- Email: [email protected]
Oesophageal motility disorders
CORRESPONDENCE
case fatality rates in inhaled anthrax can approach 100%.2 Anthrax bacteria, after being inhaled, use three toxins— protective antigen, oedema factor, and lethal factor—to enter, appropriate, and kill alveolar macrophages. Seven copies of protective antigen assemble and facilitate entry of oedema factor and lethal factor into macrophages. Oedema factor weakens the ability of macrophages to kill the bacteria. Lethal factor causes macrophages to elaborate large amounts of inflammatory cytokines such as TNF␣. Death typically results from an artificial sock-like picture caused by these cytokines. Administration of ACTH might be able to reverse the inflammatory cytokine milieu, buying time for antibiotics and other supportive measures to preserve life. Since ACTH is inexpensive, easy to use, and has few side-effects, it might be considered for inhaled anthrax.
the curves of the subgroup of patients taking and not taking open-label thienopyridine. This possible effect in no way weakens the argument for benefit of clopidogrel in this population of patients, but would help explain the pathophysiology of the benefit of pretreatment if the same divergence were seen in the group who received open-label thienopyridine.
Eric Lewin Altschuler
Authors’ reply
1
2
Noera G, Lamarra M, Guarini S, Bertolini A. Survival rate after early treatment for acute type-A aortic dissection with ACTH-(1-24). Lancet 2001; 358: 469–70. Dixon TC, Meselson M, Guillemin J, Hanna PC. Anthrax. N Engl J Med 1999; 341: 815–26.
Clopidogrel and percutaneous coronary intervention Sir—Shamir Mehta and colleagues (Aug 18, p 527)1 present compelling data on the benefit of treatment with clopidogrel, as well as long-term treatment with clopidogrel, in patients undergoing percutaneous coronary interventions (PCI). The researchers note that, since most of the patients (80%) were treated with open-label thienopyridine in the first 30 days after PCI because of stenting, they attribute the divergence of the event curves to the pretreatment. However, 20% of patients who did not undergo stenting continued on masked clopidogrel or placebo. Thus, the divergence of the curve overall at day 30 might have been due to the (well reported) benefit of clopidogrel over placebo in that group of patients, with relatively little divergence in the curves in patients on open-label thienopyridine. The subgroup analysis is for only the long-term results, which show benefit in patients who had stenting and those who did not. It would be helpful to see
Christopher Cannon Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA 1
Mehta SR, Yusuf S, Peters RJG, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary interventions: the PCI-CURE study. Lancet 2001; 358: 527–33.
Sir—When considering the effect of clopidogrel pretreatment, it is helpful to separate the effects of open-label thienopyridine given before and after PCI. First, if the divergence in the event curves in the first 30 days were due to pretreatment, any benefit would only be observed among those who recieved blinded medication but not in those who received open-label thienopyridine before PCI. This is exactly what we observed. All of the benefit was noted in patients who received double-blind treatment before PCI, in whom there was a striking benefit of clopidogrel compared with placebo at 30 days, with no difference in those who did not adhere to the protocol. Second, in patients on blinded medication until PCI, who were those given an intracoronary stent during 0·12 Cumulative hazard rates
Brain and Perception Laboratory, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA (e-mail: [email protected])
C Cannon recieves grant support from Aventis, Bayer, BMS, and COI therapeutics
0·10
RR 0·56 (0·35–0·90) p=0·017
0·08
Placebo, pretreated
0·06 0·04 Clopidogrel, pretreated
0·02 0 0
5
10 15 20 Follow-up (days)
25
30
Cumulative hazard rates of cardiovascular death, myocardial infarction, and urgent target-vessel revascularisation in stented patients who did not receive open-label thienopyridine before PCI All patients received open-label thienopyridine after PCI for a median of 30 days.
THE LANCET • Vol 359 • January 12, 2002 • www.thelancet.com
PCI (all of whom were given openlabel thienopyridine for a median of 30 days after PCI), there was a consistent and significant benefit of clopidogrel pretreatment (figure). Thus, in the 30 days after PCI, when treatment between the two groups was virtually identical, the events curves continued to separate, which implies that this divergence was indeed due to the effects of pretreatment. In the few patients who did not receive a stent, there was a consistent trend in favour of clopidogrel, which is also possibly due to the effects of clopidogrel pretreatment. However, as Christopher Cannon points out, the effect might also be due to restarting double-blind treatment shortly after angioplasty without stent implantation. These data further reinforce our conclusion that clopidogrel pretreatment before PCI results in a significant and clinically relevant benefit after the procedure, in patients undergoing PCI. *Shamir R Mehta, Feng Zhao, Salim Yusuf McMaster University, Hamilton, Ontario, L8L 2X2, Canada
Oesophageal motility disorders Sir—In his report on oesophageal motility disorders. Joel Richter (Sept 8, p 823)1 does not mention the beneficial effect of sildenafil in achalasia cardia. Sildenafil shows an intense and sustained inhibitory effect on the smooth-muscle cells of the human corpus cavernosum by blocking phosphodiesterase type 5 that destroys nitric-oxide-stimulated guanosine 3⬘,5⬘-cyclic monophosphate (cGMP). Bortolotti and colleagues2 investigated whether sildenafil possesses a similar effect on the oesophageal musculature of patients with achalasia who have an impairment of nitric-oxide production similar to that of erectile dysfunction. In a double-blind placebo-controlled study in 14 achalasia patients, they compared the effect of 50 mg sildenafil tablets dissolved in water and infused in the stomach with placebo. Sildenafil significantly decreased lower oesophageal sphincter tone, residual pressure, and wave amplitude compared with the basal period and the placebo group. There was pronounced variability between patients. The inhibitory effect reached its maximum 15–20 min after the infusion and the effect lasted less than 1 h.
169
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
Patients with other spastic oesophageal motor disorders, such as diffuse spasm, nutcracker oesophagus, and hypertensive lower oesophageal sphincter tone, could also benefit from the use of an oesophageal phosphodiesterase inhibitor, because the nonadrenergic, non-cholinergic inhibitory neurons are present in all disorders,3 although they are functionally impaired,4 and presumably still produce some cGMP.2 *A S Kashyap, Surekha Kashyap Departments of *Medicine and Hospital Administration, Armed Forces Medical College, Pune 411 040, India 1 2
3
4
Richter JE. Oesophageal motility disorders. Lancet 2001; 358: 823–28. Bortolotti M, Mari C, Lopilato C, Porrazzo G, Miglioli M. Effects of sildenafil on esophageal motility of patients with idiopathic achalasia. Gastroenterology 2000; 118: 253–57. Craddock DR, Logan A, Waldbaum PR. Diffuse esophageal spasm. Thorax 1966; 21: 511–17. Nicks R, Gillies M, Skyring A. Diffuse muscular spasm (diffuse muscular hypertrophy of the esophagus). Bull Soc Int Chir 1968; 6: 637–48.
Sir—Joel E Richter’s seminar1 deserves, I think, another title to appeal to other interested physicians—ie, cardiologists. Since the 1960s, I have been interested in this subject as a clinical cardiologist2 and, in my opinion, the widest clinical experience belongs to heart physicians, who are generally the first doctors contacted by patients complaining of chest pain. The close connection between the heart and oesophagus is noted in many reports, from 1966 onwards, on linked angina.3,4 Because of the tremendous use in the media of the terms angina, coronary disease, and so on, for many years the term oesophageal angina has been used. One of the most frequent forms is the spasm of the oesophageal sphincters, enclosing an air bubble (when oesophageal peristalsis is lost) with a straining of the walls; my treatment, which is generally effective, is to give the person something to swallow with water. The action of swallowing acts on the spasm of the sphincters. Useful drugs to use are trimebutine and otilonium bromide, associated with medazepam or diazepam. Pier Andrea Maccarini Libero Docente Semeiotica Medica, University of Pisa, Via Galgana 6, Pisa, Italy 1 2
3
Richter JE. Oesophageal motility disorders. Lancet 2001; 358: 823–28. Maccarini PA. Sindrome coronarica intrecciata. XII Congress of the Italian Society of Cardiology, vol II, 1959: 41. Bennet JR, Atkinson M. The differentiation
170
magnetic resonance imaging revealed a slight cerebellar atrophy. Physical examination between attacks showed a gaze-evoked nystagmus and gait and limb ataxia. Idiopathic focal epilepsy, EA 2, and migraine without aura were diagnosed. Seizures were controlled by valproic acid and oxcarbazepine and the ataxic episodes responded well to sulthiame, a carboanhydrase inhibitor. Her father (II-6), aged 39 years, had had isolated somatosensory auras and secondary generalised tonicclonic seizures since age 34. From about age 6 years he developed infrequent ataxic episodes. Additionally, he had simple motor tics. Postictal electroencephalography showed a slowing over the right hemisphere, and cranial magnetic resonance imaging was normal. Between attacks he showed cerebellar eye signs, dysarthria, and gait ataxia. He was diagnosed as having idiopathic focal epilepsy, EA 2, and migraine without aura. Seizures responded well to carbamazepine. Among the extended family, one individual (II-1) had a definite history of seizures, but details were not sufficient to diagnose a specific epilepsy syndrome. Another individual (II-4) reported seizures, but whether these were true epileptic seizures remained unclear. Four individuals had common migraine. In this family, there is a striking cooccurrence of periodic neurological disorders that have been attributed to mutations in CACNA1A. Although this association of EA 2, focal epilepsy, and migraine might be coincidence, we purport that the cases are similar to that presented by Jouvenceau and colleagues. The observed disorders are different manifestations of an inherited dysfunction of the brain P/Q-type calcium channel. This hypothesis lends support to the assumption that
between oesophageal and cardiac pain. Lancet 1966; 2: 1123–27. Chauhan A, Petch MC, Shofield PM. Cardio-oesophageal reflex in humans as a mechanism for “linked anginal”. Eur Heart J 1996; 17: 407–13.
4
Human epilepsy, episodic ataxia type 2, and migraine Sir—Anne Jouvenceau and colleagues (Sept 8, p 801)1 report a patient with a complex phenotype, including absence epilepsy and episodic ataxia type 2. They present direct evidence that human idiopathic generalised epilepsy can be associated with mutations of CACNA1A, a gene linked to chromosome 19p13 and encoding for the ␣1A subunit of a neuronal voltagegated P/Q-type calcium channel. Dysfunction of this calcium channel can lead to different paroxysmal disorders: familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA 2) and spinocerebellar atrophy 6 in human beings,2 and absence seizures in mice3 and human beings.1 We describe a family with the cooccurrence of idiopathic focal epilepsy, EA 2, and migraine. The paroxysmal disorders were noted over three generations (figure). The patient, III-5, was referred to our clinic at age 12 years because of recurrent nocturnal psychomotor seizures that had begun at around age 9 years. Additionally, she had had isolated episodes of common migraine since childhood and recurrent paroxysmal attacks of statokinetic ataxia, dysarthria, nystagmus, vertigo, headache, and diplopia that had begun at age 8 years. These frequent periods occurred independent of seizures and migraine. Interictal electroencephalography showed focal sharp waves. Cranial
I
1
2
3
II 1
2
3
4
5
6
7
5
6
8
9
10
11
12
13
III 1
2
3
4
migraine
episodic ataxia type 2
deceased
focal epilepsy
unclassified seizures
unconfirmed seizures
Pedigree of family with epilepsy, episodic ataxia type 2, and migrane
THE LANCET • Vol 359 • January 12, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
case fatality rates in inhaled anthrax can approach 100%.2 Anthrax bacteria, after being inhaled, use three toxins— protective antigen, oedema factor, and lethal factor—to enter, appropriate, and kill alveolar macrophages. Seven copies of protective antigen assemble and facilitate entry of oedema factor and lethal factor into macrophages. Oedema factor weakens the ability of macrophages to kill the bacteria. Lethal factor causes macrophages to elaborate large amounts of inflammatory cytokines such as TNF␣. Death typically results from an artificial sock-like picture caused by these cytokines. Administration of ACTH might be able to reverse the inflammatory cytokine milieu, buying time for antibiotics and other supportive measures to preserve life. Since ACTH is inexpensive, easy to use, and has few side-effects, it might be considered for inhaled anthrax.
the curves of the subgroup of patients taking and not taking open-label thienopyridine. This possible effect in no way weakens the argument for benefit of clopidogrel in this population of patients, but would help explain the pathophysiology of the benefit of pretreatment if the same divergence were seen in the group who received open-label thienopyridine.
Eric Lewin Altschuler
Authors’ reply
1
2
Noera G, Lamarra M, Guarini S, Bertolini A. Survival rate after early treatment for acute type-A aortic dissection with ACTH-(1-24). Lancet 2001; 358: 469–70. Dixon TC, Meselson M, Guillemin J, Hanna PC. Anthrax. N Engl J Med 1999; 341: 815–26.
Clopidogrel and percutaneous coronary intervention Sir—Shamir Mehta and colleagues (Aug 18, p 527)1 present compelling data on the benefit of treatment with clopidogrel, as well as long-term treatment with clopidogrel, in patients undergoing percutaneous coronary interventions (PCI). The researchers note that, since most of the patients (80%) were treated with open-label thienopyridine in the first 30 days after PCI because of stenting, they attribute the divergence of the event curves to the pretreatment. However, 20% of patients who did not undergo stenting continued on masked clopidogrel or placebo. Thus, the divergence of the curve overall at day 30 might have been due to the (well reported) benefit of clopidogrel over placebo in that group of patients, with relatively little divergence in the curves in patients on open-label thienopyridine. The subgroup analysis is for only the long-term results, which show benefit in patients who had stenting and those who did not. It would be helpful to see
Christopher Cannon Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA 1
Mehta SR, Yusuf S, Peters RJG, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary interventions: the PCI-CURE study. Lancet 2001; 358: 527–33.
Sir—When considering the effect of clopidogrel pretreatment, it is helpful to separate the effects of open-label thienopyridine given before and after PCI. First, if the divergence in the event curves in the first 30 days were due to pretreatment, any benefit would only be observed among those who recieved blinded medication but not in those who received open-label thienopyridine before PCI. This is exactly what we observed. All of the benefit was noted in patients who received double-blind treatment before PCI, in whom there was a striking benefit of clopidogrel compared with placebo at 30 days, with no difference in those who did not adhere to the protocol. Second, in patients on blinded medication until PCI, who were those given an intracoronary stent during 0·12 Cumulative hazard rates
Brain and Perception Laboratory, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA (e-mail: [email protected])
C Cannon recieves grant support from Aventis, Bayer, BMS, and COI therapeutics
0·10
RR 0·56 (0·35–0·90) p=0·017
0·08
Placebo, pretreated
0·06 0·04 Clopidogrel, pretreated
0·02 0 0
5
10 15 20 Follow-up (days)
25
30
Cumulative hazard rates of cardiovascular death, myocardial infarction, and urgent target-vessel revascularisation in stented patients who did not receive open-label thienopyridine before PCI All patients received open-label thienopyridine after PCI for a median of 30 days.
THE LANCET • Vol 359 • January 12, 2002 • www.thelancet.com
PCI (all of whom were given openlabel thienopyridine for a median of 30 days after PCI), there was a consistent and significant benefit of clopidogrel pretreatment (figure). Thus, in the 30 days after PCI, when treatment between the two groups was virtually identical, the events curves continued to separate, which implies that this divergence was indeed due to the effects of pretreatment. In the few patients who did not receive a stent, there was a consistent trend in favour of clopidogrel, which is also possibly due to the effects of clopidogrel pretreatment. However, as Christopher Cannon points out, the effect might also be due to restarting double-blind treatment shortly after angioplasty without stent implantation. These data further reinforce our conclusion that clopidogrel pretreatment before PCI results in a significant and clinically relevant benefit after the procedure, in patients undergoing PCI. *Shamir R Mehta, Feng Zhao, Salim Yusuf McMaster University, Hamilton, Ontario, L8L 2X2, Canada
Oesophageal motility disorders Sir—In his report on oesophageal motility disorders. Joel Richter (Sept 8, p 823)1 does not mention the beneficial effect of sildenafil in achalasia cardia. Sildenafil shows an intense and sustained inhibitory effect on the smooth-muscle cells of the human corpus cavernosum by blocking phosphodiesterase type 5 that destroys nitric-oxide-stimulated guanosine 3⬘,5⬘-cyclic monophosphate (cGMP). Bortolotti and colleagues2 investigated whether sildenafil possesses a similar effect on the oesophageal musculature of patients with achalasia who have an impairment of nitric-oxide production similar to that of erectile dysfunction. In a double-blind placebo-controlled study in 14 achalasia patients, they compared the effect of 50 mg sildenafil tablets dissolved in water and infused in the stomach with placebo. Sildenafil significantly decreased lower oesophageal sphincter tone, residual pressure, and wave amplitude compared with the basal period and the placebo group. There was pronounced variability between patients. The inhibitory effect reached its maximum 15–20 min after the infusion and the effect lasted less than 1 h.
169
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
Patients with other spastic oesophageal motor disorders, such as diffuse spasm, nutcracker oesophagus, and hypertensive lower oesophageal sphincter tone, could also benefit from the use of an oesophageal phosphodiesterase inhibitor, because the nonadrenergic, non-cholinergic inhibitory neurons are present in all disorders,3 although they are functionally impaired,4 and presumably still produce some cGMP.2 *A S Kashyap, Surekha Kashyap Departments of *Medicine and Hospital Administration, Armed Forces Medical College, Pune 411 040, India 1 2
3
4
Richter JE. Oesophageal motility disorders. Lancet 2001; 358: 823–28. Bortolotti M, Mari C, Lopilato C, Porrazzo G, Miglioli M. Effects of sildenafil on esophageal motility of patients with idiopathic achalasia. Gastroenterology 2000; 118: 253–57. Craddock DR, Logan A, Waldbaum PR. Diffuse esophageal spasm. Thorax 1966; 21: 511–17. Nicks R, Gillies M, Skyring A. Diffuse muscular spasm (diffuse muscular hypertrophy of the esophagus). Bull Soc Int Chir 1968; 6: 637–48.
Sir—Joel E Richter’s seminar1 deserves, I think, another title to appeal to other interested physicians—ie, cardiologists. Since the 1960s, I have been interested in this subject as a clinical cardiologist2 and, in my opinion, the widest clinical experience belongs to heart physicians, who are generally the first doctors contacted by patients complaining of chest pain. The close connection between the heart and oesophagus is noted in many reports, from 1966 onwards, on linked angina.3,4 Because of the tremendous use in the media of the terms angina, coronary disease, and so on, for many years the term oesophageal angina has been used. One of the most frequent forms is the spasm of the oesophageal sphincters, enclosing an air bubble (when oesophageal peristalsis is lost) with a straining of the walls; my treatment, which is generally effective, is to give the person something to swallow with water. The action of swallowing acts on the spasm of the sphincters. Useful drugs to use are trimebutine and otilonium bromide, associated with medazepam or diazepam. Pier Andrea Maccarini Libero Docente Semeiotica Medica, University of Pisa, Via Galgana 6, Pisa, Italy 1 2
3
Richter JE. Oesophageal motility disorders. Lancet 2001; 358: 823–28. Maccarini PA. Sindrome coronarica intrecciata. XII Congress of the Italian Society of Cardiology, vol II, 1959: 41. Bennet JR, Atkinson M. The differentiation
170
magnetic resonance imaging revealed a slight cerebellar atrophy. Physical examination between attacks showed a gaze-evoked nystagmus and gait and limb ataxia. Idiopathic focal epilepsy, EA 2, and migraine without aura were diagnosed. Seizures were controlled by valproic acid and oxcarbazepine and the ataxic episodes responded well to sulthiame, a carboanhydrase inhibitor. Her father (II-6), aged 39 years, had had isolated somatosensory auras and secondary generalised tonicclonic seizures since age 34. From about age 6 years he developed infrequent ataxic episodes. Additionally, he had simple motor tics. Postictal electroencephalography showed a slowing over the right hemisphere, and cranial magnetic resonance imaging was normal. Between attacks he showed cerebellar eye signs, dysarthria, and gait ataxia. He was diagnosed as having idiopathic focal epilepsy, EA 2, and migraine without aura. Seizures responded well to carbamazepine. Among the extended family, one individual (II-1) had a definite history of seizures, but details were not sufficient to diagnose a specific epilepsy syndrome. Another individual (II-4) reported seizures, but whether these were true epileptic seizures remained unclear. Four individuals had common migraine. In this family, there is a striking cooccurrence of periodic neurological disorders that have been attributed to mutations in CACNA1A. Although this association of EA 2, focal epilepsy, and migraine might be coincidence, we purport that the cases are similar to that presented by Jouvenceau and colleagues. The observed disorders are different manifestations of an inherited dysfunction of the brain P/Q-type calcium channel. This hypothesis lends support to the assumption that
between oesophageal and cardiac pain. Lancet 1966; 2: 1123–27. Chauhan A, Petch MC, Shofield PM. Cardio-oesophageal reflex in humans as a mechanism for “linked anginal”. Eur Heart J 1996; 17: 407–13.
4
Human epilepsy, episodic ataxia type 2, and migraine Sir—Anne Jouvenceau and colleagues (Sept 8, p 801)1 report a patient with a complex phenotype, including absence epilepsy and episodic ataxia type 2. They present direct evidence that human idiopathic generalised epilepsy can be associated with mutations of CACNA1A, a gene linked to chromosome 19p13 and encoding for the ␣1A subunit of a neuronal voltagegated P/Q-type calcium channel. Dysfunction of this calcium channel can lead to different paroxysmal disorders: familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA 2) and spinocerebellar atrophy 6 in human beings,2 and absence seizures in mice3 and human beings.1 We describe a family with the cooccurrence of idiopathic focal epilepsy, EA 2, and migraine. The paroxysmal disorders were noted over three generations (figure). The patient, III-5, was referred to our clinic at age 12 years because of recurrent nocturnal psychomotor seizures that had begun at around age 9 years. Additionally, she had had isolated episodes of common migraine since childhood and recurrent paroxysmal attacks of statokinetic ataxia, dysarthria, nystagmus, vertigo, headache, and diplopia that had begun at age 8 years. These frequent periods occurred independent of seizures and migraine. Interictal electroencephalography showed focal sharp waves. Cranial
I
1
2
3
II 1
2
3
4
5
6
7
5
6
8
9
10
11
12
13
III 1
2
3
4
migraine
episodic ataxia type 2
deceased
focal epilepsy
unclassified seizures
unconfirmed seizures
Pedigree of family with epilepsy, episodic ataxia type 2, and migrane
THE LANCET • Vol 359 • January 12, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.