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J Headache Pain. 2010 June; 11(3): 181–186.
Published online 2010 March 12. doi:  10.1007/s10194-010-0203-6
PMCID: PMC3451909

Diagnostic criteria for CADASIL in the International Classification of Headache Disorders (ICHD-II): are they appropriate?


We reviewed the characteristics of headache in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), to verify the appropriateness of the International Classification of Headache Disorders, second edition (ICHD-II) criteria. Available data were found through Medline/PubMed using the keyword “cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)”. The search was restricted to studies published in English in the years between 1993 and 2008. We excluded studies that did not report original data on CADASIL and information regarding the presence of headache. We found 34 studies reporting data on 749 patients overall; 387 (51.7%) patients had headache. According to the authors’ definition, 356 (92%) patients were reported as having migraine and 31 (8%) as having headache. Of the 356 patients who were defined as migraineurs, 125 (35.1%) had migraine with aura, 7 (2%) migraine without aura, 156 (43.8%) unspecified migraine and 68 (19.1%) had more than one type of migraine. Among the 31 patients reported as suffering from headache, the headache was not further detailed in 18 (58.1%) patients; it was defined as chronic in 6 (19.3%), as resembling migraine with aura in 4 (12.9%), as resembling migraine without aura in 2 (6.5%) and as tension type in 1 (3.2%) patient. In patients with CADASIL, the headache was usually referred to as migraine and mostly as migraine with aura. However, this referral is formally incorrect since the diagnostic criteria for any type of migraine in the ICHD-II require that the disturbance is not attributed to another disorder. For this reason, we suggest updating the ICHD-II in relation to CADASIL. Our suggestion is to insert a new category referred to as Headache attributed to genetic disorder including Headache attributed to CADASIL.

Keywords: Migraine, Headache, CADASIL, International Classification of Headache Disorders

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Selected References

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1. Chabriat H, Vahedi K, Iba-Zizen MT, Joutel A, Nibbio A, Nagy TG, Krebs MO, Julien J, Dubois B, Ducrocq X, Levasseur M, Homeyer P, Mas JL, Lyon-Caen O, Tournier Lasserve E, Bousser MG. Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lancet. 1995;346:934–939. doi: 10.1016/S0140-6736(95)91557-5. [PubMed] [Cross Ref]
2. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cécillion M, Marechai E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier–Lasserve E. Notch 3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996;383:707–710. doi: 10.1038/383707a0. [PubMed] [Cross Ref]
3. Sacco S, Olivieri L, Bastianello S, Carolei A. Comorbid neuropathologies in migraine. J Headache Pain. 2006;7:222–230. doi: 10.1007/s10194-006-0300-8. [PMC free article] [PubMed] [Cross Ref]
4. Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. CADASIL. Lancet Neurol. 2009;8:643–653. doi: 10.1016/S1474-4422(09)70127-9. [PubMed] [Cross Ref]
5. Vahedi K, Chabriat H, Levy C, Joutel A, Tournier-Lasserve E, Bousser MG. Migraine with aura and brain magnetic resonance imaging abnormalities in patients with CADASIL. Arch Neurol. 2004;61:1237–1240. doi: 10.1001/archneur.61.8.1237. [PubMed] [Cross Ref]
6. Schon F, Martin RJ, Prevett M, Clough C, Enevoldson TP, Markus HS. “CADASIL coma”: an underdiagnosed acute encephalopathy. J Neurol Neurosurg Psychiatry. 2003;74:249–252. doi: 10.1136/jnnp.74.2.249. [PMC free article] [PubMed] [Cross Ref]
7. Valko PO, Siccoli MM, Schiller A, Wieser HG, Jung HH. Non-convulsive status epilepticus causing focal neurological deficits in CADASIL. J Neurol Neurosurg Psychiatry. 2007;78:1287–1289. doi: 10.1136/jnnp.2007.124800. [PMC free article] [PubMed] [Cross Ref]
8. Headache Classification Committee of the International Headache Society Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia. 1988;8:1–96. doi: 10.1046/j.1468-2982.1988.0801001.x. [PubMed] [Cross Ref]
9. Headache Classification Subcommittee of the International Headache Society The international headache classification of headache disorders, 2nd edn. Cephalalgia. 2004;24(Suppl 1):9–160. [PubMed]
10. Sacco S, Carolei A. Migraine attributed to genetic disorder. Funct Neurol. 2007;22:117–118. [PubMed]
11. Arboleda-Velasquez JF, Lopera F, Lopez E, Frosch MP, Sepulveda-Falla D, Gutierrez JE, Vargas S, Medina M, Martinez de Arrieta C, Lebo RV, Slaugenhaupt SA, Betensky RA, Villegas A, Arcos-Burgos M, Rivera D, Restrepo JC, Kosik KS. C455R notc3 mutation in a Colombian CADASIL kindred with early onset of stroke. Neurology. 2002;59:277–279. [PubMed]
12. Bergman M, Ebke M, Yuan Y, Brück W, Mugler M, Schwendemann G. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): a morphological study of a German family. Acta Neuropathol. 1996;92:341–350. doi: 10.1007/s004010050528. [PubMed] [Cross Ref]
13. Bohlega S, Al Shubili A, Alreshaid A, Alkhairallah T, AlSous MW, Farah S, Abu-Amero KK. CADASIL in Arabs: clinical and genetic findings. BMC Med Genet. 2007;8:67. doi: 10.1186/1471-2350-8-67. [PMC free article] [PubMed] [Cross Ref]
14. Brulin P, Godfraind C, Leteurtre E, Ruchoux MM. Morphometric analysis of ultrastructural vascular changes in CADASIL: analysis of 50 skin biopsy specimens and pathogenetic implications. Acta Neuropathol. 2002;104:241–248. [PubMed]
15. Ceroni M, Poloni TE, Tonietti S, Fabozzi D, Uggetti C, Frediani F, Simonetti F, Malaspina A, Alimonti D, Celano M, Ferrari M, Carrera P. Migraine with aura and white matter abnormalities: Notch3 mutation. Neurology. 2000;54:1869–1871. [PubMed]
16. Choi JC, Kang SY, Kang JH, Park JK. Intracerebral hemorrhages in CADASIL. Neurology. 2006;67:2042–2044. doi: 10.1212/01.wnl.0000246601.70918.06. [PubMed] [Cross Ref]
17. Coto E, Menéndez M, Navarro R, Garcia-Castro M, Alvarez V. A new de novo Notch3 mutation causing CADASIL. Eur J Neurol. 2006;13:628–631. doi: 10.1111/j.1468-1331.2006.01337.x. [PubMed] [Cross Ref]
18. Dichgans M, Mayer M, Uttner I, Brüning R, Müller-Höcker J, Rungger G, Ebke M, Klockgether T, Gasser T. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol. 1998;44:731–739. doi: 10.1002/ana.410440506. [PubMed] [Cross Ref]
19. Engelter ST, Rueegg S, Kirsch EC, Fluri F, Probst A, Steck AJ, Lyrer PA. CADASIL mimicking primary angiitis of the central nervous system. Arch Neurol. 2002;59:1480–1483. doi: 10.1001/archneur.59.9.1480. [PubMed] [Cross Ref]
20. Finnilä S, Tuisku S, Herva R. A novel mitochondrial DNA mutation and a mutation in the Notch3 gene in a patient with myopathy and CADASIL. J Mol Med. 2001;79:641–647. doi: 10.1007/s001090100268. [PubMed] [Cross Ref]
21. Hutchinson M, O’Riordan J, Javed M, Quin E, Macerlaine D, Wilcox T, Parfrey N, Nagy TG, Tournier-Lasserve E. Familial hemiplegic migraine and autosomal dominant arteriopathy with leukoencephalopathy (CADASIL) Ann Neurol. 1995;38:817–824. doi: 10.1002/ana.410380517. [PubMed] [Cross Ref]
22. Iwatsuki K, Murakami T, Manabe Y, Narai H, Warita H, Hayashi T, Abe K. Two cases of Japanese CADASIL with corpus callosum lesion. Tohoku J Exp Med. 2001;195:135–140. doi: 10.1620/tjem.195.135. [PubMed] [Cross Ref]
23. Jung H, Bassetti C, Tournier-Lasserve E, Vahedi K, Arnaboldi M, Arifi VB, Burgunder JM. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a clinicopathological and genetic study of a Swiss family. J Neurol Neurosurg Psychiatry. 1995;59:138–143. doi: 10.1136/jnnp.59.2.138. [PMC free article] [PubMed] [Cross Ref]
24. Kim Y, Kim JS, Kim G, No YJ, Yoo HW. Two novel mutations of the NOTCH3 gene in Korean patients with CADASIL. Mutat Res. 2006;593:116–120. [PubMed]
25. Lesnik Oberstein SA, Boom R, Middelkoop HA, Ferrari MD, Knaap YM, Houwelingen HC, Breuning MH, Buchem MA, Haan J. Incipient CADASIL. Arch Neurol. 2003;60:707–712. doi: 10.1001/archneur.60.5.707. [PubMed] [Cross Ref]
26. Malandrini A, Carrera P, Palmeri S, Cavallaro T, Fabrizi GM, Villanova M, Fattaposta M, Vismara L, Brancolini V, Tanganelli P, Calì A, Morocutti C, Zeviani M, Ferrari M, Guazzi GC. Clinicopathological and genetic studies of two further Italian families with cerebral autosomal dominant arteriopathy. Acta Neuropathol. 1996;92:115–122. doi: 10.1007/s004010050498. [PubMed] [Cross Ref]
27. Mandellos D, Limbitaki G, Papadimitriou A, Anastasopoulos D. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in a Greek family. Neurol Sci. 2005;26:278–281. doi: 10.1007/s10072-005-0472-z. [PubMed] [Cross Ref]
28. Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH, Powell JF. Diagnostic strategies in CADASIL. Neurology. 2002;59:1134–1138. [PubMed]
29. Mellies JK, Bäumer T, Müller JA, Tournier-Lasserve E, Chabriat H, Knobloch O, Hackelöer HJ, Goebel HH, Wetzig L, Haller P. SPECT study of a German CADASIL family. Neurology. 1998;50:1715–1721. [PubMed]
30. Pantoni L, Sarti C, Pescini F, Bianchi S, Bartolini L, Nencini P, Basile AM, Lamassa M, Kalaria RN, Dotti MT, Federico A, Inzitari D. Thrombophilic risk factors and unusual clinical features in three Italian CADASIL patients. Eur J Neurol. 2004;11:782–787. doi: 10.1111/j.1468-1331.2004.00915.x. [PubMed] [Cross Ref]
31. Peters N, Herzog J, Opherk C, Dichgans M. A two-year clinical follow-up study in 80 CADASIL subjects: progression patterns and implications for clinical trials. Stroke. 2004;35:1603–1608. doi: 10.1161/01.STR.0000131546.71733.f1. [PubMed] [Cross Ref]
32. Ragno M, Fabrizi GM, Cacchiò G, Scarcella M, Sirocchi G, Selvaggio F, Taioli F, Ferrarini M, Trojano L. Two novel Italian CADASIL families from Central Italy with mutation CGC-TGC at codon 1006 in the exon 19 Notch3 gene. Neurol Sci. 2006;27:252–256. doi: 10.1007/s10072-006-0679-7. [PubMed] [Cross Ref]
33. Razvi SSM, Davidson R, Bone I, Muir KW. Is inadequate family history a barrier to diagnosis in CADASIL? Acta Neurol Scand. 2005;112:323–326. doi: 10.1111/j.1600-0404.2005.00495.x. [PubMed] [Cross Ref]
34. Rubio A, Rifkin D, Powers JM, Patel U, Stewart J, Faust P, Goldman JE, Mohr JP, Numaguchi Y, Jensen K. Phenotypic variability of CADASIL and novel morphologic findings. Acta Neuropathol. 1997;94:247–254. doi: 10.1007/s004010050700. [PubMed] [Cross Ref]
35. Rufa A, Stefano N, Dotti MT, Bianchi S, Sicurelli F, Stromillo ML, D’Aniello B, Federico A. Acute unilateral visual loss as the first symptom of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Arch Neurol. 2004;61:577–580. doi: 10.1001/archneur.61.4.577. [PubMed] [Cross Ref]
36. Sacco S, Rasura M, Cao M, Bozzao A, Carolei A. CADASIL presenting as status migrainosus and persisting aura without infarction. J Headache Pain. 2009;10:51–53. doi: 10.1007/s10194-008-0079-x. [PMC free article] [PubMed] [Cross Ref]
37. Singhal S, Rich P, Markus HS. The spatial distribution of MR imaging abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and their relationship to age and clinical features. Am J Neuroradiol. 2005;26:2481–2487. [PubMed]
38. Sullivan AA, Teh BT, Jeavons S, Schalling M, Silburn P, Larsson C, Boyle R. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. J Clin Neurosci. 1997;4:176–180. doi: 10.1016/S0967-5868(97)90070-9. [PubMed] [Cross Ref]
39. Vérin M, Rolland Y, Landgraf F, Chabriat H, Bompais B, Michel A, Vahedi K, Martinet JP, Tournier-Lasserve E, Lemaitre MH, Edan G. New phenotype of the cerebral autosomal dominant arteriopathy mapped to chromosome 19: migraine as the prominent clinical feature. J Neurol Neurosurg Psychiatry. 1995;59:579–585. doi: 10.1136/jnnp.59.6.579. [PMC free article] [PubMed] [Cross Ref]
40. Williamson EE, Chukwudelunzu FE, Meschia JF, Witte RJ, Dickson DW, Cohen MD. Distinguishing primary angiitis of the central nervous system from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Arthritis Rheum. 1999;42:2243–2248. doi: 10.1002/1529-0131(199910)42:10<2243::AID-ANR30>3.0.CO;2-D. [PubMed] [Cross Ref]
41. Dichgans M. CADASIL: a monogenic condition causing stroke and subcortical vascular dementia. Cerebrovasc Dis. 2002;13:37–41. doi: 10.1159/000049148. [PubMed] [Cross Ref]

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