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Headache in beta-thalassemia: An Italian multicenter clinical, conventional MRI and MR-angiography case-control study
Blood Cells, Molecules and Diseases 81 (2020) 102403
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Headache in beta-thalassemia: An Italian multicenter clinical, conventional MRI and MR-angiography case-control study
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Immacolata Tartaglionea, , Martina Caiazzaa, Rosanna Di Conciliob, Angela Ciancioc, Elisa De Micheled, Caterina Maiettaa, Maria Sole Valentinoa, Camilla Russoe, Domenico Robertia, Maddalena Casalea, Andrea Elefantee, Gianluca Feminaf, Fabrizio Espositof, Sara Ponticorvof, Andrea G. Russof, Antonietta Cannaf, Mario Ermanig, Mario Cirilloh, Silverio Perrottaa, Renzo Manaraf Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Università degli studi della Campania “Luigi Vanvitelli”, Napoli, Italy Dipartimento di Pediatria, Ospedale “Umberto I”, Nocera Inferiore, Italy c Unità Operativa Ematologia - Day Hospital di Talassemia, Ospedale “Madonna delle Grazie”, Matera, Italy d Medicina Trasfusionale AUO “San Giovanni di Dio e Ruggi D'Aragona”, Salerno, Italy e Neuroradiologia, Università degli Studi di Napoli “Federico II”, Napoli, Italy f Dipartimento di Medicina e Chirurgia, Scuola Medica Salernitana, Sezione di Neuroscienze, Università di Salerno, Salerno, Italy g Dipartimento di Neuroscienze (DNS), Unità di Statistica e di Informatica, Scuola di Medicina, Università of Padova, Padova, Italy h Dipartimento di Scienze Mediche, Chirurgiche, Neurologiche, Metaboliche e dell'Invecchiamento, Università della Campania “Luigi Vanvitelli”, Napoli, Italy a
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A R T I C LE I N FO
A B S T R A C T
Editor: Mohandas Narla
Objectives: A strikingly increased headache prevalence was recently noted in Sri Lankan beta-thalassemia patients, raising several concerns regarding long-term neurological involvement in this condition. Methods: We interviewed on headache occurrence and characteristics 102 Italian beta-thalassemia patients and 129 healthy controls. 3T-MRI, MR-angiography, MR-venography, cognitive and psychiatric findings were considered. Results: Headache was diagnosed in 39/102 (38.2%) beta-thalassemia patients without significant phenotyperelated differences and in 51/129 (39.5%) controls. Patients and controls did not differ significantly regarding episode number (5.9 ± 6.2 vs 5.4 ± 4.4 days/month), subjective severity-score (6.8 ± 1.4 vs 7.1 ± 1.3), age-at-onset (24.3 ± 13.0 vs 19.5 ± 9.6 years) and headache-subtype rate. No main demographic, clinical or laboratory data was associated with headache but female gender. Headache was not associated with white matter lesions (number or maximal diameter), intracranial aneurysms, intracranial artery stenoses or venous sinus thrombosis. Cognitive and psychiatric evaluations were worse in beta-thalassemia, however, headache did not correlate with full-scale Intelligence Quotient (75.4 ± 18.0 vs 76.7 ± 15.3, with and without headache, respectively) or Brief Psychiatric Rating Scale scores (29.1 ± 2.7 vs 28.5 ± 3.4). Conclusions: Among Italian beta-thalassemia patients, headache does not seem to be more common or severe than in the general population. In addition, patients with headache do not seem to present increased conventional MRI, MR-angiography and cognitive/psychiatric changes.
Keywords: Brain MRI MR-angiography Transfusions Anemia
1. Introduction Beta-thalassemia is a heterogeneous group of inherited disorders characterized by defective production of the beta chain of hemoglobin. In the last decades, its survival has dramatically improved due to advances in medical and/or surgical treatments (e.g. blood transfusions,
splenectomy, iron chelation treatments, etc.). In these patients, longterm neurological involvement is poorly known and it is still matter of concern. A recent study focused on headache and white matter lesions (WMLs) in Sri Lankan adults with beta-thalassemia [1]. This study provided interesting data on MRI, MR-angiography and cognitive findings in transfusion-dependent (TDT), non-transfusion dependent
⁎ Corresponding author at: Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Università degli studi della Campania “Luigi Vanvitelli”, Via L. De Crecchio 4, 80138 Napoli, NA, Italy. E-mail address: [email protected] (I. Tartaglione).
https://doi.org/10.1016/j.bcmd.2019.102403 Received 23 November 2019; Received in revised form 30 December 2019; Accepted 30 December 2019 Available online 31 December 2019 1079-9796/ © 2019 Published by Elsevier Inc.
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2.2. Clinical interview
(NTDT) and E-beta (EBT) thalassemia patients and added novel data on headache prevalence and on its possible relationship with MR findings. In particular, recurrent headache was observed in > 60% of patients, with significant differences according to the geno-phenotype, compared to < 25% of healthy age-matched controls, raising several concerns regarding long-term neurological involvement in this condition. Indeed, the etiology of headaches in thalassemia could be multifactorial, since beta thalassemia is a complex disease with multiorgan involvement. Heart and liver failure, endocrine glands dysfunction, anemia severity beside chelation therapy side effects are all factors that are each other intermingled and that could all, by themselves or in association, result in headache. As we also are studying brain involvement in a large Italian beta-thalassemia population [2–4], we investigated these aspects in our sample aiming at broadening the discussion among groups involved in beta-thalassemia management worldwide and at providing possible pathogenic clues of neurological involvement.
The interview investigated the mean number of episodes/month lasting > 4 h: headache was considered in subjects presenting at least 2 episodes/month. The interview also investigated the subjective mean severity-score (from 0 to 10, where 0 meant no pain and 10 meant pain as bad as it can be), the age-at-onset and the headache-subtype, focusing on migraine (with or without aura) and tension type headache according to the International Classification of Headache Disorders 3rd edition. The headache was considered mixed if the features encompassed both migraine and tension-type headache features. Chronic headache was diagnosed if the subject complained of headache ≥15 days/month for at least 3 months. The interview also investigated the presence of triggering events or conditions. 2.3. MRI and MR angiography Study participants underwent brain MRI on the same 3T MRI scanner (MAGNETOM Skyra, Siemens, Erlangen Germany) with a 20channel head coil.
2. Material and methods 2.1. Study population
2.4. The full MR study protocol included
We interviewed on headache and its characteristics 102 beta-thalassemia patients (mean-age 34.7 ± 11.0 years; 63/102 females; 77/ 102 TDT and 25/102 NTDT) followed at 4 Referral Centers for Beta Thalassemia in the South of Italy (Napoli, Salerno, Nocera Inferiore, Matera). Inclusion criteria were diagnosis of beta-thalassemia and age > 16 years; patients not on regular transfusions and never transfused in the last 48 weeks were classified as NTDT. We also interviewed 129 healthy controls (mean-age 31.1 ± 10.6 years; 82/129 females; Table 1); most of the subjects had participated as controls to previous studies and had MRI evaluation on the same 3T scanner (see below). The study was approved by the local Ethical Committee (Napoli Federico II; #161/15) and all subjects gave their written informed consent before study participation.
1) 3D fluid attenuated inversion recovery (FLAIR, TR/TE/TI 5000/ 387/1800 ms; voxel-size 1 × 1 × 1 mm; echo train length 278; field of view 230; acquisition-time 4 min 32 s); 2) 3D multi-slab Time of Flight MR angiography investigating the intracranial arteries (TR/TE 21/3.43 ms; voxel-size 0.6 ∗ 0.6 ∗ 0.7 mm; field of view 200 mm; number of slabs 120; number of partitions/slab 40; acquisition-time 3 min 34 s); 3) Phase contrast MR-venography covering all intracranial venous sinuses (TR/TE 80.55/10.6 ms; matrix 192 ∗ 192; slice thickness 1 mm; field of view 192 mm; velocity-encoding 8 cm/s; acquisitiontime 6 min 53 s). Axial, coronal and sagittal multiplanar reconstructions of the whole
Table 1 Baseline characteristics of study population. LIC: liver iron concentration; ICT: iron chelation therapy; DFO: deferoxamine; DFP: deferiprone; DFX: deferasirox; PLT: platelet; WBC: white blood cell; nRBC nucleated red blood cell; laboratory data collected as mean of last year's values; n.a.: not available/applicable. No comparison between subjects with and without headache was significant except for gender that showed a higher percentage of females in almost all headache subgroups (p = 0.01–0.03). Beta-thalassemia patients Whole sample (# = 102) Headache Age, years, range Female sex, # (%) Splenectomized, # (%) Mean hemoglobin, g/dL On aspirin, # (%) Ferritin, ng/mL LIC, mg/gdw History of thrombotic events CT, # (%) DFO DFP DFX DFX + DFO PLT (×103/μL) WBC (×103/μL) nRBC (×103/μL) FSIQ
Transfusion-dependent (# = 77)
Yes (# = 39) 33.5 ± 10.0 (15–49) 29 (74.3%) 19 (48.7%)
No (# = 63) 35.5 ± 11.6 (17–72) 34 (54.0%) 36 (57.1%)
Yes (# = 30) 34.5 ± 9.4 (15–49)
9.5 ± 0.9
Healthy controls Non-transfusion-dependent (# = 25)
(# = 129)
24 (80%) 16 (53.3%)
No (# = 47) 37.4 ± 10.9 (19–72) 25 (53.2%) 30 (63.8%)
Yes (# = 9) 30.1 ± 11.8 (16–49) 5 (55.5%) 3 (33.3%)
No (# = 16) 30.1 ± 11.9 (17–52) 9 (56.2%) 6 (37.5%)
Yes (# = 51) 31.0 ± 10.6 (17–65) 38 (74.5%) n.a.
No (# = 78) 31.1 ± 10.5 (18–66) 44 (56.4) n.a.
9.4 ± 0.8
9.2 ± 0.6
9.4 ± 0.8
9.6 ± 1.5
9.9 ± 0.9
n.a.
n.a.
12 (30.8%) 994.9 ± 851.9 4.1 ± 2.8 3 (7.7%)
27 (42.8%) 709.7 ± 595.0 4.9 ± 3.7 1 (1.6%)
9 (30%) 1130.1 ± 884.4 3.7 ± 2.5 3 (10%)
21 (44.7%) 824.2 ± 630.5 4.6 ± 3.0 1 (2.1%)
3 (33.3%) 348.2 ± 306.6 5.6 ± 3.8 0
6 (37.5%) 373.2 ± 287.1 6.5 ± 6.0 0
n.a. n.a. n.a. n.a.
n.a. n.a. n.a. n.a.
10 (25.6%) 0 21 (53.8%) 1 (2.6%) 432.8 ± 242.3 13.6 ± 22.9 15.6 ± 22.6 75.4 ± 18.0
7 (11.1%) 8 (12.7%) 36 (57.1%) 0 480.3 ± 282.9 13.3 ± 8.2 10.8 ± 19.2 76.7 ± 15.3
9 (30%) 0 20 (66.7%) 1 (3.3%) 444.3 ± 210.7 10.4 ± 7.4 16.3 ± 27.0 70.7 ± 17.1
6 (12.8%) 7 (14.9%) 32 (68.1%) 0 511.4 ± 269.7 13.7 ± 7.8 7.8 ± 11.0 76 ± 16.4
1 (11.1%) 0 1 (11.1%) 0 394.5 ± 340.5 24.3 ± 46.1 14.2 ± 11.1 86.3 ± 15.8
1 (6.2%) 0 4 (25%) 0 394.5 ± 340.5 12.1 ± 9.6 23.7 ± 36.0 78.6 ± 12.2
n.a. n.a. n.a. n.a. n.a. n.a. n.a. 98.4 ± 16.8
n.a. n.a. n.a. n.a. n.a. n.a. n.a. 102.7 ± 16.0
2
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brain were obtained from FLAIR (slice thickness 3 mm without interslice gap). Maximum intensity projections views were obtained in the three orthogonal axes (12 views each covering 180°) from artery MR angiography to allow the precise visualization of artery segments. Three orthogonal maximum intensity projections of the MR-venography were automatically produced by the scanner and used for evaluation. FLAIR imaging was available in 73 beta-thalassemia patients (meanage 33.9 ± 10.3 years; 44/73 females; 22/73 NTDT) and 100 controls (mean-age 29.4 ± 9.6 years; 65/100 females). Intracranial artery and venous sinus MR-angiography was available in 73 beta-thalassemia patients and in 47 controls (mean-age 34.6 ± 10.9 years; 31/47 females), who had participated to a multimodal MR study on beta-thalassemia [3] and completed the headache interview. White matter lesions (WML) were evaluated on FLAIR images. Lesion number and maximum diameter (< 0.5 cm or ≥0.5 cm) were also recorded; all MR-exams were evaluated by a neuroradiologist with 15-year experience on cerebrovascular diseases.
(p = 0.10) or with (but not exclusively) lesions < 5 mm (p = 0.17). No subject presented intracranial stenosis or sign of venous sinus thrombosis. As reported elsewhere, our beta-thalassemia had lower IQ and lower Brief Psychiatric Rating Scale scores than controls [2–4]. These findings were confirmed among those who participated to the clinical interview. However, among beta-thalassemia patients, headache was not associated with Brief Psychiatric Rating Scale scores, mainly determined by anxiety and depression scores (29.1 ± 2.7 vs 28.5 ± 3.4, with and without headache, respectively), or full-scale Intelligence Quotient (75.4 ± 18.0 vs 76.7 ± 15.3).
2.5. Neurocognitive findings
4.1. Headache in beta-thalassemia
Seventy-four patients and 39 controls had undergone the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) providing a global scale used to derive the Intelligence Quotient (IQ) and the Brief Psychiatric Rating Scale (BPRS), that measures psychiatric symptoms such as depression, anxiety and unusual behavior [2–4].
This study did not find headache differences (headache frequencyrate and features) between beta-thalassemia patients and controls or between different beta-thalassemia subgroups (i.e. TDT vs NTDT). Actually, our findings are in striking contrast with the sole study on headache in beta-thalassemia available so far, that revealed in Sri Lankan adults with beta-thalassemia a nearly three-time higher headache rate compared to healthy controls (61% vs 22.5%) [1]. The reasons for study discordance are unclear and likely encompass environmental, treatment and methodological issues. However, while headache prevalence in TDT subgroups was substantially confirmed (39% vs 48% in Premawardhena et al.), the rate in NTDT was strikingly different (36% vs 58.3%), thus minimizing the role of environmental factors (that would have affected also TDT patients) and pointing to countryrelated differences in NTDT management as likely explanation. Considering that among beta-thalassemia patients “low level of hemoglobin” was self-reported as the commonest triggering factor for headache episodes, differences in hemoglobin management via blood transfusions appear an intriguing explanation for the study differences, suggesting that full adherence to current transfusion guidelines might contribute in tempering the headache rate in beta-thalassemia. Additional reasons of headache rate differences certainly include the following facts: 1) our study did not include EBT patients (the subgroup showing the highest rate of headache in the study by Premawardhena) [1] since this form is not common in our country and 2) our controls had headache prevalence close to 40%, consistent with previous studies on the general population in our country [5]. In contrast, as noted by the authors themselves, the headache rate among their controls was much lower than reported in the same world region. As a consequence, the difference between patients and controls was partly amplified.
4. Discussion According to our study, headache does not seem to afflict betathalassemia patients more than the general population and patients with headache do not seem to present an increased rate of conventional MRI, MR-angiography and cognitive or psychiatric changes. The following paragraphs will address in details the main findings taking into account the scarce literature on the topics.
2.6. Statistical analysis t-Test and Mann–Whitney U test for continuous variables and Chi square and Fisher's exact tests for qualitative variables were applied to compare data between patients and controls; TDT and NTDT patients were then analyzed as subgroups. Statistical significance was set at p < 0.05 (two-tailed p values). 3. Results Headache was diagnosed in 38.2% beta-thalassemia patients without significant phenotype-related differences (39% TDT vs 36% NTDT, p = 0.79) and in 39.5% controls. Patients and controls did not differ significantly in terms of number of episodes (5.9 ± 6.2 vs 5.4 ± 4.4 days/month), subjective severity-score (6.8 ± 1.4 vs 7.1 ± 1.3), age-at-onset (24.3 ± 13.0 vs 19.5 ± 9.6 years) and headache-subtype rate (chronic headache: 4/102 vs 2/129, p = 0.41; migraine: 28/102 vs 38/129, p = 0.68; migraine without aura: 20/102 vs 17/129, p = 0.20; tension-type: 23/102 vs 24/129 p = 0.50; mixed headache: 14/102 vs 13/129, p = 0.42) except for migraine with aura that was nearly significantly less common in beta-thalassemia patients (8/102 vs 21/129, p = .055, uncorrected for multiple comparisons). Table 1 shows main demographic, clinical and laboratory data of our sample; no finding was associated with headache but female gender in all groups and subgroups except for NTDT. Triggering factors for headache were reported by 35/39 beta-thalassemia patients: low hemoglobin levels (26/39), treatments (9/39), blood transfusions (11/ 39), stress (5/39), menstruations (5/39). Among controls, 38/51 identified heterogeneous triggering factors: the most common were menstruations (9/51), stress (19/51), climatic changes (13/51). Table 2 reports WML detection rate according to number and maximal diameter and according to headache complain. No difference was found between patients and controls. Considering WML size, headache was associated with patients presenting exclusively lesions < 5 mm (12/31 vs 6/42, p = 0.02) but significance did not survive after correction for multiple comparisons. In addition, there was no significant association between headache and patients with WMLs
4.2. MRI vascular-like parenchymal changes WMLs have been repeatedly claimed to be very common among beta-thalassemia patients. However, most studies lacked of a control group making any relationship with the disease rather difficult to define. Premawardhena et al. found on conventional MRI a trend of increased WMLs in patients compared to controls (24% vs 7%; p = 0.07) that suggested a lack of significance merely due to sample size [1]. WMLs were significantly more common in headache patients, unveiling a possible causal relationship or, at least, to be both epiphenomena of the same pathological brain involvement. In the same Journal issue, we showed no difference in terms of WML prevalence-rate (47.5% vs 50%) and features (e.g. number, size, site) 3
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Table 2 Headache prevalence and characteristics, and correlation with WML. Controls 129 subjects
Beta-thalassemia patients 102 subjects Whole group
Headache Chronic headache Migraine Migraine without aura Migraine with aura Tension type Mixed
51 2 38 17 21 24 13
(39.5%) (1.6%) (29.5%) (13.2%) (16.3%) (18.6%) (10.1%)
39 4 28 20 8 23 14
16/39 (41.0%) 5/39 (12.8%) 16/39 (41.0%) 11/39 (28.2%)
(38.2%) (3.9%) (27.4%) (19.6%) (7.8%) (22.5%) (13.7%)
30 (39%)/9 (36%) 3 (3.9%)/1 (4.0%) 21 (27.3%)/7 (28%) 18 (23.4%)/2 (8%) 3 (3.9%)/5 (20%)° 19 (24.7%)/4 (16%) 10 (13%)/4 (16%)
Controls 100 subjects
Beta-thalassemia patients 73 subjects
Headache
Headache
Yes WML WML > 5 mm WML < 5 mm Only WML < 5 mm
TDT/NTDT (77/25)
No 27/61 10/61 25/61 17/61
(44.3%) (16.4%) (41.0%) (27.9%)
Yes
No
17/31 (54.8%) 5/31 (16.1%) 16/31 (51.6%) 12/31 (38.7%)
15/42 (35.7%) 9/42 (21.4%) 15/42 (35.7%) 6/42 (14.3%)
account that rarely moyamoya syndrome thalassemia cases are diagnosed in adults (4/18 cases in the literature) [7,8], and that headache in most cases has onset in early adulthood (mean-age close to 25 years), the relationship between these two conditions appears unlikely. Therefore, headache in adult thalassemia should not primarily raise the suspicion of moyamoya syndrome, even though anecdotal cases have been described [8]. Regarding intracranial aneurysms, a few of them were found in our sample [3]; however, their prevalence-rate did not differ between patients and healthy controls and, most importantly for the study purposes, aneurysms did not show any association with headache. In general, larger MR-angiography studies collated on different countries would hopefully help to understand possible treatment, environment or genetic factors that led to such a different prevalence rate between Musallam's and the two more recent and larger studies.
thus challenging, at least in our country, the hypothesis of an increased cerebrovascular vulnerability in beta-thalassemia (the high prevalence of WMLs was primarily attributable to the more powerful 3T MRscanner) [3]. The same patient and control samples underwent further very sensitive advanced semiquantitative and quantitative imaging analyses (magnetization transfer and diffusion tensor imaging) that confirmed the lack of even subtle signs of increased brain vascular-like involvement both in the whole sample of patients or in specific phenotypic subgroups (TDT or NTDT) [2]. Therefore, cerebrovascular vulnerability in beta-thalassemia seems to be partly country-related (i.e. due to environmental or treatment-related factors). Regarding headache, in our study the association with WMLs was not confirmed both among patients and controls (see Table 2). Considering WML size, headache was associated with patients presenting exclusively lesions < 5 mm (12/31 vs 6/42, p = 0.017) but this finding in the whole context is unclear (only one patient had exclusively WML > 5 mm and there was no significant association between headache and patients with any WML < 5 mm, 16/31 vs 15/42, p = 0.17). Notably, in all studies on beta-thalassemia patients, most WMLs were rather small. In the study by Premawardhena, 75% of patients harbored only lesions < 5 mm and 40% had a single small lesion thus downsizing the possible clinical role of these MRI abnormalities, even in spite of their association with headache.
4.4. Neuropsychiatric findings Compared to controls, beta-thalassemia adults repeatedly showed increased levels of depression and anxiety and lower cognitive performances, especially in the TDT phenotype [4,9,10]. The study by Premawardhena showed only a trend of lower cognitive performances that were unexpectedly worse in the NTDT and EBT subgroups, albeit comparisons among studies are arduous due to different testing (MoCA score vs WAIS or WAIS-subtests) or study populations. Regarding headache, in our beta-thalassemia patients we found no association with Brief Psychiatric Rating Scale scores, mainly determined by anxiety and depression scores, or full-scale Intelligence Quotient, thus corroborating the study by Premawardhena and confirming the unlikelihood of any causal relationship.
4.3. MR-angiography Musallam's et al. reported intracranial artery stenosis in about 1/4 and aneurysms in about 1/6 of splenectomized NTDT adults [6]. In contrast, Premawardhena et al. did not report vascular abnormalities among TDT and NTDT patients [1], thus confirming our experience regarding intracranial stenoses in beta-thalassemia [3]. These latter findings seem to discard possible associations between intracranial artery changes and headache and suggest that, among beta-thalassemia patients, intracranial artery stenoses and aneurysms are uncommon or absent, that patients do not differ from healthy controls and that, therefore, MR-angiography monitoring is unnecessary in beta-thalassemia, unless a specific country-related vulnerability has emerged. In addition, considering that our study and the study by Premawardhena collated intracranial artery evaluations of nearly 125 adult NTDT and TDT patients and no one showed intracranial stenosis, the occurrence of moyamoya syndrome appears to be relatively uncommon. Taking into
5. Conclusions As several factors might impact on the quality-of-life in beta-thalassemia, the exclusion in our study population of increased headache rate or severity might be of utmost importance for focusing on other disease-related aspects and attaining not only longer, but truly better, lives for our patients [11]. Future studies will help to understand whether a strict adherence of our patients to the current treatment guidelines of beta-thalassemia might be the clue for avoiding the increased headache prevalence-rate or the increased prevalence-rate of 4
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Validation, Writing - review & editing. Renzo Manara: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Supervision, Visualization, Writing - original draft, Writing - review & editing.
intracranial parenchymal and vascular changes reported in previous studies. Authorship contribution
Declaration of competing interest
RM and IT designed the study; RM, IT and MC analyzed the data and drafted the manuscript; all authors collected data, critically reviewed the draft and approved the final version. RM and IT take full responsibility for the content of the manuscript.
The authors declare that there is no conflict of interest. References
Funding [1] A. Premawardhena, U. Ranawaka, T. Pilapitiya, G. Weerasinghe, A. Hapangama, S. Hettiarachchi, A. Pathmeswaran, K. Salvin, I. Silva, N. Hameed, M. Weatherall, N. Olivieri, D. Weatherall, Headache: an important symptom possibly linked to white matter lesions in thalassaemia, Br. J. Haematol. 185 (2019) 541–548. [2] A.G. Russo, S. Ponticorvo, I. Tartaglione, M. Caiazza, D. Roberti, A. Elefante, M. Casale, R. Di Concilio, A. Ciancio, E. De Michele, A. Canna, M. Cirillo, S. Perrotta, F. Esposito, R. Manara, No increased cerebrovascular involvement in adult beta-thalassemia by advanced MRI analyses, Blood Cells Mol. Dis. 78 (2019) 9–13. [3] I. Tartaglione, C. Russo, A. Elefante, M. Caiazza, M. Casale, R. Di Concilio, A. Ciancio, E. De Michele, G. Amendola, P. Gritti, P.A. Carafa, T. Ferrantino, A. Centanni, N. Ippolito, V. Caserta, T. Oliveto, I. Granato, G. Femina, F. Esposito, S. Ponticorvo, A.G. Russo, A. Canna, M. Ermani, M. Cirillo, S. Perrotta, R. Manara, No evidence of increased cerebrovascular involvement in adult neurologicallyasymptomatic β-thalassaemia. A multicentre multimodal magnetic resonance study, Br. J. Haematol. 185 (2019) 733–742. [4] I. Tartaglione, R. Manara, M. Caiazza, P.A. Carafa, V. Caserta, T. Ferrantino, I. Granato, N. Ippolito, C. Maietta, T. Oliveto, M. Casale, R. Di Concilio, A. Ciancio, E. De Michele, C. Russo, A. Elefante, S. Ponticorvo, A.G. Russo, G. Femina, A. Canna, M. Ermani, M. Cirillo, F. Esposito, A. Centanni, P. Gritti, S. Perrotta, Brain functional impairment in beta-thalassaemia: the cognitive profile in Italian neurologically asymptomatic adult patients in comparison to the reported literature, Br. J. Haematol. (2019), https://doi.org/10.1111/bjh.15959. [5] T. Ferrante, P. Castellini, G. Abrignani, L. Latte, M. Russo, C. Camarda, L. Veronesi, C. Pasquarella, G.C. Manzoni, P. Torelli, The PACE study: past-year prevalence of migraine in Parma’s adult general population, Cephalalgia 32 (2012) 358–365. [6] K.M. Musallam, A. Beydoun, R. Hourani, W. Nasreddine, R. Raad, S. Koussa, A.T. Taher, Brain magnetic resonance angiography in splenectomized adults with βthalassemia intermedia, Eur. J. Haematol. 87 (2011) 539–546, https://doi.org/10. 1111/j.1600-0609.2011.01706.x. [7] S. Das, S. Dubey, M. Acharya, S. Chatterjee, D. Lahiri, G. Das, B.K. Ray, M. Kraemer, Thalassemia and Moyamoya syndrome: unfurling an intriguing association, J. Neurol. (2019), https://doi.org/10.1007/s00415-019-09497-5. [8] S. Akpınar, G. Yılmaz, E. Çelebioğlu, Cyclic headaches in β-thalassemia intermedia case presenting as moyamoya syndrome, Iran J Neurol 14 (2015) 110–112. [9] R. Monastero, G. Monastero, C. Ciaccio, A. Padovani, R. Camarda, Cognitive deficits in beta-thalassemia major, Acta Neurol. Scand. 102 (2000) 162–168. [10] M.S. Elalfy, R.H. Aly, H. Azzam, K. Aboelftouh, R.H. Shatla, M. Tarif, M. Abdatty, R.M. Elsayed, Neurocognitive dysfunction in children with β thalassemia major: psychometric, neurophysiologic and radiologic evaluation, Hematology 22 (2017) 617–622. [11] D. Rund, Cognition in thalassaemia: the next milestone, Br. J. Haematol. (2019), https://doi.org/10.1111/bjh.15956.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. CRediT authorship contribution statement Immacolata Tartaglione: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Visualization, Writing - original draft, Writing review & editing. Martina Caiazza: Data curation, Formal analysis, Investigation, Resources, Writing - original draft, Writing - review & editing. Rosanna Di Concilio: Data curation, Investigation, Resources, Writing - review & editing. Angela Ciancio: Data curation, Investigation, Resources, Writing - review & editing. Elisa De Michele: Data curation, Investigation, Resources, Writing - review & editing. Caterina Maietta: Data curation, Investigation, Resources, Writing review & editing. Maria Sole Valentino: Data curation, Investigation, Resources, Writing - review & editing. Camilla Russo: Data curation, Investigation, Resources, Writing - review & editing. Domenico Roberti: Data curation, Investigation, Resources, Writing - review & editing. Maddalena Casale: Data curation, Formal analysis, Investigation, Resources, Writing - original draft, Writing - review & editing. Andrea Elefante: Data curation, Investigation, Resources, Writing - review & editing. Gianluca Femina: Data curation, Investigation, Resources, Writing - review & editing. Fabrizio Esposito: Data curation, Investigation, Resources, Writing - review & editing. Sara Ponticorvo: Data curation, Investigation, Resources, Validation, Writing - review & editing. Andrea G. Russo: Data curation, Investigation, Resources, Writing - review & editing. Antonietta Canna: Data curation, Investigation, Resources, Writing - review & editing. Mario Ermani: Data curation, Investigation, Resources, Writing - review & editing. Mario Cirillo: Data curation, Formal analysis, Investigation, Resources, Writing - original draft, Writing - review & editing. Silverio Perrotta: Data curation, Investigation, Resources,
5
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Blood Cells, Molecules and Diseases journal homepage: www.elsevier.com/locate/bcmd
Headache in beta-thalassemia: An Italian multicenter clinical, conventional MRI and MR-angiography case-control study
T
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Immacolata Tartaglionea, , Martina Caiazzaa, Rosanna Di Conciliob, Angela Ciancioc, Elisa De Micheled, Caterina Maiettaa, Maria Sole Valentinoa, Camilla Russoe, Domenico Robertia, Maddalena Casalea, Andrea Elefantee, Gianluca Feminaf, Fabrizio Espositof, Sara Ponticorvof, Andrea G. Russof, Antonietta Cannaf, Mario Ermanig, Mario Cirilloh, Silverio Perrottaa, Renzo Manaraf Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Università degli studi della Campania “Luigi Vanvitelli”, Napoli, Italy Dipartimento di Pediatria, Ospedale “Umberto I”, Nocera Inferiore, Italy c Unità Operativa Ematologia - Day Hospital di Talassemia, Ospedale “Madonna delle Grazie”, Matera, Italy d Medicina Trasfusionale AUO “San Giovanni di Dio e Ruggi D'Aragona”, Salerno, Italy e Neuroradiologia, Università degli Studi di Napoli “Federico II”, Napoli, Italy f Dipartimento di Medicina e Chirurgia, Scuola Medica Salernitana, Sezione di Neuroscienze, Università di Salerno, Salerno, Italy g Dipartimento di Neuroscienze (DNS), Unità di Statistica e di Informatica, Scuola di Medicina, Università of Padova, Padova, Italy h Dipartimento di Scienze Mediche, Chirurgiche, Neurologiche, Metaboliche e dell'Invecchiamento, Università della Campania “Luigi Vanvitelli”, Napoli, Italy a
b
A R T I C LE I N FO
A B S T R A C T
Editor: Mohandas Narla
Objectives: A strikingly increased headache prevalence was recently noted in Sri Lankan beta-thalassemia patients, raising several concerns regarding long-term neurological involvement in this condition. Methods: We interviewed on headache occurrence and characteristics 102 Italian beta-thalassemia patients and 129 healthy controls. 3T-MRI, MR-angiography, MR-venography, cognitive and psychiatric findings were considered. Results: Headache was diagnosed in 39/102 (38.2%) beta-thalassemia patients without significant phenotyperelated differences and in 51/129 (39.5%) controls. Patients and controls did not differ significantly regarding episode number (5.9 ± 6.2 vs 5.4 ± 4.4 days/month), subjective severity-score (6.8 ± 1.4 vs 7.1 ± 1.3), age-at-onset (24.3 ± 13.0 vs 19.5 ± 9.6 years) and headache-subtype rate. No main demographic, clinical or laboratory data was associated with headache but female gender. Headache was not associated with white matter lesions (number or maximal diameter), intracranial aneurysms, intracranial artery stenoses or venous sinus thrombosis. Cognitive and psychiatric evaluations were worse in beta-thalassemia, however, headache did not correlate with full-scale Intelligence Quotient (75.4 ± 18.0 vs 76.7 ± 15.3, with and without headache, respectively) or Brief Psychiatric Rating Scale scores (29.1 ± 2.7 vs 28.5 ± 3.4). Conclusions: Among Italian beta-thalassemia patients, headache does not seem to be more common or severe than in the general population. In addition, patients with headache do not seem to present increased conventional MRI, MR-angiography and cognitive/psychiatric changes.
Keywords: Brain MRI MR-angiography Transfusions Anemia
1. Introduction Beta-thalassemia is a heterogeneous group of inherited disorders characterized by defective production of the beta chain of hemoglobin. In the last decades, its survival has dramatically improved due to advances in medical and/or surgical treatments (e.g. blood transfusions,
splenectomy, iron chelation treatments, etc.). In these patients, longterm neurological involvement is poorly known and it is still matter of concern. A recent study focused on headache and white matter lesions (WMLs) in Sri Lankan adults with beta-thalassemia [1]. This study provided interesting data on MRI, MR-angiography and cognitive findings in transfusion-dependent (TDT), non-transfusion dependent
⁎ Corresponding author at: Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Università degli studi della Campania “Luigi Vanvitelli”, Via L. De Crecchio 4, 80138 Napoli, NA, Italy. E-mail address: [email protected] (I. Tartaglione).
https://doi.org/10.1016/j.bcmd.2019.102403 Received 23 November 2019; Received in revised form 30 December 2019; Accepted 30 December 2019 Available online 31 December 2019 1079-9796/ © 2019 Published by Elsevier Inc.
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2.2. Clinical interview
(NTDT) and E-beta (EBT) thalassemia patients and added novel data on headache prevalence and on its possible relationship with MR findings. In particular, recurrent headache was observed in > 60% of patients, with significant differences according to the geno-phenotype, compared to < 25% of healthy age-matched controls, raising several concerns regarding long-term neurological involvement in this condition. Indeed, the etiology of headaches in thalassemia could be multifactorial, since beta thalassemia is a complex disease with multiorgan involvement. Heart and liver failure, endocrine glands dysfunction, anemia severity beside chelation therapy side effects are all factors that are each other intermingled and that could all, by themselves or in association, result in headache. As we also are studying brain involvement in a large Italian beta-thalassemia population [2–4], we investigated these aspects in our sample aiming at broadening the discussion among groups involved in beta-thalassemia management worldwide and at providing possible pathogenic clues of neurological involvement.
The interview investigated the mean number of episodes/month lasting > 4 h: headache was considered in subjects presenting at least 2 episodes/month. The interview also investigated the subjective mean severity-score (from 0 to 10, where 0 meant no pain and 10 meant pain as bad as it can be), the age-at-onset and the headache-subtype, focusing on migraine (with or without aura) and tension type headache according to the International Classification of Headache Disorders 3rd edition. The headache was considered mixed if the features encompassed both migraine and tension-type headache features. Chronic headache was diagnosed if the subject complained of headache ≥15 days/month for at least 3 months. The interview also investigated the presence of triggering events or conditions. 2.3. MRI and MR angiography Study participants underwent brain MRI on the same 3T MRI scanner (MAGNETOM Skyra, Siemens, Erlangen Germany) with a 20channel head coil.
2. Material and methods 2.1. Study population
2.4. The full MR study protocol included
We interviewed on headache and its characteristics 102 beta-thalassemia patients (mean-age 34.7 ± 11.0 years; 63/102 females; 77/ 102 TDT and 25/102 NTDT) followed at 4 Referral Centers for Beta Thalassemia in the South of Italy (Napoli, Salerno, Nocera Inferiore, Matera). Inclusion criteria were diagnosis of beta-thalassemia and age > 16 years; patients not on regular transfusions and never transfused in the last 48 weeks were classified as NTDT. We also interviewed 129 healthy controls (mean-age 31.1 ± 10.6 years; 82/129 females; Table 1); most of the subjects had participated as controls to previous studies and had MRI evaluation on the same 3T scanner (see below). The study was approved by the local Ethical Committee (Napoli Federico II; #161/15) and all subjects gave their written informed consent before study participation.
1) 3D fluid attenuated inversion recovery (FLAIR, TR/TE/TI 5000/ 387/1800 ms; voxel-size 1 × 1 × 1 mm; echo train length 278; field of view 230; acquisition-time 4 min 32 s); 2) 3D multi-slab Time of Flight MR angiography investigating the intracranial arteries (TR/TE 21/3.43 ms; voxel-size 0.6 ∗ 0.6 ∗ 0.7 mm; field of view 200 mm; number of slabs 120; number of partitions/slab 40; acquisition-time 3 min 34 s); 3) Phase contrast MR-venography covering all intracranial venous sinuses (TR/TE 80.55/10.6 ms; matrix 192 ∗ 192; slice thickness 1 mm; field of view 192 mm; velocity-encoding 8 cm/s; acquisitiontime 6 min 53 s). Axial, coronal and sagittal multiplanar reconstructions of the whole
Table 1 Baseline characteristics of study population. LIC: liver iron concentration; ICT: iron chelation therapy; DFO: deferoxamine; DFP: deferiprone; DFX: deferasirox; PLT: platelet; WBC: white blood cell; nRBC nucleated red blood cell; laboratory data collected as mean of last year's values; n.a.: not available/applicable. No comparison between subjects with and without headache was significant except for gender that showed a higher percentage of females in almost all headache subgroups (p = 0.01–0.03). Beta-thalassemia patients Whole sample (# = 102) Headache Age, years, range Female sex, # (%) Splenectomized, # (%) Mean hemoglobin, g/dL On aspirin, # (%) Ferritin, ng/mL LIC, mg/gdw History of thrombotic events CT, # (%) DFO DFP DFX DFX + DFO PLT (×103/μL) WBC (×103/μL) nRBC (×103/μL) FSIQ
Transfusion-dependent (# = 77)
Yes (# = 39) 33.5 ± 10.0 (15–49) 29 (74.3%) 19 (48.7%)
No (# = 63) 35.5 ± 11.6 (17–72) 34 (54.0%) 36 (57.1%)
Yes (# = 30) 34.5 ± 9.4 (15–49)
9.5 ± 0.9
Healthy controls Non-transfusion-dependent (# = 25)
(# = 129)
24 (80%) 16 (53.3%)
No (# = 47) 37.4 ± 10.9 (19–72) 25 (53.2%) 30 (63.8%)
Yes (# = 9) 30.1 ± 11.8 (16–49) 5 (55.5%) 3 (33.3%)
No (# = 16) 30.1 ± 11.9 (17–52) 9 (56.2%) 6 (37.5%)
Yes (# = 51) 31.0 ± 10.6 (17–65) 38 (74.5%) n.a.
No (# = 78) 31.1 ± 10.5 (18–66) 44 (56.4) n.a.
9.4 ± 0.8
9.2 ± 0.6
9.4 ± 0.8
9.6 ± 1.5
9.9 ± 0.9
n.a.
n.a.
12 (30.8%) 994.9 ± 851.9 4.1 ± 2.8 3 (7.7%)
27 (42.8%) 709.7 ± 595.0 4.9 ± 3.7 1 (1.6%)
9 (30%) 1130.1 ± 884.4 3.7 ± 2.5 3 (10%)
21 (44.7%) 824.2 ± 630.5 4.6 ± 3.0 1 (2.1%)
3 (33.3%) 348.2 ± 306.6 5.6 ± 3.8 0
6 (37.5%) 373.2 ± 287.1 6.5 ± 6.0 0
n.a. n.a. n.a. n.a.
n.a. n.a. n.a. n.a.
10 (25.6%) 0 21 (53.8%) 1 (2.6%) 432.8 ± 242.3 13.6 ± 22.9 15.6 ± 22.6 75.4 ± 18.0
7 (11.1%) 8 (12.7%) 36 (57.1%) 0 480.3 ± 282.9 13.3 ± 8.2 10.8 ± 19.2 76.7 ± 15.3
9 (30%) 0 20 (66.7%) 1 (3.3%) 444.3 ± 210.7 10.4 ± 7.4 16.3 ± 27.0 70.7 ± 17.1
6 (12.8%) 7 (14.9%) 32 (68.1%) 0 511.4 ± 269.7 13.7 ± 7.8 7.8 ± 11.0 76 ± 16.4
1 (11.1%) 0 1 (11.1%) 0 394.5 ± 340.5 24.3 ± 46.1 14.2 ± 11.1 86.3 ± 15.8
1 (6.2%) 0 4 (25%) 0 394.5 ± 340.5 12.1 ± 9.6 23.7 ± 36.0 78.6 ± 12.2
n.a. n.a. n.a. n.a. n.a. n.a. n.a. 98.4 ± 16.8
n.a. n.a. n.a. n.a. n.a. n.a. n.a. 102.7 ± 16.0
2
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brain were obtained from FLAIR (slice thickness 3 mm without interslice gap). Maximum intensity projections views were obtained in the three orthogonal axes (12 views each covering 180°) from artery MR angiography to allow the precise visualization of artery segments. Three orthogonal maximum intensity projections of the MR-venography were automatically produced by the scanner and used for evaluation. FLAIR imaging was available in 73 beta-thalassemia patients (meanage 33.9 ± 10.3 years; 44/73 females; 22/73 NTDT) and 100 controls (mean-age 29.4 ± 9.6 years; 65/100 females). Intracranial artery and venous sinus MR-angiography was available in 73 beta-thalassemia patients and in 47 controls (mean-age 34.6 ± 10.9 years; 31/47 females), who had participated to a multimodal MR study on beta-thalassemia [3] and completed the headache interview. White matter lesions (WML) were evaluated on FLAIR images. Lesion number and maximum diameter (< 0.5 cm or ≥0.5 cm) were also recorded; all MR-exams were evaluated by a neuroradiologist with 15-year experience on cerebrovascular diseases.
(p = 0.10) or with (but not exclusively) lesions < 5 mm (p = 0.17). No subject presented intracranial stenosis or sign of venous sinus thrombosis. As reported elsewhere, our beta-thalassemia had lower IQ and lower Brief Psychiatric Rating Scale scores than controls [2–4]. These findings were confirmed among those who participated to the clinical interview. However, among beta-thalassemia patients, headache was not associated with Brief Psychiatric Rating Scale scores, mainly determined by anxiety and depression scores (29.1 ± 2.7 vs 28.5 ± 3.4, with and without headache, respectively), or full-scale Intelligence Quotient (75.4 ± 18.0 vs 76.7 ± 15.3).
2.5. Neurocognitive findings
4.1. Headache in beta-thalassemia
Seventy-four patients and 39 controls had undergone the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) providing a global scale used to derive the Intelligence Quotient (IQ) and the Brief Psychiatric Rating Scale (BPRS), that measures psychiatric symptoms such as depression, anxiety and unusual behavior [2–4].
This study did not find headache differences (headache frequencyrate and features) between beta-thalassemia patients and controls or between different beta-thalassemia subgroups (i.e. TDT vs NTDT). Actually, our findings are in striking contrast with the sole study on headache in beta-thalassemia available so far, that revealed in Sri Lankan adults with beta-thalassemia a nearly three-time higher headache rate compared to healthy controls (61% vs 22.5%) [1]. The reasons for study discordance are unclear and likely encompass environmental, treatment and methodological issues. However, while headache prevalence in TDT subgroups was substantially confirmed (39% vs 48% in Premawardhena et al.), the rate in NTDT was strikingly different (36% vs 58.3%), thus minimizing the role of environmental factors (that would have affected also TDT patients) and pointing to countryrelated differences in NTDT management as likely explanation. Considering that among beta-thalassemia patients “low level of hemoglobin” was self-reported as the commonest triggering factor for headache episodes, differences in hemoglobin management via blood transfusions appear an intriguing explanation for the study differences, suggesting that full adherence to current transfusion guidelines might contribute in tempering the headache rate in beta-thalassemia. Additional reasons of headache rate differences certainly include the following facts: 1) our study did not include EBT patients (the subgroup showing the highest rate of headache in the study by Premawardhena) [1] since this form is not common in our country and 2) our controls had headache prevalence close to 40%, consistent with previous studies on the general population in our country [5]. In contrast, as noted by the authors themselves, the headache rate among their controls was much lower than reported in the same world region. As a consequence, the difference between patients and controls was partly amplified.
4. Discussion According to our study, headache does not seem to afflict betathalassemia patients more than the general population and patients with headache do not seem to present an increased rate of conventional MRI, MR-angiography and cognitive or psychiatric changes. The following paragraphs will address in details the main findings taking into account the scarce literature on the topics.
2.6. Statistical analysis t-Test and Mann–Whitney U test for continuous variables and Chi square and Fisher's exact tests for qualitative variables were applied to compare data between patients and controls; TDT and NTDT patients were then analyzed as subgroups. Statistical significance was set at p < 0.05 (two-tailed p values). 3. Results Headache was diagnosed in 38.2% beta-thalassemia patients without significant phenotype-related differences (39% TDT vs 36% NTDT, p = 0.79) and in 39.5% controls. Patients and controls did not differ significantly in terms of number of episodes (5.9 ± 6.2 vs 5.4 ± 4.4 days/month), subjective severity-score (6.8 ± 1.4 vs 7.1 ± 1.3), age-at-onset (24.3 ± 13.0 vs 19.5 ± 9.6 years) and headache-subtype rate (chronic headache: 4/102 vs 2/129, p = 0.41; migraine: 28/102 vs 38/129, p = 0.68; migraine without aura: 20/102 vs 17/129, p = 0.20; tension-type: 23/102 vs 24/129 p = 0.50; mixed headache: 14/102 vs 13/129, p = 0.42) except for migraine with aura that was nearly significantly less common in beta-thalassemia patients (8/102 vs 21/129, p = .055, uncorrected for multiple comparisons). Table 1 shows main demographic, clinical and laboratory data of our sample; no finding was associated with headache but female gender in all groups and subgroups except for NTDT. Triggering factors for headache were reported by 35/39 beta-thalassemia patients: low hemoglobin levels (26/39), treatments (9/39), blood transfusions (11/ 39), stress (5/39), menstruations (5/39). Among controls, 38/51 identified heterogeneous triggering factors: the most common were menstruations (9/51), stress (19/51), climatic changes (13/51). Table 2 reports WML detection rate according to number and maximal diameter and according to headache complain. No difference was found between patients and controls. Considering WML size, headache was associated with patients presenting exclusively lesions < 5 mm (12/31 vs 6/42, p = 0.02) but significance did not survive after correction for multiple comparisons. In addition, there was no significant association between headache and patients with WMLs
4.2. MRI vascular-like parenchymal changes WMLs have been repeatedly claimed to be very common among beta-thalassemia patients. However, most studies lacked of a control group making any relationship with the disease rather difficult to define. Premawardhena et al. found on conventional MRI a trend of increased WMLs in patients compared to controls (24% vs 7%; p = 0.07) that suggested a lack of significance merely due to sample size [1]. WMLs were significantly more common in headache patients, unveiling a possible causal relationship or, at least, to be both epiphenomena of the same pathological brain involvement. In the same Journal issue, we showed no difference in terms of WML prevalence-rate (47.5% vs 50%) and features (e.g. number, size, site) 3
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Table 2 Headache prevalence and characteristics, and correlation with WML. Controls 129 subjects
Beta-thalassemia patients 102 subjects Whole group
Headache Chronic headache Migraine Migraine without aura Migraine with aura Tension type Mixed
51 2 38 17 21 24 13
(39.5%) (1.6%) (29.5%) (13.2%) (16.3%) (18.6%) (10.1%)
39 4 28 20 8 23 14
16/39 (41.0%) 5/39 (12.8%) 16/39 (41.0%) 11/39 (28.2%)
(38.2%) (3.9%) (27.4%) (19.6%) (7.8%) (22.5%) (13.7%)
30 (39%)/9 (36%) 3 (3.9%)/1 (4.0%) 21 (27.3%)/7 (28%) 18 (23.4%)/2 (8%) 3 (3.9%)/5 (20%)° 19 (24.7%)/4 (16%) 10 (13%)/4 (16%)
Controls 100 subjects
Beta-thalassemia patients 73 subjects
Headache
Headache
Yes WML WML > 5 mm WML < 5 mm Only WML < 5 mm
TDT/NTDT (77/25)
No 27/61 10/61 25/61 17/61
(44.3%) (16.4%) (41.0%) (27.9%)
Yes
No
17/31 (54.8%) 5/31 (16.1%) 16/31 (51.6%) 12/31 (38.7%)
15/42 (35.7%) 9/42 (21.4%) 15/42 (35.7%) 6/42 (14.3%)
account that rarely moyamoya syndrome thalassemia cases are diagnosed in adults (4/18 cases in the literature) [7,8], and that headache in most cases has onset in early adulthood (mean-age close to 25 years), the relationship between these two conditions appears unlikely. Therefore, headache in adult thalassemia should not primarily raise the suspicion of moyamoya syndrome, even though anecdotal cases have been described [8]. Regarding intracranial aneurysms, a few of them were found in our sample [3]; however, their prevalence-rate did not differ between patients and healthy controls and, most importantly for the study purposes, aneurysms did not show any association with headache. In general, larger MR-angiography studies collated on different countries would hopefully help to understand possible treatment, environment or genetic factors that led to such a different prevalence rate between Musallam's and the two more recent and larger studies.
thus challenging, at least in our country, the hypothesis of an increased cerebrovascular vulnerability in beta-thalassemia (the high prevalence of WMLs was primarily attributable to the more powerful 3T MRscanner) [3]. The same patient and control samples underwent further very sensitive advanced semiquantitative and quantitative imaging analyses (magnetization transfer and diffusion tensor imaging) that confirmed the lack of even subtle signs of increased brain vascular-like involvement both in the whole sample of patients or in specific phenotypic subgroups (TDT or NTDT) [2]. Therefore, cerebrovascular vulnerability in beta-thalassemia seems to be partly country-related (i.e. due to environmental or treatment-related factors). Regarding headache, in our study the association with WMLs was not confirmed both among patients and controls (see Table 2). Considering WML size, headache was associated with patients presenting exclusively lesions < 5 mm (12/31 vs 6/42, p = 0.017) but this finding in the whole context is unclear (only one patient had exclusively WML > 5 mm and there was no significant association between headache and patients with any WML < 5 mm, 16/31 vs 15/42, p = 0.17). Notably, in all studies on beta-thalassemia patients, most WMLs were rather small. In the study by Premawardhena, 75% of patients harbored only lesions < 5 mm and 40% had a single small lesion thus downsizing the possible clinical role of these MRI abnormalities, even in spite of their association with headache.
4.4. Neuropsychiatric findings Compared to controls, beta-thalassemia adults repeatedly showed increased levels of depression and anxiety and lower cognitive performances, especially in the TDT phenotype [4,9,10]. The study by Premawardhena showed only a trend of lower cognitive performances that were unexpectedly worse in the NTDT and EBT subgroups, albeit comparisons among studies are arduous due to different testing (MoCA score vs WAIS or WAIS-subtests) or study populations. Regarding headache, in our beta-thalassemia patients we found no association with Brief Psychiatric Rating Scale scores, mainly determined by anxiety and depression scores, or full-scale Intelligence Quotient, thus corroborating the study by Premawardhena and confirming the unlikelihood of any causal relationship.
4.3. MR-angiography Musallam's et al. reported intracranial artery stenosis in about 1/4 and aneurysms in about 1/6 of splenectomized NTDT adults [6]. In contrast, Premawardhena et al. did not report vascular abnormalities among TDT and NTDT patients [1], thus confirming our experience regarding intracranial stenoses in beta-thalassemia [3]. These latter findings seem to discard possible associations between intracranial artery changes and headache and suggest that, among beta-thalassemia patients, intracranial artery stenoses and aneurysms are uncommon or absent, that patients do not differ from healthy controls and that, therefore, MR-angiography monitoring is unnecessary in beta-thalassemia, unless a specific country-related vulnerability has emerged. In addition, considering that our study and the study by Premawardhena collated intracranial artery evaluations of nearly 125 adult NTDT and TDT patients and no one showed intracranial stenosis, the occurrence of moyamoya syndrome appears to be relatively uncommon. Taking into
5. Conclusions As several factors might impact on the quality-of-life in beta-thalassemia, the exclusion in our study population of increased headache rate or severity might be of utmost importance for focusing on other disease-related aspects and attaining not only longer, but truly better, lives for our patients [11]. Future studies will help to understand whether a strict adherence of our patients to the current treatment guidelines of beta-thalassemia might be the clue for avoiding the increased headache prevalence-rate or the increased prevalence-rate of 4
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Validation, Writing - review & editing. Renzo Manara: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Supervision, Visualization, Writing - original draft, Writing - review & editing.
intracranial parenchymal and vascular changes reported in previous studies. Authorship contribution
Declaration of competing interest
RM and IT designed the study; RM, IT and MC analyzed the data and drafted the manuscript; all authors collected data, critically reviewed the draft and approved the final version. RM and IT take full responsibility for the content of the manuscript.
The authors declare that there is no conflict of interest. References
Funding [1] A. Premawardhena, U. Ranawaka, T. Pilapitiya, G. Weerasinghe, A. Hapangama, S. Hettiarachchi, A. Pathmeswaran, K. Salvin, I. Silva, N. Hameed, M. Weatherall, N. Olivieri, D. Weatherall, Headache: an important symptom possibly linked to white matter lesions in thalassaemia, Br. J. Haematol. 185 (2019) 541–548. [2] A.G. Russo, S. Ponticorvo, I. Tartaglione, M. Caiazza, D. Roberti, A. Elefante, M. Casale, R. Di Concilio, A. Ciancio, E. De Michele, A. Canna, M. Cirillo, S. Perrotta, F. Esposito, R. Manara, No increased cerebrovascular involvement in adult beta-thalassemia by advanced MRI analyses, Blood Cells Mol. Dis. 78 (2019) 9–13. [3] I. Tartaglione, C. Russo, A. Elefante, M. Caiazza, M. Casale, R. Di Concilio, A. Ciancio, E. De Michele, G. Amendola, P. Gritti, P.A. Carafa, T. Ferrantino, A. Centanni, N. Ippolito, V. Caserta, T. Oliveto, I. Granato, G. Femina, F. Esposito, S. Ponticorvo, A.G. Russo, A. Canna, M. Ermani, M. Cirillo, S. Perrotta, R. Manara, No evidence of increased cerebrovascular involvement in adult neurologicallyasymptomatic β-thalassaemia. A multicentre multimodal magnetic resonance study, Br. J. Haematol. 185 (2019) 733–742. [4] I. Tartaglione, R. Manara, M. Caiazza, P.A. Carafa, V. Caserta, T. Ferrantino, I. Granato, N. Ippolito, C. Maietta, T. Oliveto, M. Casale, R. Di Concilio, A. Ciancio, E. De Michele, C. Russo, A. Elefante, S. Ponticorvo, A.G. Russo, G. Femina, A. Canna, M. Ermani, M. Cirillo, F. Esposito, A. Centanni, P. Gritti, S. Perrotta, Brain functional impairment in beta-thalassaemia: the cognitive profile in Italian neurologically asymptomatic adult patients in comparison to the reported literature, Br. J. Haematol. (2019), https://doi.org/10.1111/bjh.15959. [5] T. Ferrante, P. Castellini, G. Abrignani, L. Latte, M. Russo, C. Camarda, L. Veronesi, C. Pasquarella, G.C. Manzoni, P. Torelli, The PACE study: past-year prevalence of migraine in Parma’s adult general population, Cephalalgia 32 (2012) 358–365. [6] K.M. Musallam, A. Beydoun, R. Hourani, W. Nasreddine, R. Raad, S. Koussa, A.T. Taher, Brain magnetic resonance angiography in splenectomized adults with βthalassemia intermedia, Eur. J. Haematol. 87 (2011) 539–546, https://doi.org/10. 1111/j.1600-0609.2011.01706.x. [7] S. Das, S. Dubey, M. Acharya, S. Chatterjee, D. Lahiri, G. Das, B.K. Ray, M. Kraemer, Thalassemia and Moyamoya syndrome: unfurling an intriguing association, J. Neurol. (2019), https://doi.org/10.1007/s00415-019-09497-5. [8] S. Akpınar, G. Yılmaz, E. Çelebioğlu, Cyclic headaches in β-thalassemia intermedia case presenting as moyamoya syndrome, Iran J Neurol 14 (2015) 110–112. [9] R. Monastero, G. Monastero, C. Ciaccio, A. Padovani, R. Camarda, Cognitive deficits in beta-thalassemia major, Acta Neurol. Scand. 102 (2000) 162–168. [10] M.S. Elalfy, R.H. Aly, H. Azzam, K. Aboelftouh, R.H. Shatla, M. Tarif, M. Abdatty, R.M. Elsayed, Neurocognitive dysfunction in children with β thalassemia major: psychometric, neurophysiologic and radiologic evaluation, Hematology 22 (2017) 617–622. [11] D. Rund, Cognition in thalassaemia: the next milestone, Br. J. Haematol. (2019), https://doi.org/10.1111/bjh.15956.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. CRediT authorship contribution statement Immacolata Tartaglione: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Visualization, Writing - original draft, Writing review & editing. Martina Caiazza: Data curation, Formal analysis, Investigation, Resources, Writing - original draft, Writing - review & editing. Rosanna Di Concilio: Data curation, Investigation, Resources, Writing - review & editing. Angela Ciancio: Data curation, Investigation, Resources, Writing - review & editing. Elisa De Michele: Data curation, Investigation, Resources, Writing - review & editing. Caterina Maietta: Data curation, Investigation, Resources, Writing review & editing. Maria Sole Valentino: Data curation, Investigation, Resources, Writing - review & editing. Camilla Russo: Data curation, Investigation, Resources, Writing - review & editing. Domenico Roberti: Data curation, Investigation, Resources, Writing - review & editing. Maddalena Casale: Data curation, Formal analysis, Investigation, Resources, Writing - original draft, Writing - review & editing. Andrea Elefante: Data curation, Investigation, Resources, Writing - review & editing. Gianluca Femina: Data curation, Investigation, Resources, Writing - review & editing. Fabrizio Esposito: Data curation, Investigation, Resources, Writing - review & editing. Sara Ponticorvo: Data curation, Investigation, Resources, Validation, Writing - review & editing. Andrea G. Russo: Data curation, Investigation, Resources, Writing - review & editing. Antonietta Canna: Data curation, Investigation, Resources, Writing - review & editing. Mario Ermani: Data curation, Investigation, Resources, Writing - review & editing. Mario Cirillo: Data curation, Formal analysis, Investigation, Resources, Writing - original draft, Writing - review & editing. Silverio Perrotta: Data curation, Investigation, Resources,
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