara U, et al. Treatment of Duchenne muscular dystrophy with ciclosporin A: a randomised, double-blind, placebo-controlled multicentre trial. Lancet Neurol 2010; 9: 1053–59. Florence JM, Pandya S, King WM, et al. Intrarater reliability of manual muscle test (Medical Research Council scale) grades in Duchenne’s muscular dystrophy. Phys Ther 1992; 72: 115–22. Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev 2008; 1: CD003725. Scott OM, Hyde SA, Goddard C, Dubowitz V. Quantitation of muscle function in children: a prospective study in Duchenne muscular dystrophy. Muscle Nerve 1982; 5: 291–301. Stuberg WA, Metcalf WK. Reliability of quantitative muscle testing in healthy children and in children with Duchenne muscular dystrophy using a hand-held dynamometer. Phys Ther 1988; 68: 977–82.
Accurate prevalence and uptake of testing for Huntington’s disease Laura Spinney1 comments on the apparent lack of accurate figures on the prevalence and number of people at risk of Huntington’s disease in the UK. Most studies were done more than 20 years ago, and the most recent study was published by myself and my colleagues in 1995.2
This latest study was the first to use genetically confirmed cases in the Northern Ireland population and reported a prevalence in 1991 of 6·4 people per 100 000.2 The prevalence quoted for the UK is usually 7 per 100 000. Genetic confirmation of Huntington’s disease has eliminated error in diagnoses of similar disorders worldwide.3 We have now repeated the survey in Northern Ireland and the prevalence for 2001 has increased to 10·6 people per 100 000.4 A major reason for the increased prevalence is that life expectancy has increased and therefore much of the 1991 cohort is still alive, suggesting that treatment of depression, swallowing, and other aspects of the disorder can make a difference by improving survival, and so the Huntington’s disease gene is not solely responsible for the age of onset or disease progression.5 If this increase in prevalence occurred in the UK population as a whole, the prevalence should have been 14–16 people per 100 000 in 2001, and even higher in 2010, because the prevalence in southeast England is generally higher than in Northern Ireland.6 Given improved care and life expectancy, the prevalence should continue to rise. We also had the opportunity to accurately define the number of people at risk in our population and then calculate the uptake of predictive testing, which has never been done in a total population before, apart from by statistical estimation. The uptake of testing in people at 50% risk of Huntington’s disease was 12·3–14·6%, dependent on the statistical analysis used, which is the approximate figure expected for this disorder. Importantly, although the caudate brain atrophy in Huntington’s disease is relentlessly progressive and irreversible with drug treatment, much can be done for patients with this disease. The reasons for low uptake of testing include stigma, low expectations
www.thelancet.com/neurology Vol 9 December 2010
of medical interventions, potential discrimination by employers or insurers, and the rarity of the disease, which means that people with Huntington’s disease often do not get adequate information from their general practitioner. Geneticists can argue that the true prevalence of Huntington’s disease is not important for all parts of the UK because the best services on offer for patients with the disease are specialist clinics providing help and encouragement. The All Party Parliamentary Group on Huntington’s Disease,1 established in June, 2010, is to be welcomed and should concentrate on improvement of access to specialist clinics to support patients with Huntington’s disease. I declare that I have no conflicts of interest.
Patrick J Morrison [email protected] Regional Medical Genetics Centre, Belfast City Hospital, Belfast BT9 7AB, UK; and School of Biomedical Sciences, University of Ulster, Coleraine, UK 1
2
3
4
5
6
Spinney L. Uncovering the true prevalence of Huntington’s disease. Lancet Neurol 2010; 9: 760–61. Morrison PJ, Johnston WP, Nevin NC. The epidemiology of Huntington’s disease in Northern Ireland. J Med Genet 1995; 32: 524–30. MacMillan JC, Morrison PJ, Nevin NC, et al. Identification of an expanded CAG repeat in the Huntington’s disease gene (IT15) in a family reported to have benign hereditary chorea. J Med Genet 1993; 30: 1012–13. Morrison PJ, Harding-Lester S, Bradley A. Uptake of Huntington disease predictive testing in a complete population. Clin Genet 2010; published online Sept 6. DOI:10.1111/j.1399-0004.2010.01538.x. Li JL, Hayden MR, Warby SC, et al. Genomewide significance for a modifier of age at neurological onset in Huntington’s disease at 6q23-24: the HD MAPS study. BMC Med Genet 2006; 7: 71. Bates G, Harper PS, Jones L, eds. Huntington’s disease, 3rd edn. Oxford: Oxford University Press, 2002.
Vaccination and Dravet syndrome I read with great interest the Article by Anne McIntosh and colleagues.1 I believe this paper makes an important contribution to our 1147
Correspondence
knowledge of child neurology. However, I strongly disagree with the authors’ conclusion—that there is no evidence that vaccination before or after disease onset affects outcome. There is nothing in the data presented to justify their conclusion that an asymptomatic child with a severe SCN1A mutation should be vaccinated. This conclusion is premature and maybe even dangerous. The study showed an association between vaccination and onset of the seizures of Dravet syndrome. From the data, one can see that the risk of the onset of seizures during a day that falls within 48 h after one of the three diphtheria-tetanus-pertussis (DTP) vaccinations during the first 6 months of life is 12·4-times higher than for any of the other 177 days of these 6 months. A similar relative risk can be derived from Nieto Barrera and colleagues’ report.2 The most crucial matter regarding syndrome severity is the difference in intellectual outcome between vaccine-proximate and vaccine-distant groups. The authors grouped together patients with no intellectual disability and those with mild disability; moderate and severe disabilities formed the other group. The authors’ comparison ignores the tendency towards severe intellectual disability in the vaccination-proximate group: one of 28 vaccination-distant patients had no disability, but none of the 12 vaccination-proximate patients. Six (50%) vaccination-proximate patients had severe disability versus nine (32%) vaccination-distant patients. Children with Dravet syndrome are developmentally normal until onset of seizures, and progressively fall behind their peers as seizures progress. Other channelopathies have also shown age-dependent vulnerability. Moreover, seizures in the neonatal and infant brain might be more harmful developmentally 1148
than are seizures at an older age.3 Variability in syndrome severity has been described even in identical twins with identical mutations.4 The data do not answer the question of whether Dravet syndrome might be avoided or ameliorated by postponement of vaccination in patients with known mutations who have not had seizures. The only way to answer this question is by neonatal screening for SCN1A mutations. Such a screen is feasible and not unjustified in view of the severity and poor prognosis of this syndrome compared with other genetic conditions for which screening is common. The question of whether asymptomatic or mildly symptomatic infants carrying SCN1A mutations similar to those found by McIntosh and colleagues exist could also be answered by such a screen. Two possible ways to try to delay or prevent the syndrome in children identified in such a screen are to postpone vaccination and maybe use prophylactic antiepileptic treatments. I am testifying as a paid expert witness in the US Court of Federal Claims on behalf of a child with Dravet syndrome who had his first seizure after a DTP vaccine, who is petitioning for compensation according to the US Federal Vaccine Compensation Act.
Yuval Shafrir [email protected] Sinai Hospital of Baltimore, Pediatrics, Baltimore, MD 21215, USA 1
2
3
4
McIntosh AM, McMahon J, Dibbens LM, et al. Effects of vaccination on onset and outcome of Dravet syndrome: a retrospective study. Lancet Neurol 2010; 9: 592–98. Nieto Barrera M, Candau Fernandez Mensaque R, Nieto Jiménez M. Severe myoclonic epilepsy in infancy (Dravet’s syndrome). Its nosological characteristics and therapeutic aspects. Rev Neurol 2003; 37: 64–68. Swann JW, Baram TZ, Jensen FE, Moshe SL. Seizure mechanisms and vulnerability in the developing brain. In: Engel J, Pedley TA, eds. Epilepsy: a comprehensive textbook , 2nd edn. Philadelphia, PA, USA: Lippincott Williams & Wilkins, 2008: 469–80. Miyama S, Goto T, Inoue Y, Yamakawa K. Monozygotic twins with severe myoclonic epilepsy in infancy discordant for clinical features. Pediatr Neurol 2008; 39: 120–22.
Authors’ reply Yuval Shafrir disagrees with our conclusion that there is no evidence that vaccination before or after onset of Dravet syndrome affects outcome, and is concerned that our recommendation on immunisation could be “dangerous”. First, childhood vaccination has both individual and community benefits in prevention of communicable diseases. Any recommendations to delay or withhold vaccination should take into account the increased public health risk and individual cost of these diseases. Our findings do not support change to accepted vaccination policy. Second, Shafrir focuses on one non-significant trend in our data, regarding intellectual outcome. We a-priori dichotomised intellectual outcome into mild disability or normal intellect (3/12 in the vaccine-proximate group and 10/28 in the vaccine-distant group) versus moderate or severe intellectual disability (9/12 vaccine-proximate and 18/28 vaccine-distant), since this distinction is clinically important. Shafrir is concerned that we might have ignored an effect on severe intellectual disability, but post-hoc analysis for severe disability versus all other cases did not reveal an effect (6/12 vaccineproximate patients had severe disability, vs 9/28 vaccine-distant; Fisher’s exact p=0·31). Vaccination fear is rife and unfounded; our data show no evidence of an effect of the vaccination on outcome, although, as pointed out in our Article,1 we cannot exclude a type 2 error. Third, although uncontrolled and post hoc, perhaps our best evidence against his assertion is our data for children vaccinated after disorder onset, in whom no effect or negative trends regarding regression or intellectual outcome were seen. Fourth, Shafrir cites evidence that young brains are more vulnerable to certain forms of damage. This is true, but differences
www.thelancet.com/neurology Vol 9 December 2010
therapy with ciclosporin A or placebo (adjusted group difference estimate, ciclosporin A compared with placebo –2·2, 95% CI –7·1 to 2·7; p=0·38) or after an additional 12 months (month 15) of combined treatment with intermittent prednisone (2·8, –2·6 to 8·1; p=0·30). We believe that we have used appropriate and clinically meaningful methods to assess and analyse the effect of ciclosporin A on muscle strength in ambulant patients with Duchenne muscular dystrophy.1 We declare that we have no conflicts of interest.
Janbernd Kirschner, Gabriele Ihorst, Rudolf Korinthenberg janbernd.kirschner@uniklinik-freiburg. de Division of Neuropaediatrics and Muscle Disorders (JK, RK), and Clinical Trials Centre (GI), University Medical Centre, Freiburg, Germany 1
2
3
4
5
Kirschner J, Schessl J, Schara U, et al. Treatment of Duchenne muscular dystrophy with ciclosporin A: a randomised, double-blind, placebo-controlled multicentre trial. Lancet Neurol 2010; 9: 1053–59. Florence JM, Pandya S, King WM, et al. Intrarater reliability of manual muscle test (Medical Research Council scale) grades in Duchenne’s muscular dystrophy. Phys Ther 1992; 72: 115–22. Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev 2008; 1: CD003725. Scott OM, Hyde SA, Goddard C, Dubowitz V. Quantitation of muscle function in children: a prospective study in Duchenne muscular dystrophy. Muscle Nerve 1982; 5: 291–301. Stuberg WA, Metcalf WK. Reliability of quantitative muscle testing in healthy children and in children with Duchenne muscular dystrophy using a hand-held dynamometer. Phys Ther 1988; 68: 977–82.
Accurate prevalence and uptake of testing for Huntington’s disease Laura Spinney1 comments on the apparent lack of accurate figures on the prevalence and number of people at risk of Huntington’s disease in the UK. Most studies were done more than 20 years ago, and the most recent study was published by myself and my colleagues in 1995.2
This latest study was the first to use genetically confirmed cases in the Northern Ireland population and reported a prevalence in 1991 of 6·4 people per 100 000.2 The prevalence quoted for the UK is usually 7 per 100 000. Genetic confirmation of Huntington’s disease has eliminated error in diagnoses of similar disorders worldwide.3 We have now repeated the survey in Northern Ireland and the prevalence for 2001 has increased to 10·6 people per 100 000.4 A major reason for the increased prevalence is that life expectancy has increased and therefore much of the 1991 cohort is still alive, suggesting that treatment of depression, swallowing, and other aspects of the disorder can make a difference by improving survival, and so the Huntington’s disease gene is not solely responsible for the age of onset or disease progression.5 If this increase in prevalence occurred in the UK population as a whole, the prevalence should have been 14–16 people per 100 000 in 2001, and even higher in 2010, because the prevalence in southeast England is generally higher than in Northern Ireland.6 Given improved care and life expectancy, the prevalence should continue to rise. We also had the opportunity to accurately define the number of people at risk in our population and then calculate the uptake of predictive testing, which has never been done in a total population before, apart from by statistical estimation. The uptake of testing in people at 50% risk of Huntington’s disease was 12·3–14·6%, dependent on the statistical analysis used, which is the approximate figure expected for this disorder. Importantly, although the caudate brain atrophy in Huntington’s disease is relentlessly progressive and irreversible with drug treatment, much can be done for patients with this disease. The reasons for low uptake of testing include stigma, low expectations
www.thelancet.com/neurology Vol 9 December 2010
of medical interventions, potential discrimination by employers or insurers, and the rarity of the disease, which means that people with Huntington’s disease often do not get adequate information from their general practitioner. Geneticists can argue that the true prevalence of Huntington’s disease is not important for all parts of the UK because the best services on offer for patients with the disease are specialist clinics providing help and encouragement. The All Party Parliamentary Group on Huntington’s Disease,1 established in June, 2010, is to be welcomed and should concentrate on improvement of access to specialist clinics to support patients with Huntington’s disease. I declare that I have no conflicts of interest.
Patrick J Morrison [email protected] Regional Medical Genetics Centre, Belfast City Hospital, Belfast BT9 7AB, UK; and School of Biomedical Sciences, University of Ulster, Coleraine, UK 1
2
3
4
5
6
Spinney L. Uncovering the true prevalence of Huntington’s disease. Lancet Neurol 2010; 9: 760–61. Morrison PJ, Johnston WP, Nevin NC. The epidemiology of Huntington’s disease in Northern Ireland. J Med Genet 1995; 32: 524–30. MacMillan JC, Morrison PJ, Nevin NC, et al. Identification of an expanded CAG repeat in the Huntington’s disease gene (IT15) in a family reported to have benign hereditary chorea. J Med Genet 1993; 30: 1012–13. Morrison PJ, Harding-Lester S, Bradley A. Uptake of Huntington disease predictive testing in a complete population. Clin Genet 2010; published online Sept 6. DOI:10.1111/j.1399-0004.2010.01538.x. Li JL, Hayden MR, Warby SC, et al. Genomewide significance for a modifier of age at neurological onset in Huntington’s disease at 6q23-24: the HD MAPS study. BMC Med Genet 2006; 7: 71. Bates G, Harper PS, Jones L, eds. Huntington’s disease, 3rd edn. Oxford: Oxford University Press, 2002.
Vaccination and Dravet syndrome I read with great interest the Article by Anne McIntosh and colleagues.1 I believe this paper makes an important contribution to our 1147
Correspondence
knowledge of child neurology. However, I strongly disagree with the authors’ conclusion—that there is no evidence that vaccination before or after disease onset affects outcome. There is nothing in the data presented to justify their conclusion that an asymptomatic child with a severe SCN1A mutation should be vaccinated. This conclusion is premature and maybe even dangerous. The study showed an association between vaccination and onset of the seizures of Dravet syndrome. From the data, one can see that the risk of the onset of seizures during a day that falls within 48 h after one of the three diphtheria-tetanus-pertussis (DTP) vaccinations during the first 6 months of life is 12·4-times higher than for any of the other 177 days of these 6 months. A similar relative risk can be derived from Nieto Barrera and colleagues’ report.2 The most crucial matter regarding syndrome severity is the difference in intellectual outcome between vaccine-proximate and vaccine-distant groups. The authors grouped together patients with no intellectual disability and those with mild disability; moderate and severe disabilities formed the other group. The authors’ comparison ignores the tendency towards severe intellectual disability in the vaccination-proximate group: one of 28 vaccination-distant patients had no disability, but none of the 12 vaccination-proximate patients. Six (50%) vaccination-proximate patients had severe disability versus nine (32%) vaccination-distant patients. Children with Dravet syndrome are developmentally normal until onset of seizures, and progressively fall behind their peers as seizures progress. Other channelopathies have also shown age-dependent vulnerability. Moreover, seizures in the neonatal and infant brain might be more harmful developmentally 1148
than are seizures at an older age.3 Variability in syndrome severity has been described even in identical twins with identical mutations.4 The data do not answer the question of whether Dravet syndrome might be avoided or ameliorated by postponement of vaccination in patients with known mutations who have not had seizures. The only way to answer this question is by neonatal screening for SCN1A mutations. Such a screen is feasible and not unjustified in view of the severity and poor prognosis of this syndrome compared with other genetic conditions for which screening is common. The question of whether asymptomatic or mildly symptomatic infants carrying SCN1A mutations similar to those found by McIntosh and colleagues exist could also be answered by such a screen. Two possible ways to try to delay or prevent the syndrome in children identified in such a screen are to postpone vaccination and maybe use prophylactic antiepileptic treatments. I am testifying as a paid expert witness in the US Court of Federal Claims on behalf of a child with Dravet syndrome who had his first seizure after a DTP vaccine, who is petitioning for compensation according to the US Federal Vaccine Compensation Act.
Yuval Shafrir [email protected] Sinai Hospital of Baltimore, Pediatrics, Baltimore, MD 21215, USA 1
2
3
4
McIntosh AM, McMahon J, Dibbens LM, et al. Effects of vaccination on onset and outcome of Dravet syndrome: a retrospective study. Lancet Neurol 2010; 9: 592–98. Nieto Barrera M, Candau Fernandez Mensaque R, Nieto Jiménez M. Severe myoclonic epilepsy in infancy (Dravet’s syndrome). Its nosological characteristics and therapeutic aspects. Rev Neurol 2003; 37: 64–68. Swann JW, Baram TZ, Jensen FE, Moshe SL. Seizure mechanisms and vulnerability in the developing brain. In: Engel J, Pedley TA, eds. Epilepsy: a comprehensive textbook , 2nd edn. Philadelphia, PA, USA: Lippincott Williams & Wilkins, 2008: 469–80. Miyama S, Goto T, Inoue Y, Yamakawa K. Monozygotic twins with severe myoclonic epilepsy in infancy discordant for clinical features. Pediatr Neurol 2008; 39: 120–22.
Authors’ reply Yuval Shafrir disagrees with our conclusion that there is no evidence that vaccination before or after onset of Dravet syndrome affects outcome, and is concerned that our recommendation on immunisation could be “dangerous”. First, childhood vaccination has both individual and community benefits in prevention of communicable diseases. Any recommendations to delay or withhold vaccination should take into account the increased public health risk and individual cost of these diseases. Our findings do not support change to accepted vaccination policy. Second, Shafrir focuses on one non-significant trend in our data, regarding intellectual outcome. We a-priori dichotomised intellectual outcome into mild disability or normal intellect (3/12 in the vaccine-proximate group and 10/28 in the vaccine-distant group) versus moderate or severe intellectual disability (9/12 vaccine-proximate and 18/28 vaccine-distant), since this distinction is clinically important. Shafrir is concerned that we might have ignored an effect on severe intellectual disability, but post-hoc analysis for severe disability versus all other cases did not reveal an effect (6/12 vaccineproximate patients had severe disability, vs 9/28 vaccine-distant; Fisher’s exact p=0·31). Vaccination fear is rife and unfounded; our data show no evidence of an effect of the vaccination on outcome, although, as pointed out in our Article,1 we cannot exclude a type 2 error. Third, although uncontrolled and post hoc, perhaps our best evidence against his assertion is our data for children vaccinated after disorder onset, in whom no effect or negative trends regarding regression or intellectual outcome were seen. Fourth, Shafrir cites evidence that young brains are more vulnerable to certain forms of damage. This is true, but differences
www.thelancet.com/neurology Vol 9 December 2010