- Email: [email protected]
Death in children with epilepsy
CORRESPONDENCE
doctors who had various types of cancer and who too were doing much personal investigation. We came to the broad conclusion that chemotherapy clearly justified its toxic effects with several leukaemias, lymphomas, and testicular tumours. We also concluded that for most other tumours we would be reluctant to tolerate the adverse effects of treatment in return for very small therapeutic gains. We were not impressed by progress in chemotherapy for most cancers and were surprised by this conclusion because previously, as non-oncologists, we had a more positive view. Physicians have locked themselves into an absurd situation, in which with many diseases we are testing only a certain number of patent-protected drugs of limited efficacy in very large trials. We have handed over therapeutic discovery to the pharmaceutical industry, which must by its nature be primarily interested in profit. Such a motive can lead to major therapeutic advance, but inevitably restricts itself to only a tiny part of the universe of possibilities. It is time we cast our net much wider by scanning a much larger range of potential treatments in smaller physician-initiated studies. David Horrobin Laxdale Ltd, Kings Park House, Laurelhill Business Park, Stirling FK7 9JQ, UK (e-mail: [email protected])
Death in children with epilepsy Sir—In the population-based study done by Carol Camfield and colleagues (June 1, p 1891),1 death is uncommon in epileptic children without severe neurological disorder (SND), and is more frequent in patients with SND and with symptomatic generalised epilepsy. This fact is useful in counselling patients and parents that death in idiopathic and cryptogenic epilepsies is rare. However, we disagree with the main conclusion. The investigators state that death in epileptic children is not related to epilepsy itself, but to the underlying SND sufficient to cause functional neurological deficit. They suppose that this functional deficit leads to terminal infections as the final cause of death (most patients died from aspiration pneumonia or sepsis). This assumption contains two speculative steps. First, that SND causes functional deficit, although the neurological findings were not assessed, nor the SND specified. Second, the assumed functional deficit is the only
1698
cause for the terminal illnesses. We cannot exclude that these speculations are true, because the final cause of death was not directly related to seizures. However, frequent seizures may cause severe disability and confine patients to bed, which can also lead to aspiration and terminal infections. Camfield and colleagues have not assessed the most important epileptological data—seizure frequency and severity. In our opinion, this is a notable limitation of the study and may lead to false interpretations for the following reasons. First, SND does not necessarily lead to neurological deficit, and severe dysgeneses or perinatal brain injuries may be associated with normal neurological function. Second, SND and epileptic seizures may cause transient functional loss, which can manifest as a permanent neurological deficit when seizure frequency is high.2 Third, evidence points to death in epilepsy being related to seizure frequency. 89% of patients with childhood-onset epilepsy who die have seizures.3 Sperling and colleagues4 have shown that, during follow-up of patients who have undergone epilepsy surgery, no seizure-free patient died compared with 5·6% of patients who had seizures. Fourth, Camfield colleagues excluded patients with progressive SND, and death occurred with equal frequency over time after epilepsy onset. We suggest that, besides stable SND, other factors have a role in developing infections and terminal outcome. SND is frequent in catastrophic epilepsy (severe frequent seizures and mental retardation).5 It is unclear which variables (neurological deficit, mental retardation, or frequent disabling seizures) are important in causing death because they all may lead to bed confinement and aspiration, and consequently terminal infections. All these variables should be controlled in any study examining the causes of death in epileptic children. Camfield and collegues suggest that seizure control is unimportant in preventing death in childhood-onset epilepsy. This conclusion is problematic because of possible consequent therapeutic nihilism that may manifest in neglecting the aim of total seizure control through conservative or surgical treatment. Moreover, children will grow up, and in adult epilepsy, the total seizure control is the most important factor in preventing death.4 *József Janszky, Anna Szücs *Epilepsy Centre, National Institute of Neurology and Psychiatry, Budapest H-1048, Hungary; and Department of Neurology, Uzsoki Hospital, Budapest (e-mail: [email protected])
1
2 3
4
5
Camfield CS, Camfield PR, Veugelers PJ. Death in children with epilepsy: a populationbased study. Lancet 2002; 359: 1891–95. Neville BGR. Reversible disability associated with epilepsy. Brain Dev 1999; 21: 82–85. Sillanpaa M, Jalava M, Kaleva O, Shinnar S. Long-term prognosis of seizure with onset in childhood. N Engl J Med 1998; 338: 1715–22. Sperling MR, Feldman H, Kinman J, Liporace JD, O’Connor MJ. Seizure control and mortality in epilepsy. Ann Neurol 1999; 46: 45–50. Shields WD. Catastrophic epilepsy in childhood. Epilepsia 2000; 41 (suppl 2): S2–6.
Authors’ reply Sir—Jósef Janszky and Anna Szücs raise an important question—did seizures contribute to the deaths of patients with severe neurological handicaps? We identified severe neurological handicap as a powerful risk factor to predict death in children with epilepsy. Risk factors are not always causative; however, we also indicated the actual cause of death. Most common was aspiration pneumonia. We had personally cared for each of these patients and it was clear that the aspirations were from severe bulbar coordination difficulties in each case. The underlying cause was nearly always severe spastic cerebral palsy. There seemed to be no clear relations with the seizures themselves. It is possible that the seizures or the medications increased the bulbar difficulties, but we did not think so. The other causes of death we listed, such as shunt blockage or heart failure, were not related to seizures, except for in the one child with status epilepticus. Janszky and Szücs are disturbed that seizure frequency was not a predictor of death. We did not explore this feature as an independent variable because all the deaths were in the severe neurological handicap group, in which multiple seizures of varying types are typically impossible to count. Although this approach may seem counterintuitive to some, we stand by our populationbased data. Centres treating patients with refractory epilepsy see more deaths, but, fortunately, in the general population, highly refractory patients are rare. It is important to emphasise that our data predict risk of death starting at the time of diagnosis and not years later when refractory seizures have developed. In practice we try to achieve complete seizure control in the patients who choose to take medication. It is clear from our data that the reason to do this is not to prevent death. It would be unethical to suggest to newly diagnosed children (especially those who are neurologically normal) that good treatment adherence will decrease the
THE LANCET • Vol 360 • November 23, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
risk of death. In fact their risk of death is exactly the same as that in children without epilepsy. The statistical risk of death in patients whose treatment is haphazard is simply not known. *Carol Camfield, Peter Camfield Division of Child Neurology, IWK Health Center, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia B3J 3G9, Canada (e-mail: [email protected])
Waterborne infections in the era of bioterrorism Sir—In Vicenza, northeast Italy, on May 17–19, 2002, suspicion of an outbreak of a waterborne infection was announced in the local newspaper, after seven players of the Vicenza football team complained of gastrointestinal symptoms. A broken sewer pipe in the football field irrigation system allowed water from the Bacchiglione River to enter the city aqueduct. Cases were defined as any gastroenteric symptoms in any citizen who had drunk tap water in the stadium area from May 16–19. The list of symptoms included fever, nausea, vomiting, and diarrhoea or bloody diarrhoea. On May 18 and 19, 71 symptomatic citizens attended the “Guardia Medica” medical centre, which provides out-of-hospital care at night and during weekends. 32 patients were referred to San Bortolo Hospital, six of whom were admitted for severe dysenteric symptoms. 20 patients were thought to be at high risk (age >60 years, comorbidity, and persistent symptoms) and prophylactic ciprofloxaxin was advised. In total, 146 stool samples (from hospital and community patients) were examined. Stools were processed for Aeromonas spp, Campylobacter spp, Salmonella spp, Shigella spp, Yersinia spp, rotavirus Escherichia coli O157:H7, parasite ova, and Cryptosporidium spp. No specific enteric agent was isolated. Microbiological examination of sampled aqueduct water revealed only a high concentration of coliforms. Since hepatitis A is another possible waterborne infection, local political and health authorities decided to vaccinate the population without screening. A survey on symptoms was done in vaccinated people. Overall, 670 (22%) of the 3006 exposed individuals reported gastrointestinal symptoms. In most people, symptoms spontaneously disappeared in a few days, and no deaths were recorded. Despite the health authority’s inability to identify the ultimate cause
of the infection, information on emergency water disinfection by boiling was quickly spread by the media. Vaccination began on May 22. More than 90% of the estimated exposed population was treated. After 1 month, the average time of incubation for hepatitis A virus, no case of acute hepatitis A infection was reported. The provision of so much vaccine created some logistical difficulties but was still undertaken quickly. This outbreak is one of the largest waterborne outbreaks reported in Italy. In 2000, in the Gulf of Taranto in southern Italy, an outbreak of Norwalk-like virus affected 344 people.1 This community in this case was fortunate that the response team was able to mobilise with effective speed to effectively limit the duration of the outbreak. Andrea Tramarin, Paolo Fabris, David Bishai, *Vittorio Selle, Fausto De Lalla San Bortolo Hospital, Via Rodolfi 3, Vicenza, Italy; and *Johns Hopkins School of Public Health, Baltimore, MD 36100, USA (e-mail: [email protected]) 1
Boccia DAE, Tozzi B, Cotter C, et al. Waterborne outbreak of norwalk-like virus gastroenteritis at a tourist resort, Italy. Emerg Infect Dis 2002; 8: 563–68.
Gastrointestinal function after elective colonic resection Sir—We think that the study by Dileep Lobo and colleagues (May 25, p 1812)1 has some major flaws. A statistical power analysis based on the results of a 65-year-old study in dogs is not very trustworthy, and the laboratory equipment, data collection, and scientific analysis described therein are hardly comparable with the current standards of research. We would be interested to know whether the three patients in the standard group who were vomiting and thus did not have gastric emptying studies were among the first ten patients who were studied. After studying these ten patients, the authors concluded that gastric emptying times were 74 min (95% CI 3–143) longer, and that only 20 patients had to be studied. This would seem a premature conclusion if the three vomiting patients were in this group. Surgeon A operated on seven of the ten patients in the restricted treatment group. This fact may have strongly influenced the results, but is not discussed at all. In the last section, the authors compare cancer patients who had
THE LANCET • Vol 360 • November 23, 2002 • www.thelancet.com
colonic surgery with a group of critically ill patients with septic shock in whom restrictive fluid therapy was an independent predictor of survival. In our opinion, these groups of patients are not comparable. The conclusions and comparisons of the authors are highly speculative. Nowadays cancer patients who are scheduled for colonic surgery are managed in most major cancer centres with thoracic epidurals that provide superior analgesia, permit early mobilisation, and have a role in the prevention of postoperative ileus by blocking sympathetic pathways.2,3 Therefore, we do not support the statement of the authors that this study will have important implications for the management of surgical patients who receive intravenous fluids. We agree with the writers of the Commentary that the findings of this study may not apply to daily clinical practice in most hospitals.4 *Johannes M Huitink, Dirk R Buitelaar Department of Anesthesiology and Intensive Care, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, Netherlands (e-mail: [email protected]) 1
2
3 4
Lobo DN, Bostock KA, Neal KR, Perkins AC, Rowlands BJ, Allison SP. Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet 2002; 359: 1812–18. Leon-Casasola AO, Parker B, Lema MJ, Harrison P, Massey J. Postoperative epidural bupivacaine-morphine therapy: experience with 4227 surgical cancer patients. Anesthesiology 1994; 81: 368–75. Kehlet H, Holte K. Review of postoperative ileus. Am J Surg 2001; 182: 3S–10S. Heyland DK, Paterson WG. Fluid restriction for postoperative patients? Lancet 2002; 359: 1792–93.
Authors’ reply Sir—Since there had been no other studies relating gastric emptying to fluid balance and serum albumin concentration since that of Mecray and colleagues1 65 years ago, it was not possible to base power calculations on any more recent studies. Mecray’s paper involved careful clinical observations and extensive animal studies, in which simple, straightforward methods were used to arrive at clear and credible conclusions. We also took professional statistical advice throughout the study. At the half-way stage, the differences were so large that it seemed to us and the statistician inappropriate, unnecessary, and unethical to continue. Only one of the three patients who were vomiting on the fourth day was in the first ten patients studied. All three had the largest positive salt and water
1699
For personal use. Only reproduce with permission from The Lancet Publishing Group.
doctors who had various types of cancer and who too were doing much personal investigation. We came to the broad conclusion that chemotherapy clearly justified its toxic effects with several leukaemias, lymphomas, and testicular tumours. We also concluded that for most other tumours we would be reluctant to tolerate the adverse effects of treatment in return for very small therapeutic gains. We were not impressed by progress in chemotherapy for most cancers and were surprised by this conclusion because previously, as non-oncologists, we had a more positive view. Physicians have locked themselves into an absurd situation, in which with many diseases we are testing only a certain number of patent-protected drugs of limited efficacy in very large trials. We have handed over therapeutic discovery to the pharmaceutical industry, which must by its nature be primarily interested in profit. Such a motive can lead to major therapeutic advance, but inevitably restricts itself to only a tiny part of the universe of possibilities. It is time we cast our net much wider by scanning a much larger range of potential treatments in smaller physician-initiated studies. David Horrobin Laxdale Ltd, Kings Park House, Laurelhill Business Park, Stirling FK7 9JQ, UK (e-mail: [email protected])
Death in children with epilepsy Sir—In the population-based study done by Carol Camfield and colleagues (June 1, p 1891),1 death is uncommon in epileptic children without severe neurological disorder (SND), and is more frequent in patients with SND and with symptomatic generalised epilepsy. This fact is useful in counselling patients and parents that death in idiopathic and cryptogenic epilepsies is rare. However, we disagree with the main conclusion. The investigators state that death in epileptic children is not related to epilepsy itself, but to the underlying SND sufficient to cause functional neurological deficit. They suppose that this functional deficit leads to terminal infections as the final cause of death (most patients died from aspiration pneumonia or sepsis). This assumption contains two speculative steps. First, that SND causes functional deficit, although the neurological findings were not assessed, nor the SND specified. Second, the assumed functional deficit is the only
1698
cause for the terminal illnesses. We cannot exclude that these speculations are true, because the final cause of death was not directly related to seizures. However, frequent seizures may cause severe disability and confine patients to bed, which can also lead to aspiration and terminal infections. Camfield and colleagues have not assessed the most important epileptological data—seizure frequency and severity. In our opinion, this is a notable limitation of the study and may lead to false interpretations for the following reasons. First, SND does not necessarily lead to neurological deficit, and severe dysgeneses or perinatal brain injuries may be associated with normal neurological function. Second, SND and epileptic seizures may cause transient functional loss, which can manifest as a permanent neurological deficit when seizure frequency is high.2 Third, evidence points to death in epilepsy being related to seizure frequency. 89% of patients with childhood-onset epilepsy who die have seizures.3 Sperling and colleagues4 have shown that, during follow-up of patients who have undergone epilepsy surgery, no seizure-free patient died compared with 5·6% of patients who had seizures. Fourth, Camfield colleagues excluded patients with progressive SND, and death occurred with equal frequency over time after epilepsy onset. We suggest that, besides stable SND, other factors have a role in developing infections and terminal outcome. SND is frequent in catastrophic epilepsy (severe frequent seizures and mental retardation).5 It is unclear which variables (neurological deficit, mental retardation, or frequent disabling seizures) are important in causing death because they all may lead to bed confinement and aspiration, and consequently terminal infections. All these variables should be controlled in any study examining the causes of death in epileptic children. Camfield and collegues suggest that seizure control is unimportant in preventing death in childhood-onset epilepsy. This conclusion is problematic because of possible consequent therapeutic nihilism that may manifest in neglecting the aim of total seizure control through conservative or surgical treatment. Moreover, children will grow up, and in adult epilepsy, the total seizure control is the most important factor in preventing death.4 *József Janszky, Anna Szücs *Epilepsy Centre, National Institute of Neurology and Psychiatry, Budapest H-1048, Hungary; and Department of Neurology, Uzsoki Hospital, Budapest (e-mail: [email protected])
1
2 3
4
5
Camfield CS, Camfield PR, Veugelers PJ. Death in children with epilepsy: a populationbased study. Lancet 2002; 359: 1891–95. Neville BGR. Reversible disability associated with epilepsy. Brain Dev 1999; 21: 82–85. Sillanpaa M, Jalava M, Kaleva O, Shinnar S. Long-term prognosis of seizure with onset in childhood. N Engl J Med 1998; 338: 1715–22. Sperling MR, Feldman H, Kinman J, Liporace JD, O’Connor MJ. Seizure control and mortality in epilepsy. Ann Neurol 1999; 46: 45–50. Shields WD. Catastrophic epilepsy in childhood. Epilepsia 2000; 41 (suppl 2): S2–6.
Authors’ reply Sir—Jósef Janszky and Anna Szücs raise an important question—did seizures contribute to the deaths of patients with severe neurological handicaps? We identified severe neurological handicap as a powerful risk factor to predict death in children with epilepsy. Risk factors are not always causative; however, we also indicated the actual cause of death. Most common was aspiration pneumonia. We had personally cared for each of these patients and it was clear that the aspirations were from severe bulbar coordination difficulties in each case. The underlying cause was nearly always severe spastic cerebral palsy. There seemed to be no clear relations with the seizures themselves. It is possible that the seizures or the medications increased the bulbar difficulties, but we did not think so. The other causes of death we listed, such as shunt blockage or heart failure, were not related to seizures, except for in the one child with status epilepticus. Janszky and Szücs are disturbed that seizure frequency was not a predictor of death. We did not explore this feature as an independent variable because all the deaths were in the severe neurological handicap group, in which multiple seizures of varying types are typically impossible to count. Although this approach may seem counterintuitive to some, we stand by our populationbased data. Centres treating patients with refractory epilepsy see more deaths, but, fortunately, in the general population, highly refractory patients are rare. It is important to emphasise that our data predict risk of death starting at the time of diagnosis and not years later when refractory seizures have developed. In practice we try to achieve complete seizure control in the patients who choose to take medication. It is clear from our data that the reason to do this is not to prevent death. It would be unethical to suggest to newly diagnosed children (especially those who are neurologically normal) that good treatment adherence will decrease the
THE LANCET • Vol 360 • November 23, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
risk of death. In fact their risk of death is exactly the same as that in children without epilepsy. The statistical risk of death in patients whose treatment is haphazard is simply not known. *Carol Camfield, Peter Camfield Division of Child Neurology, IWK Health Center, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia B3J 3G9, Canada (e-mail: [email protected])
Waterborne infections in the era of bioterrorism Sir—In Vicenza, northeast Italy, on May 17–19, 2002, suspicion of an outbreak of a waterborne infection was announced in the local newspaper, after seven players of the Vicenza football team complained of gastrointestinal symptoms. A broken sewer pipe in the football field irrigation system allowed water from the Bacchiglione River to enter the city aqueduct. Cases were defined as any gastroenteric symptoms in any citizen who had drunk tap water in the stadium area from May 16–19. The list of symptoms included fever, nausea, vomiting, and diarrhoea or bloody diarrhoea. On May 18 and 19, 71 symptomatic citizens attended the “Guardia Medica” medical centre, which provides out-of-hospital care at night and during weekends. 32 patients were referred to San Bortolo Hospital, six of whom were admitted for severe dysenteric symptoms. 20 patients were thought to be at high risk (age >60 years, comorbidity, and persistent symptoms) and prophylactic ciprofloxaxin was advised. In total, 146 stool samples (from hospital and community patients) were examined. Stools were processed for Aeromonas spp, Campylobacter spp, Salmonella spp, Shigella spp, Yersinia spp, rotavirus Escherichia coli O157:H7, parasite ova, and Cryptosporidium spp. No specific enteric agent was isolated. Microbiological examination of sampled aqueduct water revealed only a high concentration of coliforms. Since hepatitis A is another possible waterborne infection, local political and health authorities decided to vaccinate the population without screening. A survey on symptoms was done in vaccinated people. Overall, 670 (22%) of the 3006 exposed individuals reported gastrointestinal symptoms. In most people, symptoms spontaneously disappeared in a few days, and no deaths were recorded. Despite the health authority’s inability to identify the ultimate cause
of the infection, information on emergency water disinfection by boiling was quickly spread by the media. Vaccination began on May 22. More than 90% of the estimated exposed population was treated. After 1 month, the average time of incubation for hepatitis A virus, no case of acute hepatitis A infection was reported. The provision of so much vaccine created some logistical difficulties but was still undertaken quickly. This outbreak is one of the largest waterborne outbreaks reported in Italy. In 2000, in the Gulf of Taranto in southern Italy, an outbreak of Norwalk-like virus affected 344 people.1 This community in this case was fortunate that the response team was able to mobilise with effective speed to effectively limit the duration of the outbreak. Andrea Tramarin, Paolo Fabris, David Bishai, *Vittorio Selle, Fausto De Lalla San Bortolo Hospital, Via Rodolfi 3, Vicenza, Italy; and *Johns Hopkins School of Public Health, Baltimore, MD 36100, USA (e-mail: [email protected]) 1
Boccia DAE, Tozzi B, Cotter C, et al. Waterborne outbreak of norwalk-like virus gastroenteritis at a tourist resort, Italy. Emerg Infect Dis 2002; 8: 563–68.
Gastrointestinal function after elective colonic resection Sir—We think that the study by Dileep Lobo and colleagues (May 25, p 1812)1 has some major flaws. A statistical power analysis based on the results of a 65-year-old study in dogs is not very trustworthy, and the laboratory equipment, data collection, and scientific analysis described therein are hardly comparable with the current standards of research. We would be interested to know whether the three patients in the standard group who were vomiting and thus did not have gastric emptying studies were among the first ten patients who were studied. After studying these ten patients, the authors concluded that gastric emptying times were 74 min (95% CI 3–143) longer, and that only 20 patients had to be studied. This would seem a premature conclusion if the three vomiting patients were in this group. Surgeon A operated on seven of the ten patients in the restricted treatment group. This fact may have strongly influenced the results, but is not discussed at all. In the last section, the authors compare cancer patients who had
THE LANCET • Vol 360 • November 23, 2002 • www.thelancet.com
colonic surgery with a group of critically ill patients with septic shock in whom restrictive fluid therapy was an independent predictor of survival. In our opinion, these groups of patients are not comparable. The conclusions and comparisons of the authors are highly speculative. Nowadays cancer patients who are scheduled for colonic surgery are managed in most major cancer centres with thoracic epidurals that provide superior analgesia, permit early mobilisation, and have a role in the prevention of postoperative ileus by blocking sympathetic pathways.2,3 Therefore, we do not support the statement of the authors that this study will have important implications for the management of surgical patients who receive intravenous fluids. We agree with the writers of the Commentary that the findings of this study may not apply to daily clinical practice in most hospitals.4 *Johannes M Huitink, Dirk R Buitelaar Department of Anesthesiology and Intensive Care, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, Netherlands (e-mail: [email protected]) 1
2
3 4
Lobo DN, Bostock KA, Neal KR, Perkins AC, Rowlands BJ, Allison SP. Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet 2002; 359: 1812–18. Leon-Casasola AO, Parker B, Lema MJ, Harrison P, Massey J. Postoperative epidural bupivacaine-morphine therapy: experience with 4227 surgical cancer patients. Anesthesiology 1994; 81: 368–75. Kehlet H, Holte K. Review of postoperative ileus. Am J Surg 2001; 182: 3S–10S. Heyland DK, Paterson WG. Fluid restriction for postoperative patients? Lancet 2002; 359: 1792–93.
Authors’ reply Sir—Since there had been no other studies relating gastric emptying to fluid balance and serum albumin concentration since that of Mecray and colleagues1 65 years ago, it was not possible to base power calculations on any more recent studies. Mecray’s paper involved careful clinical observations and extensive animal studies, in which simple, straightforward methods were used to arrive at clear and credible conclusions. We also took professional statistical advice throughout the study. At the half-way stage, the differences were so large that it seemed to us and the statistician inappropriate, unnecessary, and unethical to continue. Only one of the three patients who were vomiting on the fourth day was in the first ten patients studied. All three had the largest positive salt and water
1699
For personal use. Only reproduce with permission from The Lancet Publishing Group.