Chronic daily headache with analgesic overuse: Epidemiology and impact on quality of life R. Colás, P. Muñoz, R. Temprano, et al. Neurology 2004;62;1338-1342 DOI 10.1212/01.WNL.0000120545.45443.93 This information is current as of April 26, 2004
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/62/8/1338.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright . All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Chronic daily headache with analgesic overuse Epidemiology and impact on quality of life R. Colás, MD; P. Muñoz, MD; R. Temprano, MD; C. Gómez, SW; and J. Pascual, MD
Abstract—Objective: To analyze the prevalence and demography of chronic daily headache (CDH) with analgesic overuse. Methods: A population of 9,984 inhabitants aged 14 or older living in Santoña, Spain, was studied. The authors personally interviewed 4,855 subjects, using a quota sampling approach. Those with headache for ⱖ10 days/month and some analgesic use were asked to fill in a diary over the course of 1 month. Then, subjects were classified into CDH with or without analgesic overuse subtypes. Quality of life (Short Form-36 Health Survey [SF-36]) was also assessed in this second interview. Results: Headache for ⱖ10 days/month with analgesic consumption was reported by 332 subjects. Seven had secondary headache. Seventy-four (standardized prevalence 1.41%, 95% CI 1.1 to 1.8) fulfilled criteria for CDH with analgesic overuse. Prevalence in women (2.6%, 2.0 to 3.3) was much higher than in men (0.19%, 0.006 to 0.52). Mean age was 56 years (range 19 to 82 years). As recalled by the subjects, the mean age at onset of CDH was 38 years (range 9 to 82 years), whereas the mean age at onset of CDH with frequent analgesic consumption was 45 years (range 19 to 80 years) and that of primary headache was 22 years (range 5 to 60 years). CDH subjects showed a significant decrease in each SF-36 health-related score as compared with healthy control subjects. Transformed migraine was diagnosed in 49 (prevalence 0.9%), chronic tension-type headache in 20 (0.4%), and new daily persistent headache in 5 (0.1%). Thirty-five percent of patients overused simple analgesics, 22% ergotics, 12.5% opioids, and 2.7% triptans; the remaining 27.8% were overusing different combinations. Conclusion: CDH with analgesic overuse is a common disorder in the general population, mainly in women in their fifties, in whom 5% meet its diagnostic criteria. NEUROLOGY 2004;62:1338 –1342
Primary daily or near-daily headache is a common problem in clinical practice, accounting for 40% of patients seen in headache clinics and 10% of outpatient general neurologic consultations.1-3 The term “chronic daily headache” (CDH) encompasses those primary headaches, including those with analgesic medication overuse, presenting ⬎15 days/month and lasting ⬎4 h/day untreated.4,5 Under the general term of CDH, Silberstein et al.4,5 classified these headaches into transformed migraine (TM), chronic tension-type headache (CTTH), new daily persistent headache (NDPH), and hemicrania continua (HC). Each of the CDH categories can meet or not criteria for symptomatic medication overuse. Secondary headache disorders may produce daily headache but are excluded from this group. The epidemiology of CDH has been investigated in a number of studies.6-11 One was conducted in Baltimore County, MD, using a validated computerassisted telephone interview with 13,343 randomly selected individuals.6 We personally interviewed 1,883 randomly selected subjects over 14 years of age in Camargo, Spain.7 Prevalence of CDH was almost identical in the two studies: 4.1% in the American survey and 4.7% in the European study. CDH preva-
lence has also been studied in other, more selected populations.8-11 The results in these epidemiologic surveys are, with the exception of a recent study in Norway,11 very coincidental and confirm that prevalence of CDH, according to the criteria of Silberstein et al., is around 4 to 5% of the general population. The epidemiology of analgesic overuse related to CDH is uncertain, as most data come from headache units. In US specialty headache clinics, 60 to 80% of patients who presented with CDH used analgesics on a daily or near-daily basis.1,2 In European headache centers, 5 to 10% of patients have drug-induced headache.2,3 These data teach us that CDH with analgesic overuse is a dramatic problem in headache clinics, but they cannot necessarily be extrapolated to the general population. To investigate the epidemiology of analgesic overuse related to CDH, we conducted a prospective survey in a large sample of the general population. Patients and methods. Study population. The study was performed in the Health Area of Santoña, located in the region of Cantabria, northern Spain. This area was selected because it is demographically diverse with regard to age and household income. The socioeconomic and demographic data of our region do not differ from those of the rest of Spain. The population in San-
From the Health Center of Santoña (Drs. Colás and Temprano, C. Gómez), Primary Care Management Unit (Dr. Muñoz), and Service of Neurology (Dr. Pascual), University Hospital Marqués de Valdecilla (UC) , Cantabria, Spain. Supported by the “Centro de Investigación de Enfermedades Neurológicas,” Nodo HUMV/UC, ISCIII, Spain. Received May 13, 2003. Accepted in final form October 6, 2003. Address correspondence and reprint requests to Dr. J. Pascual, Service of Neurology, University Hospital Marqués de Valdecilla, 39008 Santander, Spain; e-mail:
[email protected] 1338
Copyright © 2004 by AAN Enterprises, Inc.
toña aged 14 or older in 1998 was 9,984 (4,880 men and 5,104 women). Taking into account our preliminary data,7 the necessary sample size was calculated with the EPIINFO12 program, estimating a prevalence for CDH with analgesic overuse of 1.2%, with a desired precision of 0.4% for a 95% CI. Considering the differences in CDH prevalence for both sexes, the final sample size should include at least 4,432 people. To carry out this survey, we used the quota sampling approach.13 Sampling was performed according to some preconceived conditions, to minimize the potential selection bias. We established quotas for the two sexes and for eight age groups (decades). Therefore, the main strategy to complete the quotas was to gain access to groups, such as high schools, factories, and official centers, and consecutively and systematically interview all their subjects. Between July 1998 and April 1999, two local family physicians and a local social worker invited Santoña citizens to answer a general headache questionnaire. The first question was “Have you ever had headache?” Individuals responding “yes” were asked to answer also two further questions. The first was “Do you have headache 10 or more days per month?” The second question was “In the last 3 months, have you taken any analgesic for your head pain?” Subjects answering “yes” to these two questions were given an appointment in the local health center. If necessary, examination outside working hours was offered. The subjects were then personally seen by one of the two family physicians, who interviewed and examined them for about an hour. The survey included standardized sociodemographic variables, familial and personal medical antecedents, a structured headache interview, and a general and neurologic physical examination. Blood sampling, neuroimaging, and ophthalmologic checkup were electively planned. After this interview, in which no recommendation regarding headache management was offered, all subjects with no apparent history of secondary headache were given a headache diary in which they had to record for 1 complete month the number of days with headache, the duration of headache episodes, and all the symptomatic medications taken for its relief. After filling in the headache diary, patients were interviewed and examined by the family physician together with a neurologist with interest in headache. This interview included an extensive review of past and present headaches including frequency, duration, location, pain intensity, accompanying symptoms, precipitating and aggravating factors, and consumption of symptomatic medications. Based on all these data, subjects were classified or not into CDH with analgesic overuse subtypes according to the revised criteria .5 We also adopted the criteria of analgesic overuse proposed by the same authors. Triptan overuse (not included in the Silberstein et al. criteria) was defined as use of at least 1 triptan tablet for ⱖ2 days/week. Previous headache disorders were classified according to operational International Headache Society criteria.14 Quality of life was also assessed in this second interview by means of the validated Spanish version of the Short Form-36 Health Survey (SF-36).15-17 We used the standardized values for healthy sex- and age-matched individuals already reported for the population in Spain18 as a control group. SF-36 scores were adjusted for comorbid conditions using the  coefficient and a multiple regression analysis.19,20 Statistical analysis. This analysis was carried out with the EPIINFO v.6 program.12 For description of variables, percentages, mean, and SD were used. All CI were calculated for a 95% level. The 2 test was used to compare proportions and Student t-test for interval variables. Prevalence of CDH with medication overuse is shown standardized to correct for sex imbalance between the final study sample and the total population in Santoña.
Results. The screening questionnaire was answered by 4,855 subjects (49% of the population aged over 14 in this health area): 2,130 men and 2,725 women. The responders did not differ from the nonresponders or from the total population of our region in general sociodemographic variables, with the exception of sex. The proportion of women in the final sample (56%) was higher (p ⬍ 0.001) than that of the total population and that of the entire simple (51%). Headache for ⱖ10 days/month with some analgesic con-
Figure 1. Prevalence of chronic daily headache with analgesic overuse in males and females according to age at diagnosis. sumption was admitted by 332 subjects (77% females). Seven (2.1%) were diagnosed with secondary headaches: headache associated with disorders of sinuses in two cases, one case of headache associated with uncontrolled hypertension, one case of nitrite-induced headache, one with chronic posttraumatic headache, one with idiopathic intracranial hypertension, and one case with headache associated with disorders of the neck. Twenty-three (6.9%) either did not return the diary or were excluded owing to neuropsychiatric disorders. Once a diagnosis of secondary headaches was ruled out by both the family physician and the neurologist and subjects had filled in the headache diary for 1 month, 74 (standardized prevalence 1.4% of the total series, 95% CI 1.1 to 1.8) fulfilled criteria for CDH with analgesic overuse. Seventy (94.6%) were women (prevalence 2.6%, 95% CI 2.0 to 3.3) and four (5.4%) men (prevalence 0.2%, 95% CI 0.1 to 0.5). The prevalence of CDH and analgesic overuse according to age at diagnosis is illustrated in figure 1. The mean age of these subjects fulfilling criteria for CDH with overuse was 56 years (range 19 to 82 years). The mean (subjective) age at onset of CDH was 38 years (9 to 82 years), whereas the mean (subjective) age at onset of CDH with frequent analgesic consumption was 45 years (range 19 to 80 years). The mean (subjective) age at onset of the primary episodic headache was 22 years (range 5 to 60 years). Quality of life of subjects with CDH with analgesic overuse vs healthy control subjects. As illustrated in figure 2, subjects with CDH with analgesic overuse showed a clear decrease (p ⬍ 0.001) in each health-related concept of the SF-36 as compared with healthy control subjects. The highest differences were found for body pain and role physical. Subtypes of CDH with analgesic overuse. The distribution of CDH subtypes is illustrated in the table. Forty-nine individuals (47 females) met TM with analgesic overuse criteria (66.2% of all subjects with CDH and analgesic overuse, standardized prevalence 0.9%). The mean age at diagnosis was 56 years (range 25 to 78 years), and the mean age at which TM with analgesic overuse began, as subjectively recalled, was 45 years (range 20 to 67 years). Twenty (18 females) fulfilled criteria for CTTH with analgesic overuse (27% of all subjects with CDH and analgesic overuse, prevalence 0.4%). The mean age at diagnosis was 55 years (range 19 to 82 years), whereas the mean age at which TM with analgesic overuse began, as subjectively April (2 of 2) 2004
NEUROLOGY 62
1339
Figure 2. Comparison of Short Form-36 Health Survey scores between healthy subjects (squares) and those having chronic daily headache with analgesic overuse (circles). Differences were significant for all items, being more marked for role physical and bodily pain. recalled, was 45 years (range 19 to 80 years). Age distribution for TM and CTTH is shown in figure 3. Five (all females) met criteria for NDPH with analgesic overuse (6.8% of all subjects with CDH with medication overuse and 0.1% of the total population in this study). The mean age at diagnosis was 54 years (range 32 to 72 years), whereas the mean age at which NDPH with analgesic overuse began, as subjectively recalled, was 50 years (range 30 to 65 years). No subject fulfilled criteria for HC with analgesic overuse. Distribution of analgesic overuse. The distribution of analgesic overuse was as follows: 34.7% of patients overused simple analgesics, 22.2% ergotamine-containing medications, 12.5% opioids, and 2.7% triptans (2 patients taking zolmitriptan), whereas the remaining 27.8% were overusing different combination of these pharmacologic groups. The most consumed drugs were paracetamol (54.2% of subjects), caffeine (48.6%), ergotics (37.5%), propifenazone (34.7%), aspirin (18.1%), and codeine (12.5%). The mean number of units per subject and month was 50 (range 10 to 180 units). Patients were taking, on average, 2.5 different pharmacologic components simultaneously (range 1 to 6).
Discussion. CDH with analgesic overuse is a common disorder in the general population, with a prevalence of 1.4%. Our results also demonstrate that in
Figure 3. Prevalence according to age at diagnosis for transformed migraine (TM) with analgesic overuse vs chronic tension-type headache (CTTH) with analgesic overuse.
the general population, CDH with analgesic overuse itself induces a remarkable decrease in all quality-oflife aspects studied by the SF-36, with body pain and role physical being the most affected items. Even though we used here the standardized values for matched populations in Spain,18 instead of a control group, these values were totally coincidental to those obtained in our area for healthy control subjects in previous studies.21 These data are coincidental with those recently reported by our group in CDH with and without analgesic overuse21 and by other authors in migraine populations.22,23 More women (prevalence 2.6%) than men (0.2%) had CDH and analgesic overuse. The prevalence of CDH with analgesic overuse increases with age until reaching its maximum during the sixth decade of life, when 5% of women fulfill criteria for this condition. The fact that CDH with analgesic overuse begins, on average, one decade later than CDH without analgesic overuse seems to be the only difference in their general demographic profiles. The mean duration of primary headache in our patients was 35 years, whereas the mean duration of daily or near-daily drug intake was 11 years. These numbers coincide with those coming from headache clinics.1,2 We report data on the prevalence of CDH with analgesic overuse, using diagnostic operational criteria, in a representative sample of the general popula-
Table Summary of results according to diagnosis of CDH with analgesic overuse Age (SD), y Diagnosis
No. of subjects
Sex, % women
At diagnosis
At onset
Prevalence* (95% CI)
TM
49
96
56 (14)
45 (12)
0.9 (0.7–1.3)
CTTH
20
90
55 (18)
45 (15)
0.4 (0.2–0.6)
NDPH
5
100
54 (18)
50 (16)
0.1 (0.0–0.3)
Totals
74
95
56 (15)
45 (13)
1.4 (1.1–1.8)
* Estimated prevalence in the last month according to headache diary. Standardized values corrected for a 5% sex imbalance. CDH ⫽ chronic daily headache; TM ⫽ transformed migraine; CTTH ⫽ chronic tension-type headache; NDPH ⫽ new daily persistent headache. 1340
NEUROLOGY 62
April (2 of 2) 2004
tion with no age limitation and including a clinical interview as well as a general and neurologic evaluation of all participants. This approach allowed us to exclude secondary headaches (2% of the total patients referring headache ⱖ10 days/month) and a better diagnostic definition among the different CDH subcategories. We used here 10 days instead of the 15 days required for CDH diagnosis to optimize the sensibility of the sampling procedure to try not to lose any CDH subject. Our results confirm our preliminary data obtained in a smaller sample where we had found an estimated prevalence of 1.2% for CDH with analgesic overuse.7 Additionally, they concur with data in elderly people in central Italy, where 37.8% of the CDH subjects overused analgesics, which would give a prevalence for CDH with analgesic overuse of 1.7% in this age group.10 With use of a person-to-person survey method in 1,553 people aged 65 or older in China, it was recently found that 25% of that headache population overused analgesics, which would indicate a prevalence for CDH with analgesic overuse of 1%.9 One potential limitation of this study could theoretically be the lack of representativeness of the sample as we used a nonprobabilistic sampling technique. In this regard, we standardized the results as the percentage of women (56%) in the final sample was higher than in the entire sample. The validity of the quota sampling technique as compared with random sampling methods has frequently been debated.13,24,25 When survey results obtained by the two methods could be compared, they have often been remarkably close, except for occupation and education. Quota sampling showed a tendency to underrepresent low education and occupation. In our survey, however, we believe that the influence of these confounding effects is very small. First, the sample represents half the study population. Second, we took careful restrictions when electing the subjects, as the three study interviewers who selected the participants were members of the research team and knew the limitations of this sampling technique. Finally, we controlled variables such as age and sex both when designing quotas and when estimating prevalence. On the other hand, random samplings frequently contain ⱖ20% of nonresponders, which can also bias the final results. That is to say, neither the random nor the quota method systematically guarantees the representativeness of the sample. With both techniques, it is necessary to anticipate possible error sources and try to minimize them. Considering a CDH prevalence of near 5%,6,7 our results confirm that only around 30% of CDH patients in the general population meet criteria for overuse of symptomatic medication. This is a low proportion as compared with data from headache clinics.1,2 From our population results and even from data in headache clinics (where at least 15% of subjects do not show analgesic overuse), it can be concluded that chronic analgesic consumption is not always a necessary condition to transform an episodic migraine or tension-type headache into CDH.
At least for a significant proportion of patients with CDH in the general population, CDH appears to be a “natural” transformation of an episodic primary headache into a chronic daily problem. The role of analgesics in the development of CDH, however, must not be undervalued. Headache-prone patients often develop daily headaches if put on analgesics for a nonheadache indication,26 which shows that headache patients are especially vulnerable to rebound. The already-noted discrepancies between our results from a population sample and the data from the headache clinics indicate that patients with CDH associated with analgesic overuse seek medical attention much more frequently. These facts, together with the beneficial effects of analgesic withdrawal in most, although not all, CDH patients, suggest that the most probable role of analgesics in CDH is that of exacerbating the headache disorder by inducing rebound headache and interfering with the effectiveness of prophylactic headache medications. Regarding the distribution of analgesic overuse by CDH diagnostic categories and concurring with data from headache clinics,1,2 overuse was more frequent in TM (66.2% of all subjects in this series) than in CTTH (27%) subjects. The distribution of drug overuse found in our survey in the general population is comparable with that found in specialized clinics around the world, with simple analgesics (mainly paracetamol and caffeine), alone or in combination, and ergotaminecontaining medications, in this order, being the most frequently involved medications. Other uses of caffeine, for example, coffee or cola, were not investigated. To sum up, three-quarters of individuals with CDH with overuse fulfill TM criteria and two-thirds consume simple analgesics, alone or in combination, or ergotaminecontaining medications. Interestingly, as Spain is a country with a low triptan consumption, we were able to find two patients overusing triptans, which confirms that this novel therapeutic group is not devoid of overuse risks.27,28 This study highlights the public health impact of CDH with analgesic overuse, a condition that greatly decreases the quality of life and accounts for reduced efficiency at work.29 This impact is most pronounced in women in their fifties, in whom 5% meet the criteria for CDH with analgesic overuse. These impressive numbers, together with a negative influence in daily life, call for public health interventions in this segment of the population. References 1. Mathew N, Stubits E, Nigam MR. Transformation of episodic migraine into daily headache: analysis of factors. Headache 1982;22:66 – 68. 2. Mathew N, Reuveni U, Pérez F. Transformed or evolutive migraine. Headache 1987;27:102–106. 3. Pascual J, Berciano J. Cefalea crónica diaria de pacientes migrañosos inducida por abuso de analgésicos-ergotamínicos: respuesta a un protocolo de tratamiento ambulatorio. Neurologia 1993;8:212–215. 4. Silberstein SD, Lipton RB, Solomon S, Mathew NT. Classification of daily and near-daily headaches: proposed revisions to the IHS criteria. Headache 1994;34:1–7. 5. Silberstein SD, Lipton RB, Sliwinski M. Classification of daily and near-daily headaches: field trial of revised IHS criteria. Neurology 1996;47:871– 875. April (2 of 2) 2004
NEUROLOGY 62
1341
6. Scher AI, Stewart WF, Liberman J, Lipton RB. Prevalence of frequent headache in a population sample. Headache 1998;38:497–506. 7. Castillo J, Muñoz P, Guitera V, Pascual J. Epidemiology of chronic daily headache in the general population. Headache 1999;39:190 –196. 8. Mitsikostas DD, Thomas A, Gatzonis S, Illias A, Papageorgia G. An epidemiologic study of headache among the monks of Athos (Greece). Headache 1994;34:539 –541. 9. Wang SJ, Fuh JL, Lu SR, et al. Chronic daily headache in Chinese elderly. Prevalence, risk factors, and biannual follow-up. Neurology 2000;54:314 –319. 10. Prencipe M, Casini AR, Ferretti C, et al. Prevalence of headache in an elderly population: attack frequency, disability, and use of medication. J Neurol Neurosurg Psychiatry 2001;70:377–381. 11. Hagen K, Zwart JA, Vatten L, Stovner LJ, Bovim G. Prevalence of migraine and non-migrainous headache-head-HUNT, a large population-based study. Cephalalgia 2000;20:900 –906. 12. Dean JA, Dean AG, Burton A, Diker R. EPIINFO v.6. Geneva: World Health Organization, 1994. 13. Cochran WG. Quota sampling. In: Cochran WG, ed. Sampling techniques. 3rd ed. New York: Wiley, 1977:135–136. 14. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(suppl 7):1–96. 15. Ware JE, Snow KK, Kosinski M, Gandek B. The SF-36 Health Survey Manual and interpretation guide. Boston: Health Institute, New England Medical Center, 1993. 16. McHorney CA, Ware JE, Raczek A. The MOS 36-Item Short-Form Health Survey (SF-36): psychometric and clinical test of validity in measuring physical and mental health construct. Med Care 1993;31:247–263. 17. Alonso J, Prieto L, Antó JM. La versión española del SF-36 health survey (cuestionario de salud SF-36): un instrumento para la medida de los resultados clínicos. Med Clin 1995;104:771–776.
1342
NEUROLOGY 62
April (2 of 2) 2004
18. Alonso J, Regidor E, Barro G, Prieto L, Rodríguez C, de la Fuente L. Valores poblacionales de referencia de la versión española del cuestionario de salud SF-36. Med Clin 1998;111:410 – 416. 19. Stewart AL, Greefield S, Hays R, et al. Functional status and wellbeing patients with chronic conditions. Results from the Medical Outcomes Study. JAMA 1989;262(suppl 7):907–913. 20. Osterhaus JT, Townsed RJ, Gandek B, Ware JE. Measuring the functional status and well-being of patients with migraine headache. Headache 1994;34:337–343. 21. Guitera V, Muñoz P, Castillo J, Pascual J. Quality of life in chronic daily headache. A study in a general population. Neurology 2002;58: 1062–1065. 22. Lipton RB, Hamelsky SW, Kolodner KB, Steiner TJ, Stewart WF. Migraine, quality of life and depression: a population base case-control study. Neurology 2000;55:629 – 635. 23. Terwindt GM, Ferrari MD, Tijhuis M, Groenen SMA, Picavent HSJ, Launer LJ. The impact of migraine on quality of life in the general population. The GEM study. Neurology 2000;55:610 – 611. 24. Kish L. Survey sampling. New York: Wiley, 1995. 25. Moser C, Kalton G. Quota sampling. In: Moser C, Kalton G, eds. Survey methods in social investigation. 2nd ed. London: Darmouth, 1979:127–137. 26. Kudrow L. Paradoxical effects of frequent analgesic use. Adv Neurol 1982;33:335–341. 27. Kaube H, May A, Pfaffenrath V, Diener HC. Sumatriptan misuse in daily chronic headache. Br Med J 1994;308:1573. 28. Limmroth V, Kazarawa Z, Fritsche G, Diener HC. Headache after frequent use of serotonin agonists zolmitriptan and naratriptan. Lancet 1999;353:78. 29. Schwartz BS, Stewart WF, Lipton RB. Lost of workdays and decreased work effectiveness associated with headache in the workplace. J Occup Environ Med 1997;39:320 –327.
Chronic daily headache with analgesic overuse: Epidemiology and impact on quality of life R. Colás, P. Muñoz, R. Temprano, et al. Neurology 2004;62;1338-1342 DOI 10.1212/01.WNL.0000120545.45443.93 This information is current as of April 26, 2004 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/62/8/1338.full.html
References
This article cites 23 articles, 8 of which you can access for free at: http://www.neurology.org/content/62/8/1338.full.html##ref-list-1
Citations
This article has been cited by 25 HighWire-hosted articles: http://www.neurology.org/content/62/8/1338.full.html##otherarti cles
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All epidemiology http://www.neurology.org//cgi/collection/all_epidemiology All Headache http://www.neurology.org//cgi/collection/all_headache Quality of life http://www.neurology.org//cgi/collection/quality_of_life
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
