Kolkman et al (1), in the Dept. of Gastroenterology, Medisch
Spectrum Twente, Enschede, The Netherlands, have established the value of
gastric exercise tonometry in establishing the diagnosis of chronic
splanchnic disease (CSD) and those with ischaemic complaints as having
chronic splanchnic syndrome (CSS). [The practical details of exercise
tonometry are reviewed in their excellent chapter on splan...
Kolkman et al (1), in the Dept. of Gastroenterology, Medisch
Spectrum Twente, Enschede, The Netherlands, have established the value of
gastric exercise tonometry in establishing the diagnosis of chronic
splanchnic disease (CSD) and those with ischaemic complaints as having
chronic splanchnic syndrome (CSS). [The practical details of exercise
tonometry are reviewed in their excellent chapter on splanchnic ischaemia
in the fifth edition of Shoemaker's textbook of critical care(2)].
In their series of 110 patients "approximately 60% of patients with
single-vessel stenoses, including the coeliac artery compression syndrome,
[had].. CSS". These patients had fewer complications and very low
mortality but paradoxically were the most successfully treated by stenting
or surgical treatment.
Their observation may have profound significance for those admitted
to hospital with acute myocardial infarctions. Then reason for this is
that the central metabolic role of role of the liver in the lactate
shuttle hypothesis (3) may be compromised by the co-existing presence of a
coeliac axis stenosis or occlusion.
It would be of great interest to include coeliac axis disease as an
independent variable in your analysis. If this hypothesis is valid organ
dysfunctions and mortality should be greatly increased in these patients
especially if they had antecedent CSD or CSS. What is more stenting might
be an effective prophylactic or even therapeutic intervention.
References
1. Kolkman JJ, Mensink PB, van Petersen AS, Huisman AB, Geelkerken
RH. Clinical approach to chronic gastrointestinal ischaemia: from
'intestinal angina' to the spectrum of chronic splanchnic disease.
Scand J Gastroenterol Suppl. 2004;(241):9-16.
2. Textbook Of Critical Care, Fifth Edition (Hardcover)
by Mitchell P. Fink (Editor), Edward Abraham, Jean-Louis Vincent, Patrick
Kochanek Book/Electronic Media
Saunders · 2005
3. Dantzker DR. Monitoring tissue oxygenation : the quest continues.
Chest. 2001 Sep;120(3):701-2.
Given the fact that BAATAF conferred a relative risk reduction of
86%, and SPINAF conferred a relative risk reduction of 79% for embolic
complications of non valvular atrial fibrillation(NVAF) utilising INR
ranges of 1.5-2.7, and 1.4-2.8, respectively(1)(2), in a population
presumably comprising, not only NVAF patients at high risk of embolic
complications, but also those at low risk, the hypothesis...
Given the fact that BAATAF conferred a relative risk reduction of
86%, and SPINAF conferred a relative risk reduction of 79% for embolic
complications of non valvular atrial fibrillation(NVAF) utilising INR
ranges of 1.5-2.7, and 1.4-2.8, respectively(1)(2), in a population
presumably comprising, not only NVAF patients at high risk of embolic
complications, but also those at low risk, the hypothesis that now needs
to be tested is whether the risk/benefit ratio of Vitamin K
Antagonists (VKA) might be favourably modified by utilising a comparable
target INR range in NVAF patients deemed to be at low risk of embolic
complications.
The other unresolved issue is one also adressed by the
authors, namely, the initiation of anticoagulant therapy when a patient
with atrial fibrillation presents with non-haemorrhagic embolic stroke,
given the occasional occurence of haemorrhagic transformation (with
accompanying clinical deterioration) within the first 8 days of
presentation even in the case of initially small embolic infarcts(3). The
dilemna is that, whilst haemorrhagic transformation within 14 days is
significantly commoner (p<0.0001) among heparinised patients with
embolic infarcts than among their non-heparinised counterparts, recurrence
of ischaemic (presumably embolic) stroke during that time frame is also
significantly less common (p<0.001) in the heparinised group than in
their non-heparinised counterparts(4). This dilemna is compounded by the
fact that, by definition, patients presenting with embolic complications
belong to the high-risk category, justifying, on the basis of clinical
trial evidence, a target INR in the range 2.5-4.0(5). What is even more
potentially intriguing is whether the analogy of aspirin resistance
applies to some of these high-risk patients, justifying a target INR of
3.0-4.0 as opposed to 2.0-3.0 in order to confer complete prophylaxis.
A
nationwide questionnaire of anticoagulant clinics might reveal cases of
either native valve rheumatic atrial fibrillation or NVAF where
extracerebral embolic complications occured despite anticoagulation within
the INR range of 2.0-3.0. I encountered one such case (with native valve
rheumatic atrial fibrillation) during my 19 years as NHS consultant,
leading me to assume, rightly or wrongly, that some patients with native
valve rheumatic atrial fibrillation (in particular those with mitral
stenosis) might be more fully protected by utilising a target INR of 3.0-4.0.
OMP Jolobe
References
(1) The Boston Area Anticoagulant Trial for Atrial Fibrillation(BAATAF)
Investigators
The effect of low-dose warfarin on the risk of stroke in patients with non
rheumatic atrial fibrillation.
N Engl J Med 1990;323:1505-11
(2) Ezekowitz MD, bridgers SL, James KE et al
Warfarin in the prevention of stroke associated with non rheumatic atrial
fibrillation(SPINAF)
N Enlg J Med 1992;327:1406-12.
(3) Cerebral Embolism Study Group
Immediate anticoagulation of embolic stroke: brain hemorrhage and
management options
Stroke 1984;15:779-89.
(4) Saxena R., Lewis S., Berge E et al for the International Stroke trial
collaborative Group
Risk of early death and recurrent stroke and the effect of heparin in 3619
patients with acute iscemic stroke and atrial fibrillation in the
internationnal stroke trial.
Stroke 2001;32:2333-
(5)European Atrial fibrillation(EAFT) Study group
Secondary prevention in non-rheumatic atrial fibrillation after transient
iscaemic attack or minor stroke
Lancet 1993;342:1255-62.
With interest we read the new JSB guidelines but would like to
clarify an issue relating to the correct licensed indication for nicotinic
acid. Table 11 of the guidelines specifies that nicotinic acid be used in
severe hypertriglyceridaemia with prior acute pancreatitis or not
responsive to fibrates. The only formulation of nicotinic acid licensed
for the treatment of dyslipidaemia is the prolonged re...
With interest we read the new JSB guidelines but would like to
clarify an issue relating to the correct licensed indication for nicotinic
acid. Table 11 of the guidelines specifies that nicotinic acid be used in
severe hypertriglyceridaemia with prior acute pancreatitis or not
responsive to fibrates. The only formulation of nicotinic acid licensed
for the treatment of dyslipidaemia is the prolonged release formulation
(Niaspan). Other formulations of nicotinic acid are low dose immediate
preparations sold as vitamins supplements and not intended for the
treatment of dyslipidaemia. Prolonged release nicotinic acid is currently
licensed for use with a statin to treat dyslipidaemia (raised LDL-cholesterol and triglycerides and low HDL-cholesterol). These matters are
also covered in the BNF.
Furthermore we are concerned that the discrepancy between the
'compelling' or 'possible' indications of Table 11 of the guidelines and
the licensed indication of nicotinic acid is so great as to potentially
cause considerable confusion for those using JBS2 as source of reference.
This may have already happened with advice from the Scottish
Medicines Consortium issued on 6th January 2006. The advice on Niaspan
quotes JBS2 guidance on mixed dyslipidaemia and notes in relation to
nicotinic acid that 'combined use with lipid regulating drugs appears only
as a possible, rather than a compelling, indication for treatment'. The
'compelling' indication as given in Table 11 would be outside the licensed
indication and presumably, therefore, not considered relevant to a drug
being assessed within the confines of its licensed indication.
We would like the authors to clarify the role of nicotinic acid
within its licensed indication.
Respiratory tract infection has been implicated as a factor leading
to the onset of acute myocardial infarction. In contrast to previous
data,[1] Clayton et al.[2] did not observe a significant association between
recent respiratory infection and myocardial infarction, but they did find
a strong association of infarction with chest pain on breathing within the
preceding week or with fever.
Respiratory tract infection has been implicated as a factor leading
to the onset of acute myocardial infarction. In contrast to previous
data,[1] Clayton et al.[2] did not observe a significant association between
recent respiratory infection and myocardial infarction, but they did find
a strong association of infarction with chest pain on breathing within the
preceding week or with fever.
In industrialised countries, particularly in urban areas,
considerable levels of anthropogenic air pollutants can be expected.
Exposure to elevated air pollution is linked to increased respiratory
Illnesses[3] and mortality.[4] Air pollution induces an increased oxidative
stress and cytokine release and produces local pulmonary inflammation.[5] At
the same time, epidemiological and clinical evidence for the association
between air pollution, including both gaseous pollutants and particulate
matter, and occurrence of acute myocardial infarction has continued to
grow.[5,6] It is believed that local pulmonary inflammation causes a
systemic response which may elevate the risk of acute myocardial
infarction by inducing plaque destabilisation, hypercoagulability and
disturbance of the autonomic nervous system.[5] As an indicator of tightly
integrated cardiopulmonary affectability, Zanobetti and Schwartz[6] have
recently reported on a slightly higher increase in risk of myocardial
infarction due to air pollution in association with chronic obstructive
lung disease and intercurrent pneumonia.
Since air pollution may influence both respiratory pathology and
occurrence of myocardial infarction, the study of Clayton et al would be
more conclusive if controls for two important factors, i.e. the level of air
pollutants and chronic lung diseases had been established. One might
expect that increased body temperature and pain on breathing, at least in
some patients in this study, could be related to the enhanced inflammation
and exacerbation of preexisting lung disease associated with elevated air
pollution. In turn, this may be one of the reasons why Clayton et al found
an association of myocardial infarction only with chest symptoms or fever,
but not with clearly diagnosed acute respiratory infection.
The proposed mechanisms of increased risk for myocardial infarction
associated with acute respiratory infection are similar to those
associated with elevated air pollution and include increased
thrombogeneicity and risk of plaque rupture.[1,2] There is a possibility
that air pollution may independently increase the incidence of myocardial
infarction by increasing the intensity of nonspecific pulmonary
inflammatory processes as well as by increasing the incidence of acute
respiratory infections. Further investigations need to focus on acute and
chronic inflammatory response as an important pathophysiological pathway,
and on its modulation as a possible mean of prevention. Better insight
into the specific adverse effects of air pollutants and respiratory
infections may allow additional improvement of preventive strategies
especially in some populations with a higher than normal risk of a
coronary event, for example in patients with ischemic heart disease and an
accompanying lung disease.
References
1. Meier CR, Jick SS, Derby LE, et al. Acute respiratory-tract infections
and risk of first-time acute myocardial infarction. Lancet 1998;351:1467-
71.
2. Clayton TC, Capps NE, Stephens NG, et al. Recent respiratory infection
and the risk of myocardial infarction. Heart 2005;91:1601-2.
3. Schwartz J. Air pollution and hospital admissions for respiratory
disease. Epidemiology 1996;7:20-8.
4. Stieb DM, Judek S, Burnett RT. Meta-analysis of time-series studies of
air pollution and mortality: effects of gases and particles and the
influence of cause of death, age, and season. J Air Waste Manag Assoc
2002;52:470-84.
5. Routledge HC, Ayres JG, Townend JN. Why cardiologists should be
interested in air pollution. Heart 2003;89:1383-8.
6. Zanobetti A, Schwartz J. The effect of particulate air pollution on
emergency admissions for myocardial infarction: a multicity case-crossover
analysis. Environ Health Perspect 2005;113:978-82.
We recently came across a similar patient who had a Sirolimus eluting
stent implanted in his LAD in June 2004 and returned to us with an
anterior wall myocardial infarction on the 2nd of January 2006.He had
taken Aspirin and Clopidogrel for 10 months and then had switched to lower
dose Aspirin (150mg to 80 mg)and stopped the Clopidogrel. He developed
symptoms of angina during a flight back to India from...
We recently came across a similar patient who had a Sirolimus eluting
stent implanted in his LAD in June 2004 and returned to us with an
anterior wall myocardial infarction on the 2nd of January 2006.He had
taken Aspirin and Clopidogrel for 10 months and then had switched to lower
dose Aspirin (150mg to 80 mg)and stopped the Clopidogrel. He developed
symptoms of angina during a flight back to India from Kuwait and came
straight to the emergency room from the airport.
He was thrombolysed with 1 million units of Urokinase and taken up for
coronary angiography, which showed a substantial thrombosis involving the
LAD, both before and into the stent.As the distal perfusion was considered
satisfactory, we declined to re-intervene and put him on an infusion of
unfractionated heparin for 24 hours and repeated the angiogram the next
day, which showed 90% resolution of the thrombus.
In the light of such distressing reports and several theories regarding
inadequate stent endothelialisation in drug eluting stents, maybe
deployment of a sirolimus eluting stent could be thought of as an
indication for prolonged, perhaps even life-long adminsitration of
antiplatelet agents,in higher doses and including Clopidogrel for longer
periods. Current recommendations of a few months treatment with
clopidogrel might be worth reconsidering, in view of such potentially
lethal implications, if stent thrombosis were to occur.
Biagini et al (1), Rodriguez et al (2) and Dursunglu et al (3) illustrate
incorrect statistical analyses, by using the two-sample t-test. This
compares normal means assuming unknown but equal variances. While the
Central Limit Theorem justifies normality for mean inferences, making it
unnecessary to test (3) for normality, unknown variances need not be
homogeneous. This makes the two-sample t-test un...
Biagini et al (1), Rodriguez et al (2) and Dursunglu et al (3) illustrate
incorrect statistical analyses, by using the two-sample t-test. This
compares normal means assuming unknown but equal variances. While the
Central Limit Theorem justifies normality for mean inferences, making it
unnecessary to test (3) for normality, unknown variances need not be
homogeneous. This makes the two-sample t-test unsuitable for general mean
comparisons.
This difficulty is not removed by meaninglessly (4) testing for the
equality of variances or avoiding normality and its nuisance unknown
variances with nonparametric rank tests such as the Mann-Whitney test.
Being a comparison of distributions, such rank tests say nothing
specifically about the mean, median or any moment of the distributions if
significant, and are biased to one side (5) in a two-sided test.
Tsakok (6) has solved this Behrens-Fisher problem of comparing normal
population means with unknown variances at exact unconditional
significance levels, also showing that the Tsakok solution is more
effective in detecting significant mean differences even with unknown
equal variances. Its exposition (7) is available.
The software GSP implements the Tsakok technique. It is now used for some
comparisons of means at .02 (one significant figure) significance level
per pair.
For Table 2 (1), there are significant mean differences between silent
ischaema and symptomatic ischaema patients in their peak dobutamine dose
and number of dysfunctional segments at rest.
For Table 3 (2), there is a significant mean difference in the lesion
length between Rapamycin blood concentration of ≥ 8ng/ml and
<8ng/ml.
For Table 2 (3), there are significant mean differences between patients
with diastolic dysfunction and controls in their left ventricular end
systolic volume (LVESV) and left ventricular ejection fraction by Teicholz
method (EF-T).
There is little overlap, well below 95% with at least one clinical group,
between the 99% confidence intervals of the means concerned.
The attention given to the data means that they deserve correct analysis,
which they were denied.
The Tsakok article (8) on exact, unconditional, uniformly most powerful
unbiased tests extends the Tsakok technique to the nonparametric two-
sample problem, superseding the chi-squared test or Fisher ‘exact’ test
(it is neither exact nor unconditional), the Mann-Whitney test and the
Kolmogorov-Smirnov test. There is an indication (9) that the Tsakok
technique extends to dependent samples. The Tsakok articles are reprinted
(10) with further results.
References
1. Biagini E, Schinkel AFL, Bax JJ, Rizzello V, van Bonburg RT, Krenning
BJ, Bountioukos M, Pedone C, Vourvouri EC, Rapezzi C, Branzi A, Roelandt
JRTC, Poldermans D. Long term outcome in patients with silent versus
symptomatic ischaemia during dobutamine stress echocardiography. Heart
2005; 91: 737-742.
2. Rodriguez AE, Rodriguez Alemparte M, Vigo CF, Fernandez Pereira C,
LLaurado C, Vetcher D, Pocovi A, Ambrose J. Role of oral Rapamycin to
prevent restenosis in patients with de novo lesions undergoing coronary
stenting: Results of the Argentina single centre study (ORAR trial). Heart
2005; 91: 1433-1437.
3. Dursunglu D, Polat B, Evrengul H, Tanriverdi H, Kaftan A, Kilic M.
Assessment of systolic function byatrioventricular plane displacement in
patients with diastolic dysfunction. Acta Cardiol. 2004; 59: 409-415.
4. Kendall MG and Stuart A. The Advanced Theory of Statistics, Vol.2.
Charles Griffin and Co., London, 1973; p 484.
5. Lehmann, E.L. Testing Statistical Hypotheses. John Wiley and Sons Inc,
New York, 1959; p 187.
6. Tsakok AD. A solution to the generalized Behrens-Fisher problem. Metron
1978; 36: 79.
I read with great interest the letter by Hermann et al.[1] regarding dark
chocolate and endothelial dysfunction. The authors conclude "a small daily
treat of dark chocolate may substantially increase the amount of
antioxidant intake and beneficially effect vascular health".
Unfortunately, not many people are aware of the possible toxic effects of
dark chocolate: apart from its content of flavan...
I read with great interest the letter by Hermann et al.[1] regarding dark
chocolate and endothelial dysfunction. The authors conclude "a small daily
treat of dark chocolate may substantially increase the amount of
antioxidant intake and beneficially effect vascular health".
Unfortunately, not many people are aware of the possible toxic effects of
dark chocolate: apart from its content of flavanoids, it contains
substantial amounts Theobromine. Theobromine is a Xantine Alkaloid with
an action similar to caffeine on the CNS and cardiac muscle. Ingestion of
1000 mg or more of Theobromine (222 gr of dark chocolate) may cause
excitement, extrasystoles, headaches, insomnia, mils delirium, muscle
tremor, nausea, restlessness and tachycardia.[2]
Therefore, patients with arrhythmias or significant cardiovascular disease
should limit their dark chocolate intake, in order to reduce the risk of
Xantine induced arrhythmias.
References
1. Hermann E et al. Dark Chocolate improves endothelial and platelet
function. Heart 2006:92:119-120.
2. Chocolate in Professional’s handbook of complementary and alternative
medicine 3rd edition. Fetrow CW, Avila JR (eds), Lippincott Williams and
Willkins, Springhouse, PA, USA, 2004.
We do appreciate Dr Tsakok's concern regarding the correct use of the
two-sample-t-test. At our centre it is common use to apply the
Kolmogorv-Smirnov test to test the normality assumption in all our
analyses. In our study this test was not significant and therefore, we
were allowed to use the parametric tests such as the two sample t-test.
The method Dr Tsakok is proposing is unknown to us. We are not...
We do appreciate Dr Tsakok's concern regarding the correct use of the
two-sample-t-test. At our centre it is common use to apply the
Kolmogorv-Smirnov test to test the normality assumption in all our
analyses. In our study this test was not significant and therefore, we
were allowed to use the parametric tests such as the two sample t-test.
The method Dr Tsakok is proposing is unknown to us. We are not able to
download the references he is mentioning and also, we don't have the
software which he is referring to. As Dr Tsakok points out a significant
difference of peak dobutamine infusion dose was now observed between the
two patients groups. However, data should be interpreted in the context of
a stress test; a difference of 37 versus 38 mcg/ kg / minute during
dobutamine infusion is unlikely to be of clinical significance.
References
1. Elena Biagini, MD, Ron van Domburg, PhD, Jeroen J. Bax*, MD, and Don
Poldermans, MD. Department of Cardiology, Erasmus Medical
Center,Rotterdam, The Netherlands and *Department of Cardiology, Leiden
Medical Center, Leiden, the Netherlands.
We read with interest the paper by Iofina et al.[1] highlighting the
superior outcomes observed using sirolimus eluting stents (SES) versus
intra-coronary radiation therapy (IRT) for patients with in-stent
restenosis (ISR). This condition remains a significant source of morbidity
and need for repeat procedures and, up until recently, IRT has remained
the most proven treatment for ISR, with reported...
We read with interest the paper by Iofina et al.[1] highlighting the
superior outcomes observed using sirolimus eluting stents (SES) versus
intra-coronary radiation therapy (IRT) for patients with in-stent
restenosis (ISR). This condition remains a significant source of morbidity
and need for repeat procedures and, up until recently, IRT has remained
the most proven treatment for ISR, with reported restenosis rates below
20% in randomised studies.[2] The use of drug eluting stents (DES) has
more recently provided further optimism in the long term management of
such patients, particularly given the long term concerns of IRT including
late stent thrombosis and edge restenosis.
The angiographic binary in-lesion restenosis rate at six months of
11% in the SES group and 29% in the IRT group (p=0.046) identified by
Iofina et al.[1] is comparable to that in The Multicenter, Nonrandomised
Sirolimus-Eluting Stent in the Treatment of Patients With an In-Stent
Restenotic Native Coronary Artery Lesion (TROPICAL) study[3] that
enrolled 162 patients. Here, binary restenosis in the SES group was 9.7%
and the primary end point, in-lesion late loss at 6 month follow up, was
0.08 ± 0.49 mm (which compared favourably with the late loss in IRT trials
which has ranged from 0.22 ± 0.84 mm to 0.64 ± 0.69 mm).[3]
We recently reported the utility of adopting DES based therapies for
ISR with beneficial outcomes extending to 18 months of clinical follow-up.[4] In our observational study, the major adverse cardiac event (MACE)
rate was significantly lower in the SES compared with the IRT group (14% vs 40%, P=.03) at 18 months.[4] Furthermore, the use of SES for ISR
rather than IRT was associated with a significant reduction in the
procedure time (54 ± 20 min versus 88 ± 28 min p<0.001) with a
favourable reduction in the total radiation exposure to both patient and
operator.
Despite the non-randomised study design, Iofina et al.[1] offer
further credence for the use of SES for ISR. Certainly randomised studies
will be required to determine if drug-eluting stents are the best
contemporary treatment for ISR and this will be delineated by the
Sirolimus for In-stent ReStenosis (SISR) trial. In this ongoing trial,
preliminary analyses have demonstrated encouraging results for the use of
SES to treat native coronary ISR lesions with a target vessel failure
(TVF) rate at nine months of 12.4% in the SES group versus 21.6% in the
IRT group (p=0.023) and a target lesion revascularisation (TLR) rate of
8.5% in the SES group versus 19.2% in the IRT group (p=0.004).[5] Longer
term results are eagerly awaited.
References
1. Iofina E, Radke PW, Skurzewski P, Haager PK, Blindt R, Koch KC,
Hanrath P, vom Dahl J, Hoffmann R. Superiority of sirolimus eluting stent
compared with intracoronary beta radiation for treatment of in-stent
restenosis: a matched comparison. Heart. 2005;91:1584-9.
2. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary
gamma-radiation therapy to inhibit the recurrence of restenosis after
stenting. N Engl J Med. 2001; 344:250–256.
3. Neumann FJ, Desmet W, Grube E, et al. Effectiveness and safety of
sirolimus-eluting stents in the treatment of restenosis after coronary
stent placement. Circulation. 2005; 111:2107-11.
4. Barlis P, Horrigan MC, Chan RK, Ajani AE, Proimos G, Schumer W,
van Gaal WJ, Rowe M, Eccleston D, Yan BB, Mun Cheong Y, Oliver LE, Clark
DJ. What is the best contemporary treatment for in-stent restenosis?
Cardiovasc Revasc Med. 2005;6:179-81.
5. Holmes Jr DR. SISR. A prospective randomized comparison of the
sirolimus-eluting stent vs brachytherapy in patients with bare metal in-
stent restenosis. TCT 2005; October 16-21, 2005; Washington, DC
Old medical theories, like myths, never die. In every era, long after
the initial excitement evaporates, scientific theories that have not
gathered logical strength through increasing clinical associations are
recycled to address current perceptions. Such theories, like myths, offer
a vicarious resolution of the ignorances that lies between our
insecurities and our expectations.[1,2] Wilmshurst et al....
Old medical theories, like myths, never die. In every era, long after
the initial excitement evaporates, scientific theories that have not
gathered logical strength through increasing clinical associations are
recycled to address current perceptions. Such theories, like myths, offer
a vicarious resolution of the ignorances that lies between our
insecurities and our expectations.[1,2] Wilmshurst et al. recently suggest
once again that platelets may have a role in the pathogenesis of
migraine.[3] They base this impression on the seeming efficacy of the
combination of clopidogrel and aspirin in comparison to aspirin alone in
managing attacks of migraine with aura in patients who had undergone
closure of persistent foramen ovale or atrial septal defect; this salutary
effect of combined anti-platelet regimen is believed to work through an
effect on serotonin stores.
Migraine theory and therapy is a long chain of tenuously linked
assumptions coupled to serendipity of a high order.[4] Several lines of
evidence challenge the presumed pathogenetic link between platelets,
serotonin, and migraine as well as the conclusions of the authors: (i)
Platelet hyperaggregability has been noted in a range of other medical
conditions unrelated to migraine and is found with high levels of stress.
Stress affects the vast majority of the general population but migraine
afflicts only about one-fifth of humankind. (ii) Propranolol, the gold
standard migraine prophylactic agent, enhances platelet aggregability [5].
(iii) Contrary to the general impression, evidence for migraine
prophylactic value of aspirin is poor.[6] (iv) A negative correlation
exists between migraine and antibodies to phospholipids (the membrane-
binding moiety increasing platelet aggregability), suggesting a degree of
protection against development of migraine.[7] (v) Migraine headache has
been reported in patients with thrombocytopenia.[8] (vi) Although
platelet aggregation and adhesion are commonly increased in diabetes
mellitus, it is hypogylcaemia rather than hyperglycaemia that precipitates
migraine.[9] (viii) Menstrual migraine typically improves with pregnancy[10] but estrogens increase epinephrine induced platelet aggregation.[11]
(ix) Migraine-like headache is a sequela of cocaine use, [12,13]. but
cocaine inhibits platelet aggregation and dissociates preformed platelet
aggregates [14]. (x) Amitriptyline, a first-line migraine prophylactic
agent, unambiguously stimulates brain noradrenergic as well as
serotonergic function.[15] (xi) Development of carcinoid tumour remarkably
decreased migraine frequency and intensity leading to a complete remission
with postoperative recurrence.[16] (xii) Nicotine increases platelet
aggregation [17] but is considered relatively unlikely to lead to
migraine.[18] (xiii) Nitric oxide (and endothelium-derived relaxing
factor) putatively involved in vascular headaches associated with exercise
or infection inhibits platelet aggregation and adhesion.[8,19]
Proponents of the platelet theory of migraine postulate a parallel
between the platelet and the neuron by suggesting that platelet activation
mirrors trigeminovascular system inflammation. Believing that (peripheral)
platelet function tells us anything about brain neuronal function involves
complete suspension of scientific disbelief.[15] No systemic influence,
including platelet dysfunction, can rationalize the characteristic
lateralization (unilateral, bilateral or side-shift) of migraine
headache.[21] For internists, cardiologists, and neurologists (especially
researchers into primary headaches) familiar with the useful effect of
inhibition of platelet aggregation in cardiovascular and cerebrovascular
medicine, it is indeed difficult to concede that a similar benefit might
not be available to migraine patients. Nevertheless, if migraine has to
progress from a vaguely-understood syndrome to a properly defined disease,
theories that clutter our thinking need to be addressed squarely and
discarded. The platelet theory of migraine is one such concept that might
best be passed into history.
Wilmshurst et al.[3] have also reported increased frequency and
severity of migraine with aura attacks immediately following closure of
atrial shunts, a phenomenon that has important pathophysiological
implications. Yankowsky and Kuritzky have earlier reported on aggravation
of migraine with aura into a daily pattern with clocklike precision after
closure of an atrial septal defect (ASD).[21] Importantly, there is no
suggestion of a causal link between ASD and migraine but closure of ASD
appears to be associated with appearance or worsening of migraine with
aura.[3,21] In uncomplicated ASD, correction of the septal defect would
lead to decrease in the elevated right atrial pressure and plasma atrial
natriuretic peptide levels would decrease correspondingly.[22] ANP appears
to play a role as a counterregulatory hormone in many disorders
characterized by volume expansion, including hypertension; also,
orthostatic hypotension, a characteristic feature of migraine, is
associated with lower levels of ANP, and suggests that noradrenergic
hypofunction may be involved in the pathogenesis of migraine.[23,24] A
compensatory or adaptive function has been attributed to sympathetic
hypofunction associated adrenergic receptor hypersensitivity.[25] The fact
that migraine prophylactic agents such as beta-blockers or calcium
antagonists or clonidine invariably lower elevated blood pressures or tend
to maintain normotension – while only rarely causing symptomatic
hypotension – indicates that a low blood pressure is an adaptive feature
in migraine. Nausea and vomiting is another facet of a complex vasopressin
-mediated adaptive mechanism in migraine.[26,27]
Dramatic aggravation of migraine following atrial shunt closures indicates
substantial alteration of some physiological variable with prominent
circadian variation and a critical influence on the primary
pathophysiological process in migraine.[22] In ASD, the reduced filling
pressure of the left ventricle causes a smaller than normal stroke volume
and reduced cardiac output; consequently a relatively small aorta is
commonly seen. Following closure of large atrial shunts, immediate
improvement in left ventricular stroke volume and cardiac output occurs.
Precipitation of migraine following closure of atrial septal defect [3,21]
suggests that a higher stoke volume / cardiac output might worsen or
unmask a migrainous diathesis.[22,28]
The theoretical basis for a non-neuronal non-vascular origin of
migraine has been recently elucidated.[29] A selective involvement of the
ophthalmic division of the trigeminal nerve is likely in migraine and
other primary headaches; mechanical deformation of the corneo-scleral
envelope by ocular choroidal venous congestion and rise of intraocular
pressure (IOP) has been proposed to underlie both the scintillating
scotoma as well as the headache of migraine.[29,30] In contrast to the
brain, the eye is a low-volume but far more highly vascularized organ; the
eye is anatomically less capable of accommodating any sudden increase in
stroke volume. The cardiac output increasing effect of closure of larger
atrial shunts is somewhat comparable to the immediate peripheral arterial
perfusion enhancing effect of glyceryl trinitrate (GTN) manifest by
flushing of face and throbbing headache.[31] GTN is the best available
experimental human model for migraine; it generally causes migraine
headache a few hours after consumption,[32] at which time substantial
venous pooling likely develops at the ocular choroidal venous plexus in
migraine patients due to an intrinsic regional ocular sympathetic
hypofunction. Propranolol, atenolol, metoprolol, nadolol, clonidine,
flunarizine, and verapamil lower the IOP, further supporting the nexus
between migraine, autonomic dysfunction, and intraocular pressure.[29]
Immediate aggravation of migraine attacks after closure of atrial shunts
spontaneously regresses after a few months;[21] ocular tissue creep at the
level of the corneo-scleral envelope likely dissipates the headache-
provoking effect of increased cardiac output in patients with ASD.[29]
Like trait or basal autonomic function, endogenous pain control
mechanism, and corneo-scleral distensibility, increase in cardiac output
after atrial shunt closure is likely to be a highly variable,
idiosyncratic function; these important confounding features might well
explain the results of the studies of Wilmshurst et al.[3]
References
1. Gupta VK. Migrainous stroke: are antiphospholipid antibodies
pathogenetic, a biological epiphenomenon, or an incidental laboratory
aberration? Eur Neurol 1996;36:110-111.
2. Lévi-Strauss C. Then structural study of myth; in Lévi-Strauss C
(ed): Structural Anthropology. Harmondsworth, Peregrine, 1977, pp 206-231.
3. Wilmshurst PT, Nightingale S, Walsh KP, W L Morrison WL.
Clopidogrel reduces migraine with aura after transcatheter closure of
persistent foramen ovale and atrial septal defects. Heart 2005;91:1173-1175.
21. Yankovsky AE, Kuritzky A. Transformation into daily migraine with
aura following transcutaneous atrial septal defect closure. Headache
2003;43:496-498.
22. Gupta VK. Closure of atrial septal defect and migraine.
Headache;2004:44:291-292.
23. Gotoh F. Komatsumoto S, Araki N, Gomi S. Noradrenergic nervous
activity in migraine. Arch Neurol 1984;41:951-5.
24. Araki N. Autonomic nervous activity in migraine [abstract].
Rinsho Shinkeigaku 1995;35:1336-1338.
25. Boccuni M, Alessandri M, Fusco BM, Cangi F. The pressor
hyperresponsiveness to phenylephrine unmasks sympathetic hypofunction in
migraine. Cephalalgia 1989;9:239-245.
26. Gupta VK. Conceptual divide between adaptive and pathogenetic
phenomena in migraine: nausea and vomiting. Brain 2004;127:E18.
27. Gupta VK. A clinical review of the adaptive potential of
vasopressin in migraine. Cephalalgia 1997;17: 561-569.
28. Gupta VK. Percutaneous closure of patent foramen ovale reduces
the frequency of migraine attacks. Neurology 2004;63:1760-1761
29. Gupta VK. Migrainous scintillating scotoma and headache is ocular
in origin: a new hypothesis. Med Hypotheses 2005 (In press).
30. Gupta VK. Glyceryl trinitrate and migraine: nitric oxide donor
precipitating and aborting migrainous aura. J Neurol Neurosurg Psychiatry
(22 October 2005). Available
at: http://www.jnnp.com/cgi/eletters/76/8/1158#708.
31. Thomsen LL, Iversen HK, Brinck TA, Olesen J. Arterial supersensitivity
to nitric oxide (nitroglycerin) in migraine sufferers. Cephalalgia
1993;13:395-9.
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