New daily persistent headache: Should migrainous features be incorporated?

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1 Original Article New daily persistent headache: Should migrainous features be incorporated? Cephalalgia 31(15) ! International Headache Society 2011 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: / cep.sagepub.com Kuan-Po Peng 1,2, Jong-Ling Fuh 1,2, Hsiang-Kuo Yuan 3, Ben-Chang Shia 4 and Shuu-Jiun Wang 1,2 Abstract Introduction: International Classification of Headache Disorders (ICHD-2) criteria for new daily persistent headache (NDPH) require tension-type headache features. Many patients with new-onset persistent headache fail to fulfil such criteria due to prominent migrainous features. Subjects and methods: We reviewed all NDPH patients in our headache clinic, using the definition of persistent headache < 3 days after onset for > 3 months. The patients were dichotomised: patients meeting ICHD-2 criteria (NDPH-S) and patients failing to meet ICHD-2 criteria due to prominent migrainous features (NDPH-M). All patients had completed a structured intake form including demographics, headache profiles, Beck Depression Inventory (BDI), Short Form 36 (SF-36) Health Survey, and Migraine Disability Assessment (MIDAS). A telephone interview was conducted for follow-up. Results: A total of 92 NDPH patients were enrolled (59 (64.1%) NDPH-M, 33 (35.9%) NDPH-S). Between the two subgroups, the sociodemographics were indistinguishable, but the patients with NDPH-M had higher headache intensity, BDI scores, MIDAS scores, and lower scores of most SF-36 subscales. After an average of 2 years of follow-up, 57 (66%) had a good outcome ( 50% reduction in headache frequency). Cox proportional analysis showed that disease duration 6 months and NDPH-S diagnosis predicted good outcomes. Conclusion: Migrainous features were common in patients with NDPH. Unlike prior studies, our study showed NDPH-M represented a more severe subgroup with a poorer outcome compared with NDPH-S. Keywords New daily persistent headache, migraine, outcome, quality of life, impact Date received: 29 June 2011; revised: 15 August 2011; 28 August 2011; accepted: 4 September 2011 Introduction New daily persistent headache (NDPH) was first introduced as a benign syndrome by Vanast (1), but came to be regarded as one of the most recalcitrant headache disorders to treat. The prevalence of NDPH is estimated to be 0.1% and accounts for only 2.2% of chronic daily headache (CDH) in the general population (2), but up to 10.8% of CDH in tertiary headache clinics (3). The diagnostic criteria for NDPH were initially proposed by Silberstein and Lipton (4), who defined NDPH as a subtype of CDH with an acute onset of < 3 days, averaging > 15 days per month for more than 1 month. The average headache duration was > 4 hours per day if untreated, without a prior history of migraine or tension-type headache; other secondary headache disorders must be excluded. NDPH is first included in the International Classification of Headache Disorders (ICHD-2) (5) as a primary headache disorder and is regarded as an unremitting headache with an onset < 3 days, lasting for > 3 months. The headache profile is defined as having tension-type headache characteristics. However, in later NDPH studies (6 8), several authors found that many patients failed 1 Taipei Veterans General Hospital, Taiwan. 2 National Yang-Ming University School of Medicine, Taiwan. 3 Duke University, USA. 4 Fu Jen Catholic University, Taiwan. Corresponding author: Dr Shuu-Jiun Wang, Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, sjwang@vghtpe.gov.tw

2 1562 Cephalalgia 31(15) to fulfil the ICHD-2 criteria due to prominent migrainous features. Recently, modified criteria for NDPH were proposed that included patients with prominent migrainous features (7,8). Robbins et al. (8) found that NDPH patients with prominent migrainous features were more likely to be female, depressed, and with a younger age at onset. However, the impact of the presence of prominent migrainous features is unknown. The prognosis of NDPH varies among studies (1,6,8,9). Most of them were done in tertiary care centres (1,6,8,9). Information on the prognosis of community-based NDPH patients is still lacking. In addition, only one study used a battery of standardised instruments to investigate the comorbidities of NDPH (8), and only one study of NDPH was done in Asia (6). The disease burden of NDPH has not been studied yet. In this study, we investigated the sociodemographics, clinical manifestations, treatment responses, and clinical outcomes of patients with NDPH. A battery of standardised instruments was used to measure items such as psychiatric comorbidity, headache disability, and health-related quality of life. Since we also investigated the impact of prominent migrainous features, we adopted broader diagnostic criteria for NDPH, i.e. migrainous features were allowed. Methods Study participants National Health Insurance covers health care costs for more than 98% of the population in Taiwan. It allows self-referral of patients to tertiary medical centres. Taipei Veterans General Hospital (VGH) is a 2,991- bed tertiary medical centre serving both veterans and non-veteran citizens. Our headache clinic has been open since When patients first visit our headache clinic, they have to fill out a structured intake form including sociodemographics, headache profiles, family history of headache, past medical history, Beck Depression Inventory (BDI) (10), and the Short Form 36 (SF-36) Health Survey (11,12). The Migraine Disability Assessment, Taiwan version (MIDAS) was integrated into the intake form in September 2003 (13,14). Study design This is a retrospective study. A chart review of the patients seen in the headache clinic at VGH from January 2001 to February 2010 was conducted. We enrolled patients fulfilling the first two and last one of the criteria (criteria A, B and E) for NDPH in ICHD-2 (Table 1) (5). We then divided the patients into two subgroups for analyses: a subgroup that fulfilled the ICHD-2 criteria completely (NDPH-strict criteria (NDPH-S), i.e. tension-type characteristics). In contrast, the other subgroup fulfilled criteria A, B and E but not criteria C or D for NDPH due to prominent migrainous features (NDPH-modified criteria (NDPH-M)). Secondary headaches attributed to trauma, vascular disorder, infection, structural lesions, etc. were carefully excluded. Patients with 1 attack of migraine or tension-type headache per month before the diagnosis of NDPH were allowed. Patients with medication overuse headache (MOH) according to the ICHD-2R criteria (15), after the onset of NDPH, were not excluded. Patients with a previous history of CDH were also excluded. Study measures We recorded the results of neurological examination, blood tests, brain imaging, including computed tomography (CT) or magnetic resonance imaging (MRI), and spinal tapping if done according to the treating physician s judgment, to exclude possible secondary headache aetiologies. The brain imaging studies were also reviewed by neurologists (H-K.Y. and K-P.P.). The abortive or preventive medications and their responses Table 1. The International Classification of Headache Disorders criteria for new daily persistent headache (NDPH) A. Headache for more than 3 months fulfilling criteria B D B. Headache is daily and unremitting from onset or less than 3 days from onset C. At least two of the following pain characteristics: 1. Bilateral location 2. Pressing/tightening (non-pulsating) quality 3. Mild or moderate intensity 4. Not aggravated by routine physical activity such as walking or climbing stairs D. Both of the following: 1. No more than one of photophobia, phonophobia, or mild nausea 2. Neither moderate or severe nausea nor vomiting E. Not attributed to another disorder

3 Peng et al were recorded. MIDAS was used to measure headacherelated disabilities (13,14), and SF-36 for patientperceived health-related quality of life (HRQoL) (11). In this study, depression was defined as BDI 10 (10). Based on ICHD-2 (5), migrainous features were defined as unilateral location, pulsating quality, moderate or severe intensity, aggravation by physical activity, nausea or vomiting, and photophonia plus phonophobia, each counted as one migrainous feature. Case ascertainment and follow-up All patients with NDPH took part in a structured telephone interview by either of the two physicians (H-K.Y. and K-P.P.) to further clarify the disease onset, duration, changes in headache pattern, followup of outcomes, and to exclude later diagnosed secondary headache aetiologies. The follow-up outcome was rated by the patient as: persistent daily headache, < 50% reduction in frequency, 50% reduction in frequency, and no headache. In this study, the latter two outcomes were deemed good outcomes. Patients who were diagnosed to have secondary causes at follow-ups were also excluded from analyses. The study protocol was approved by the Institutional Review Board of Taipei VGH. Statistical analysis Statistical analysis was performed using the SPSS for windows, v (SPSS Inc., Chicago, IL, USA). Descriptive statistics were expressed as mean standard deviation (SD) for continuous data. Median value was used instead when continuous data were not normally distributed. Student s t-test was used to compare the continuous data with normal distributions in two independent groups; the Mann-Whitney U test was used for continuous data without normal distributions. The chi-square or Fisher s exact tests were used for categorical data. The Cox proportional hazards model was used to select independent risk factors for a good outcome at follow-up presenting as hazard ratio (HR) with 95% confidence intervals (CI). All p-values were two-tailed, and a p-value < 0.05 was defined as statistically significant. Results Study participants The medical records of 7,923 patients who first visited our headache clinic between January 2001 and February 2010 were reviewed. Of 3,690 patients presenting with CDH, i.e. 15 headache days per month, for > 3 months, 101 had the initial tentative diagnosis of NDPH. Nine patients were excluded for the following reasons: four for uncertain diagnoses, three later diagnosed as chronic migraine (CM), one as nasopharyngeal carcinoma-related headache, and the other as primary cough headache. The final sample for analysis consisted of 92 patients with NDPH, accounting for 1.2% of all headache patients and 2.5% of CDH patients. A median interval of 5 months elapsed (range 0 320) between headache onset and the first clinical visit at our hospital. Twenty-seven out of 92 patients (29.3%) had their first visit within 3 months of onset, and diagnoses of NDPH were later made during consecutive follow-ups, when headache persisted for more than 3 months. The study group consisted of 53 women and 39 men and their headache profiles are summarised in Table 2. Thirty-three patients (35.9%) fulfilled all the ICHD-2 NDPH criteria, i.e. NDPH-S subgroup, and 59 (64.1%) fulfilled only the first two and the last one of the criteria, i.e. NDPH-M subgroup. The average age at onset tended to be slightly older in the NDPH-S group ( vs years, p ¼ 0.079), but gender ratio, family history of headache or migraine, and triggers did not differ between these two subgroups. The age of onset showed a different distribution between gender groups: male patients had a right-skewed distribution with a peak incidence at age years, and female patients, a bell-shaped curve with a peak incidence at age years (Figure 1). Of the 92 patients with NDPH, 17 presented with side-locked unilateral headache. Three of them showed at least one cranial autonomic symptom, according to the ICHD-2 criteria for hemicrania continua (5), ipsilateral to the side of headache. None of the three patients responded to indomethacin up to 150 mg per day. Among the other 14 patients with side-locked unilateral headache, six reported headache improvement after non-steroid anti-inflammatory drugs other than indomethacin, six failed to respond to indomethacin, and the other two received acemetacin, a glycolic acid ester of indomethacin, acting as a prodrug of indomethacin, but were not responsive. Clinical profiles The lateralised pain was common (53.3% of all patients), and indistinguishable between the patients with NDPH-S and NDPH-M (45.5% vs 57.6%, p ¼ 0.262). Other migrainous features or associated features, such as nausea, vomiting, photophobia and phonophobia were more common in the NDPH-M subgroup. Among the NDPH-S patients, only 3 of 33 fulfilled criteria C-1 to C-4 for NDPH (Table 1), i.e. completely free of any migrainous features. The baseline average headache intensity was (0 10 scale) for NDPH-M, and for NDPH-S; the average peak intensity of headache was more severe

4 1564 Cephalalgia 31(15) Table 2. Clinical characteristics and headache profile comparison of new daily persistent headache (NDPH) NDPH-M (n ¼ 59) NDPH-S (n ¼ 33) p-value General Gender (female) 33 (55.9%) 20 (60.6%) Age at onset (range) (15 76) (18 78) Median interval between onset and first clinical visit (25th, 75th percentile) (range) 5 (2, 12) (1 216) 6 (2.8, 12) (0 320) Trigger (stress) 16 (27.1%) 8 (24.2%) Trigger (URI) 3 (5.1%) 0 No trigger 40 (67.8%) 25 (75.8%) Prior history of migraine 8 (13.6%) 3 (9.1%) Prior history of TTH 14 (23.7%) 5 (15.2%) Headache characteristics Unilateral 34 (57.6%) 15 (45.5%) Pulsatile 34 (57.6%) 4 (12.1%) <0.001 Exacerbated by physical activities 43 (72.9%) 10 (30.3%) <0.001 Moderate or severe pain intensity 56 (94.9%) 24 (72.7%) VNS (average) VNS (peak) <0.001 Accompanying symptoms Nausea 32 (54.2%) 0 (0%) <0.001 Vomiting 7 (11.9%) 0 (0%) 0.04 Photophobia 38 (64.4%) 6 (18.2%) <0.001 Phonophobia 44 (74.6%) 9 (27.3%) <0.001 Number of migrainous features <0.001 Medication overuse 23 (39.0%) 9 (27.3%) BDI BDI (69.5%) 15 (45.5%) Median MIDAS (25th, 75th percentile) # 25 (1.5, 87.5) 8.5 (0, 39.8) Family history of moderate or severe headache 28 (47.5%) 15 (45.5%) Abnormal brain imaging studies 4/27 (14.8%) 11/55 (20.0%) NDPH-M, NDPH-modified criteria; NDPH-S, NDPH-strict criteria; URI, upper respiratory tract infection; TTH, tension-type headache; VNS, verbal numeric scale of pain (0 10, 10 being the worst); BDI, Beck Depression Inventory; MIDAS, Migraine Disability Assessment, Taiwan version. p < # Patient numbers are 51 in the NDPH-M subgroup and 31 in the NDPH-S subgroup in the NDPH-M than in the NDPH-S group ( vs , p < 0.001). The overall frequency of medication overuse was 34.8% using the ICHD-2R criteria for MOH (15), and this did not differ between the two subgroups (p ¼ 0.258). Compared with the NDPH-S subgroup, the NDPH-M patients had more migrainous features ( vs , p < 0.001), a higher mean BDI score ( vs , p ¼ 0.021), a higher proportion of comorbid depression (BDI 10) (69.5% vs 45.5%, p ¼ 0.023) and a higher median MIDAS score (25 vs 8.5, p ¼ 0.036). NDPH-M patients had lower scores in six of the eight subscales in the SF- 36, except for general health and social functioning (Figure 2). A subgroup of patients with disease duration 6 months In order to decrease recall bias and to exclude the possibility of headache pattern changes after medication usage, 56 (60.9%) of the 92 patients with an interval of 6 months from headache onset to the first clinical visit were selected for subgroup analysis. Thirty-seven (66.1%) patients in this category were grouped into NDPH-M, compared with 64.1% of all NDPH patients. Further comparisons between NDPH-M and NDPH-S in this category showed similar results to those of all NDPH patients (data not shown).

5 Peng et al Patient number Brain imaging studies Eighty-two (89.1%) of the 92 patients received neuroimaging studies, either brain CT (n ¼ 9) or MRI (n ¼ 73), to investigate the possibility of intracranial lesions. All brain CT scans were normal. Of the 73 MRI scans, 62 (84.9%) included diffusion weighted image (DWI), 53 (72.6%) were done with gadolinium, and 18 included magnetic resonance venography. Among the 73 patients undergoing brain MRI, 15 had MRI abnormalities (4 in NDPH-S, 11 in NDPH- M, p ¼ 0.568), mostly non-specific findings including old lacunar infarctions (n ¼ 3), non-specific white matter spots (n ¼ 3), and empty sella (n ¼ 2). Other findings included cystic pineal gland, arterial stenosis, small (1 cm in diameter) meningioma, calcified left eyeball, dolichoectasia, angiographically occult vascular malformation, and developmental venous anomaly, with one patient each. Treatment Female Male Age of onset Figure 1. The distribution of age of onset between female and male patients with NDPH. Female patients had a peak incidence at years, whereas male patients had a peak incidence at years. NDPH, new daily persistent headache. The treatment plan was individualised according to the treating headache specialists. The mean treatment course was 6.9 months (range 0 54 months). Headache prophylactic agents were prescribed in 75 (81.5%) of the 92 patients. The commonly used (> 5% of all the patients) prophylactic agents were listed according to their frequency: flunarizine (37%), amitriptyline (35.9%), propranolol (32.6%), valproate (13.6%), topiramate (8.7%), and venlafaxine (7.6%). Overall, 34 patients (45.3%) received one prophylactic medication, 29 (38.7%) received two, and 12 (16.0%) received three or more at maximum during the treating course. The preventive medications prescribed did not differ significantly between patients with NDPH-S and NDPH-M. Follow-up Eighty-seven patients (response rate 94.6%, 56 NDPH- M, 31 NDPH-S) were followed up by telephone interview with a mean follow-up duration of months (range 3 63) from their first visit and months after their disease onset. Twentytwo (25.3%) patients still had daily persistent headache, 8 (9.2%) had < 50% reduction in headache frequency, 34 (39.1%) had 50% reduction in headache frequency, and 23 (26.4%) became headache-free. The mean headache days per month at follow-up for NDPH-M and NDPH-S were vs Cox proportional hazards analysis showed two independent predictors of a good outcome, i.e. headache-free or 50% reduction in headache frequency (n ¼ 57, 65.5%): duration of disease 6 months before the first clinical visit (HR 2.71; 95% CI, ; p ¼ 0.002), and the diagnosis of NDPH-S (HR 1.93; 95% CI, ; p ¼ 0.025) after controlling other confounding factors (Figure 3). Other variables such as gender, age at onset, headache profiles, depression scores, family history, previous headache history, or abnormal brain images were not related. As for treatment, no single prophylactic medication was associated with a better outcome than any other. Discussion Our study recruited a larger number of NDPH patients compared with previous studies (1,6 9,16). Though NDPH accounted for % of CDH in one clinic-based study (7), it accounted for only 2.5% of CDH in our study. Such a low percentage was also demonstrated in two community-based CDH studies including ours (17,18). Normally, difficult-to-treat patients are referred to tertiary centres, but due to self-referral in our medical system, our sample may be more similar to a community-based than a tertiary headache clinic-based sample. In line with prior studies, our study patients showed a female predominance (57.6% vs %) (1,7 9,16) and frequent migrainous features (64.1% vs %) (7,8,16). Family history of moderate or severe headache (46.7%), depression (60.8%) and medication overuse (34.8%) were also very common as in other series (3,8,18). Of note, similar to other studies, most of the

6 1566 Cephalalgia 31(15) n.s. PF RP BP GH VT SF RE MH patients fulfilling ICHD-2 criteria (tension-type features) for NDPH still complained of a moderate or severe intensity of pain (87.0% vs %) (6,8). In contrast to other studies, more patients presented with a unilateral headache in our study (53.3% vs %) (1,6,8,19). A possible explanation is that our patients made early clinic visits after headache onset. Episodic migraine may evolve into bilateral dull pain after chronification (20). Such a transformation might also apply to those with NDPH with initial unilateral headache. In addition, medication overuse headache is commonly bilateral (5). The relatively low frequency of medication overuse in our study compared with other studies (34.8% vs %) (3,8,18) might also have contributed to the lower frequency of bilateral headache. The clinical profiles of the NDPH-S and NDPH-M subgroups showed a major difference in number of migrainous features due to grouping criteria. Compared with the NDPH-S subgroup, the NDPH- M subgroup tended to have higher depression scores, higher headache-related disability, and more pervasive impairment of HRQoL. In fact, patients with NDPH- M showed lower scores in six of the eight subscales of SF-36 than those with NDPH-S. Taking the study results of CM and CTTH from our previous series (12) for comparisons, we found the SF-36 subscale n.s. CM NDPH-M CTTH NDPH-S Figure 2. Comparison of SF-36 health subscale scores among patients with different types of headache. Scores of patients with CM and CTTH were also added from our previous study (12). SF-36, Short Form 36 Health Survey; CM, chronic migraine; CTTH, chronic tension-type headache; NDPH, new daily persistent headache; NDPH-M, NDPH-modified criteria; NDPH-S, NDPH-strict criteria; PF, physical functioning; RP, role limitations due to physical problems; BP, bodily pain; GH, general health perceptions; VT, vitality; SF, social functioning; RE, role limitations due to emotional problems; MH, mental health. p < 0.05, p < 0.005, n.s. not significant. (A) 1.0 Cumulative propotion of good outcome (B) 1.0 Cumulative propotion of good outcome Migrainous features Tension-type features Duration of illness before the first clinical visit Follow-up duration (months) >6 months 6 months Follow-up duration (months) P= P= Figure 3. Outcome comparisons in relationship to headache features (A) and duration of illness before the first clinical visit (B). scores were quite similar between NDPH-M and CM (Figure 2). This is also true between NDPH-S and CTTH. Compared with NDPH-S and CTTH, NDPH-M and CM shared greater headache intensity, worse headache-related disability and higher depressive symptoms (21,22). Therefore, migrainous features should be explored in patients with NDPH due to its impact on the disease profiles. Nevertheless, due to similar disease burden and clinical outcome, the issue of whether NDPH-M should be considered as a subtype of NDPH or CM, NDPH-S as a subtype of NDPH or CTTH, needs further clarification. Our study showed most of the patients with NDPH did well at an average of 2 years of follow-up. Twothirds of them presented with a good outcome, i.e. 50% reduction of headache frequency. In fact, our patients showed a better outcome than most prior NDPH series (6,8) although still worse than the first series by Vanast (1). A recent series showed a comparable outcome to our series (9) (Table 3). The reasons for the discrepancy in outcomes among studies were

7 Peng et al Table 3. Outcome comparison among different studies: headache frequency used for outcome variable in most studies Headache outcome Authors (ref #) Country Year Case number Headache-free 50% improvement < 50% improvement Daily headache Duration of follow-up Vanast et al. (1) Canada % 2 years Takase et al. (6) 1 Japan % 3% 20% 50% Not mentioned Robbins et al. (8) USA % 2 8.5% % 3 54 months Wintrich et al. (9) USA % 42.8% 28.6% months Peng et al. (current study) Taiwan % 39.1% 9.2% 25.3% 3 63 months 1 Used headache severity instead of frequency for outcome. 2 Headache < 5 days per month for at least 3 months. 3 Relapsing and remitting headache. 4 Chronic daily headache. All patients strictly fulfilled International Classification of Headache Disorders (ICHD-2) criteria for new daily persistent headache (NDPH). not clear. Several possible explanations are listed. First, our study patients had a shorter duration of illness (median 5 months) before the first visit as compared to duration 6 months in one American study (16) and > 12 months (median 39.5 months) in one Japanese study (6). Of note, shorter disease duration (6 months) from onset to the first visit was a good outcome predictor for NDPH based on our study results. Thus, shorter disease duration might be associated with a self-limiting course or it is perhaps possible that early intervention could prevent chronification. Also, MOH is associated with headache persistence in patients with CDH (17,23,24). Our study showed a lower proportion of medication overuse compared with the series by Robbins et al. (8). A relatively low percentage of MOH (34.8%) in our study might be attributable to a better clinical outcome. Last, the impact of selection bias due to the self-referral system as mentioned earlier should also be considered. Nevertheless, our study suggests that the prognosis of NDPH may be better than previously thought if early cases are counted, or the early cases represented a subtype with spontaneous remission with time compared with a chronic intractable subform. Our study first noted that the diagnosis of NDPH-S was a predictor of good outcome for NDPH. Such a finding varied from previous series (8). The exact reasons remained unknown, but a higher proportion of comorbid depression in the NDPH-M subgroup might be responsible. In addition, migrainous features per se, known as a risk factor of headache persistence in CDH (24), may contribute to the poorer outcome. Though not statistically significant, patients with NDPH-M did have a higher frequency of medication overuse (39.0% vs 27.3%, p ¼ 0.258), which might also affect the outcomes. Still, a larger sample of patients might be needed to confirm the results. Several limitations should be addressed here. First, the study results should be interpreted cautiously in comparison with other series due to selection bias, different clinical setting, and ethnic difference. Second, the patients in our study were seen in an adult tertiary headache clinic. Paediatric patients might not have an adequate representation. Third, this is a retrospective chart review with a telephone interview for follow-up. The results might suffer from recall bias after a long interval from headache onset. It would have been more reliable if a headache diary had been adopted. Besides, the presence of migrainous features, which determined the subgroup diagnosis of NDPH, might not be completely remembered. However, we tried to minimise the recall bias by selecting a subgroup with an onset 6 months. In such a subgroup, the ratio of patients with NDPH-M to those with NDPH-S did not differ from that in all participating NDPH

8 1568 Cephalalgia 31(15) Table 4. Proposed revised criteria for new daily persistent headache (NDPH) A. Headache for more than 3 months fulfilling criteria B E B. Headache is daily and unremitting from onset or less than 3 days from onset C. Headache is not attributed to another headache disorder Hemicrania continua especially must be excluded Subgroup I Headache fulfilled criteria D E D. No more than one of the following pain characteristics: 1. Unilateral location 2. Pulsating quality 3. Aggravated by or causing avoidance of routine physical activity such as walking or climbing stairs E. Both of the following: No nausea or vomiting (anorexia may occur) No more than one of photophobia or phonophobia Subgroup II Headache fulfilled criteria D and/or E D. At least two of the following pain characteristics: 1. Unilateral location 2. Pulsating quality 3. Aggravated by or causing avoidance of routine physical activity such as walking or climbing stairs E. During headache, at least 1 of the following: Nausea and/or vomiting Photophobia and phonophobia patients. Moreover, NDPH-M patients were non-significantly more likely to have a previous headache history (migraine or tension-type headache). Thus, a rapid acceleration of pre-existing headache disorder could not be completely excluded, but the chance was low due to the fact that only a low frequency of previous headache ( 1 episode per month) was allowed in our sample with NDPH. Last, we could not exclude intracranial hypotension and cerebral venous thrombosis completely, despite the absence of typical clinical symptoms; however, most of the MRI studies were done with gadolinium (72.6%) and with DWI (84.9%). In conclusion, despite similar demographics, patients with NDPH-S and NDPH-M showed divergent clinical profiles. In addition, patients with NDPH-M not only showed higher psychological disturbance and a poorer HRQoL but had a worse outcome at follow-up. These divergent findings suggest that NDPH-S and NDPH-M can be treated as two subforms of NDPH (Table 4). It might be reasonable to include NDPH-M in future revision of ICHD criteria for better coverage of such a unique disease spectrum. Funding The study was supported in part by a grant from the Taipei Veterans General Hospital (V100C-087, VGHUST100- G7-1-1), NSC support for Center for Dynamical Biomarkers and Translational Medicine, National Central University, Taiwan (NSC I ) and the Ministry of Education (Aim for the Top University Plan), Taiwan. References 1. Vanast WJ. New daily-persistent headaches: deenition of a benign syndrome. Headache 1986; 26: Castillo J, Munoz P, Guitera V, et al. Kaplan Award Epidemiology of chronic daily headache in the general population. Headache 1999; 39: Bigal ME, Sheftell FD, Rapoport AM, et al. Chronic daily headache in a tertiary care population: correlation between the International Headache Society diagnostic criteria and proposed revisions of criteria for chronic daily headache. Cephalalgia 2002; 22: Silberstein SD, Lipton RB, Solomon S, et al. Classification of daily and near-daily headaches: proposed revisions to the IHS criteria. Headache 1994; 34: Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders: 2nd edn. Cephalalgia 2004; 24(Suppl. 1): Takase Y, Nakano M, Tatsumi C, et al. Clinical features, effectiveness of drug-based treatment, and prognosis of new daily persistent headache (NDPH): 30 cases in Japan. Cephalalgia 2004; 24: Kung E, Tepper SJ, Rapoport AM, et al. New daily persistent headache in the paediatric population. Cephalalgia 2009; 29: Robbins MS, Grosberg BM, Napchan U, et al. Clinical and prognostic subforms of new daily-persistent headache. Neurology 2010; 74:

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