headache: challenging conventional wisdom

3
2008 Round-up 12 www.thelancet.com/neurology Vol 8 January 2009 the results from a population-based register, indicating that these seizures are usually benign, should be reassuring. 7 Children diagnosed with febrile seizures in Denmark from 1977 to 2004 (n=55 215) were followed in the national cause of death register until August 31, 2005. Although the mortality rate was 80% higher than expected during the first year and 90% higher during the second year after the first febrile seizure, mortality was not increased among children with simple febrile seizures (<15 min in duration and no recurrence within 24 h). The increased mortality occurred only in patients with complex febrile seizures and could be partly explained by pre-existing neurological abnormalities. Emilio Perucca, Torbjörn Tomson Clinical Trial Centre, Institute of Neurology IRCCS C Mondino Foundation, Pavia and Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy (EP), Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden (TT) [email protected] Headache: challenging conventional wisdom There is a scarcity of longitudinal data that support the observation that overuse of medications for acute headache is a risk factor for increasing frequency of headache in migraineurs. In a recent population-based survey, the annual incidence of transformed migraine (TM) was 2·5%. 1 Individuals who used medications that contain barbiturates or opiates were at increased risk of developing TM, regardless of how often those drugs were used (barbiturates: OR 2·06, 95% CI 1·3–3·1; opiates 1·98, 1·4–2·2). The use of triptans was not associated with an increased risk of TM (1·25, 0·9–1·7). Overall, non-steroidal anti-inflammatory drugs (NSAIDs) were not associated with TM (0·85, 0·63–1·17); however, NSAID use reduced the risk of TM in patients with a low-to-moderate frequency of monthly headache and increased the risk in those with frequent headaches. These findings emphasise the need to monitor vigilantly patients who are prescribed opiates or barbiturates for migraine and the need for caution when prescribing acute medications to patients with a high frequency of headaches. The results of previous studies have suggested that migraineurs are at increased risk of brain lesions and that a high frequency of attacks is associated with a greater risk of these lesions, which has led to the hypothesis that migraine is a progressive disorder. In a recent study, patients with a long duration of migraine (>15 years) and higher attack frequency (>3 migraines per month) were more likely to have brain MRI abnormalities than those with a shorter duration of migraine (<15 years) and lower attack frequency (<3 migraines per month). 2 Those with a high frequency of attacks had reduced grey matter density in the frontal, limbic, and parietal regions, and reduced white matter density in the frontal lobes. Migraineurs with a long duration of disease had reduced frontal anisotropy, increased white matter density in the cerebellum, and reduced grey matter density in the brainstem and lentiform nucleus. Large, longitudinal, population-based studies are needed to confirm these data, define whether these anatomical changes result in clinical sequelae, and determine the extent to which preventive therapy minimises the development of these imaging abnormalities. Nevertheless, these findings suggest that chronic migraine, similar to other chronic pain states (eg, back pain or fibromyalgia), can EP has received speaker’s or consultancy fees and/or research grants from Novartis, Johnson & Johnson, BIAL, Pfizer, GlaxoSmithKline, UCB Pharma, Valeant, Sanofi-Aventis, and Eisai. TT has received speaker’s fees and/or research grants from Novartis, Johnson & Johnson, Pfizer, GlaxoSmithKline, UCB Pharma, Sanofi-Aventis, and Eisai. 1 Noachtar S, Andermann E, Meyvisch P, Andermann F, Gough WB, Schiemann-Delgado J; N166 Levetiracetam Study Group. Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures. Neurology 2008; 70: 607–16. 2 Mpimbaza A, Ndeezi G, Staedke S, Rosenthal PJ, Byarugaba J. Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children: a randomized clinical trial. Pediatrics 2008; 121: e58–64. 3 Appleton R, Macleod S, Martland T. Drug management for acute tonic- clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev 2008; 3: CD001905. 4 Neal EG, Chaffe H, Schwartz RH, et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol 2008; 7: 500–06. 5 Freeman JM, Vining EP, Kossoff EH, Pyzik PL, Ye X, Goodman SN. A blinded, crossover study of the efficacy of the ketogenic diet. Epilepsia 2008; published online August 20. DOI:10.1111/j.1528- 1167.2008.01740.x 6 Faught E, Duh MS, Weiner JR, Guérin A, Cunnington MC. Nonadherence to antiepileptic drugs and increased mortality. Findings from the RANSOM study. Neurology 2008; published online June 18. DOI:10.1212/01. wnl.0000319693.10338.b9. 7 Vestergaard M, Giortz Pedersen M, Ostergaard JR, Bocker Pedersen C, Olsen J, Christensen J. Death in children with febrile seizures: a population- based cohort study. Lancet 2008; 372: 457–63.

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Page 1: Headache: challenging conventional wisdom

2008 Round-up

12 www.thelancet.com/neurology Vol 8 January 2009

the results from a population-based register, indicating that these seizures are usually benign, should be reassuring.7 Children diagnosed with febrile seizures in Denmark from 1977 to 2004 (n=55 215) were followed in the national cause of death register until August 31, 2005. Although the mortality rate was 80% higher than expected during the fi rst year and 90% higher during the second year after the fi rst febrile seizure, mortality was not increased among children with simple febrile seizures (<15 min in duration and no recurrence within 24 h). The increased mortality occurred only in patients with complex febrile seizures and could be partly explained by pre-existing neurological abnormalities.

Emilio Perucca, Torbjörn TomsonClinical Trial Centre, Institute of Neurology IRCCS C Mondino Foundation, Pavia and Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy (EP), Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden (TT) [email protected]

Headache: challenging conventional wisdom

There is a scarcity of longitudinal data that support the observation that overuse of medications for acute headache is a risk factor for increasing frequency of headache in migraineurs. In a recent population-based survey, the annual incidence of transformed migraine (TM) was 2·5%.1 Individuals who used medications that contain barbiturates or opiates were at increased risk of developing TM, regardless of how often those drugs were used (barbiturates: OR 2·06, 95% CI 1·3–3·1; opiates 1·98, 1·4–2·2). The use of triptans was not associated with an increased risk of TM (1·25, 0·9–1·7). Overall, non-steroidal anti-infl ammatory drugs (NSAIDs) were not associated with TM (0·85, 0·63–1·17); however, NSAID use reduced the risk of TM in patients with a low-to-moderate frequency of monthly headache and increased the risk in those with frequent headaches. These fi ndings emphasise the need to monitor vigilantly patients who are prescribed opiates or barbiturates for migraine and the need for caution when prescribing acute medications to patients with a high frequency of headaches.

The results of previous studies have suggested that migraineurs are at increased risk of brain lesions and

that a high frequency of attacks is associated with a greater risk of these lesions, which has led to the hypothesis that migraine is a progressive disorder. In a recent study, patients with a long duration of migraine (>15 years) and higher attack frequency (>3 migraines per month) were more likely to have brain MRI abnormalities than those with a shorter duration of migraine (<15 years) and lower attack frequency (<3 migraines per month).2 Those with a high frequency of attacks had reduced grey matter density in the frontal, limbic, and parietal regions, and reduced white matter density in the frontal lobes. Migraineurs with a long duration of disease had reduced frontal anisotropy, increased white matter density in the cerebellum, and reduced grey matter density in the brainstem and lentiform nucleus. Large, longitudinal, population-based studies are needed to confi rm these data, defi ne whether these anatomical changes result in clinical sequelae, and determine the extent to which preventive therapy minimises the development of these imaging abnormalities. Nevertheless, these fi ndings suggest that chronic migraine, similar to other chronic pain states (eg, back pain or fi bromyalgia), can

EP has received speaker’s or consultancy fees and/or research grants from Novartis, Johnson & Johnson, BIAL, Pfi zer, GlaxoSmithKline, UCB Pharma, Valeant, Sanofi -Aventis, and Eisai. TT has received speaker’s fees and/or research grants from Novartis, Johnson & Johnson, Pfi zer, GlaxoSmithKline, UCB Pharma, Sanofi -Aventis, and Eisai.

1 Noachtar S, Andermann E, Meyvisch P, Andermann F, Gough WB, Schiemann-Delgado J; N166 Levetiracetam Study Group. Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures. Neurology 2008; 70: 607–16.

2 Mpimbaza A, Ndeezi G, Staedke S, Rosenthal PJ, Byarugaba J. Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children: a randomized clinical trial. Pediatrics 2008; 121: e58–64.

3 Appleton R, Macleod S, Martland T. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev 2008; 3: CD001905.

4 Neal EG, Chaff e H, Schwartz RH, et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol 2008; 7: 500–06.

5 Freeman JM, Vining EP, Kossoff EH, Pyzik PL, Ye X, Goodman SN. A blinded, crossover study of the effi cacy of the ketogenic diet. Epilepsia 2008; published online August 20. DOI:10.1111/j.1528-1167.2008.01740.x

6 Faught E, Duh MS, Weiner JR, Guérin A, Cunnington MC. Nonadherence to antiepileptic drugs and increased mortality. Findings from the RANSOM study. Neurology 2008; published online June 18. DOI:10.1212/01.wnl.0000319693.10338.b9.

7 Vestergaard M, Giortz Pedersen M, Ostergaard JR, Bocker Pedersen C, Olsen J, Christensen J. Death in children with febrile seizures: a population-based cohort study. Lancet 2008; 372: 457–63.

Page 2: Headache: challenging conventional wisdom

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lead to structural and morphological changes in the brain.

Several of the central tenets of migraine patho-physiology have been questioned by two recent functional imaging studies. Cortical spreading depression is widely thought to be the mechanism that underlies the aura of migraine. Throughout the past 20 years, many imaging techniques (single photon emission computed tomography, functional MRI, perfusion MRI, and PET) have shown spreading oligaemia during migraine aura, which is thought to be secondary to reduced metabolic demand during cortical spreading depression. In a recent study of seven patients with migraine without aura, hypoperfusion in the bilateral occipital, posterior temporal, and parietal cortices was seen during migraine compared with the headache-free interval.3 These fi ndings suggest that migraine with aura and migraine without aura have similar underlying pathophysiological processes, which might partially explain why the same acute and preventive migraine medications work equally well for migraine with aura and migraine without aura.

Vasodilation of the intracranial arteries is still thought to be integral for the generation of migraine headache, whereas vasoconstriction has long been deemed important for the relief of migraine headache. However, most evidence to support the notion of intracranial vasodilation during migraine has come from experiments in animal models, with restricted data in human beings. In a recent controlled study, magnetic resonance angiography with a 3T scanner was used to image the cerebral and meningeal arteries in 32 patients with migraine: 27 patients with episodic migraine were randomly assigned to intravenous nitroglycerin and fi ve patients to placebo.4 During the infusion of nitroglycerin there was a signifi cant but expected vasodilation of all blood vessels compared with baseline diameters; however, during nitroglycerin-induced migraine headache, there were no signifi cant diff erences in blood vessel diameter compared with baseline. Although further studies that replicate these fi ndings with diff erent methods of measurement are now needed, the results of this investigation suggest that migraine headache can occur without a change in the calibre of cerebral blood vessels. This fi nding challenges the hypothesis that activation of trigeminovascular aff erents is necessary

for the development of migraine headache and suggests that medications without vasoconstrictive properties might be eff ective for relief from acute migraine headache.

Antagonists to the receptor for calcitonin gene-related peptide (CGRP) can relieve headache and its associated symptoms without the vasoconstrictor eff ects and cardiovascular concerns of current migraine-specifi c medications. Telcagepant, an oral antagonist of CGRP, was recently shown to be as eff ective as 5 mg zolmitriptan for the acute treatment of migraine. In a recent, large, randomised, phase III, double-blind trial, 300 mg telcagepant was more eff ective than placebo for all primary endpoints (p<0·001 for freedom from pain, relief from pain, phonophobia, and photophobia; p=0·006 for nausea). 150 mg telcagepant and 5 mg zolmitriptan were also signifi cantly more eff ective than placebo for all primary endpoints (p≤0·005 and p≤0·001, respectively). The rates of adverse events were 105 of 334 patients (31%) for 150 mg telcagepant, 131 of 352 (37%) for 30 mg telcagepant, 175 of 345 (51%) for 5 mg zolmitriptan, and 112 of 349 (32%) for placebo.5

With each passing year, our understanding of the fundamental anatomy and pathophysiology of migraine is being refi ned, the risk factors associated with its progression are being better defi ned, and these advances are leading to more selective treatments and management strategies.

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Page 3: Headache: challenging conventional wisdom

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14 www.thelancet.com/neurology Vol 8 January 2009

David W Dodick, Todd SchwedtDepartment of Neurology, Mayo Clinic Arizona, Phoenix, AZ 85054, USA (DWD); Washington University Headache Center, Washington University School of Medicine, St Louis, MO 63110, USA (TS)[email protected]

DWD has been an advisory board consultant for Merck, Allergan, Endo, Pfi zer, Coherex, Neuralieve, MAP Pharmaceuticals, and Minster Pharmaceuticals. He has received research support from ANS, Medtronic, and St Jude, and was the principal investigator for the ESCAPE study (Eff ect of Septal Closure of Atrial PFO on Events of Migraine With Premere). TS has received research support from the National Institutes of Health and National Headache Foundation and has consulted for VerusMed. He has particpated in industry-sponsored research from Allergan, GlaxoSmithKline, and AGA Medical.

Paediatric neurology: advances on many frontsPaediatric neurology is sometimes regarded as a sub-speciality that involves diagnosis of rare disorders but specialists are rarely able to provide curative treatment. Neurological disorders in children are common, particularly in developing countries where these conditions cause substantial mortality and long-term morbidity. In 2008, epidemiological studies have dispelled spurious associations and have provided the estimated burden of paediatric disorders. Other studies have rapidly used advances in the basic sciences to provide novel insights into neurological disorders and clinical trials have improved the outcome of severe neurological conditions.

Febrile seizures are the most common paediatric neurological condition, occurring in 2–5% of children. The link between febrile seizures and sudden infant death is controversial; aetiological, environmental, and genetic factors are thought to be similar in both disorders. However, in a nationwide Danish study, no association between febrile seizures and sudden infant death was found1 and the prognosis of febrile seizures was confi rmed to be good, provided there was no underlying neurological condition or the seizures were not complex.

Although status epilepticus is the most common neurological emergency in children, little is known about the epidemiology, causes, and outcome. Until a recent study in London, UK,2 there were few epidemiological studies of convulsive status epilepticus in children. The incidence in London was found to be 20 out of 100 000, of which 32% were febrile seizures and 6% were pyogenic meningitis, with an overall acute mortality of 3%. A study of the incidence of status epilepticus in

Kenya shows that the situation in resource-poor regions is startlingly worse.3 Defi nite and probable cases were eight times the incidence of that of the London study, as ascertained by hospital admission, but this calculation is probably an underestimation because many children die before reaching hospital. Overall, 15% of patients died in hospital, 21% died during follow up, and 12% had neurological sequelae. Prevention of this poor outcome is possible because 71% of cases have an infective cause (53% malaria, 11% bacteraemia, and 9% acute bacterial meningitis, with overlap between these conditions). This study highlights a major treatment gap in the management of infection-related prolonged seizures in countries that have limited resources. Both the primary prevention of infections and acute treatment could help to reduce the number of casualties to a level that is similar to that of higher income nations.

The ketogenic diet has been used for more than 50 years in epilepsy, but until recently no randomised clinical trials had been done in children. In a randomised trial in 2008, the effi cacy of the ketogenic diet was of similar magnitude to that of currently used antiepileptic drugs when used as add-on therapy: 38% had a more than 50% decrease in seizure frequency, although seizure freedom was rare and a decrease in seizures by more than 90% was uncommon (7%).4 This trial enrolled a group of patients with particularly intractable forms of epilepsy and several severe epilepsy syndromes and investigated both a classic and a medium chain triglyceride diet. Only 103 of the original 145 recruited patients completed the trial, but only six dropped out because of poor tolerance of the diet. Nearly a half had gastrointestinal side-eff ects

1 Bigal ME, Sarrono D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine mediactions and evolution for episodic to chronic migraine: a longitudinal population-based study. Headache 2008; 48: 1157–68.

2 Schmitz N, Admiraal-Behloul F, Arkink EB, et al. Attack frequency and disease duration as indicators for brain damage in migraine. Headache 2008; 48: 1044–55.

3 Denuelle M, Fabre N, Payoux P, Chollet F, Geraud G. Posterior cerebral hypoperfusion in migraine without aura. Cephalalgia 2008; 28: 856–62.

4 Schoonman GG, van der Grond J, Kortmann C, van der Geest RJ, Terwindt GM, Ferrari MD. Migraine headache is not associated with cerebral or meningeal vasodilatation—a 3T magnetic resonance angiography study. Brain 2008; 131: 2192–200.

5 Ho TW, Ferrari MD, Dodick DW, et al. Acute antimigraine effi cacy and tolerability of the novel oral CGRP receptor antagonist MK-0974: a phase III clinical trial versus placebo and zolmitriptan. Headache 2008; 48: S7–8.