Neuroimaging for Migraine: The AHS Evidence-Based Guideline

Table 1. Characteristics of Included Studies
Authors and Year of Publication	Study Location	Sample Size	Age (As Reported in Manuscript)	Sex (n [%] Female)	Imaging Outcome Measures
Akpek et al (1995)²⁴	Ankare, Turkey	592	Mean: 44.3, range: 8–88	416 (70.3%)	Normal findings, minor pathologies, or gross intracranial pathology on CT
Cala and Mastaglia (1980)¹⁸	Perth, Australia	94	Not specified	Not specified	Presence of discrete lesions and their anatomical location on CT
Clarke et al (2010)⁴³	Birmingham, England	530 undergoing imaging out of 3655 total headache patients	Mean: 42 (of 3655 total patients)	69% (of 3655 total patients)	Normal, insignificant abnormality, or significant abnormality on CT or MRI
Cooney et al (1996)³¹	Philadelphia, USA	185	Median: 38, range: 15–83	145 (78.4%)	Frequency of white matter abnormalities and association of white matter abnormalities with age, sex, migraine type, duration of symptoms, and the presence or absence of concomitant medical risk factors on MRI
Cuetter and Aita (1983)²¹	USA	435	Range: 17–52	Not specified	Results of head CT scans
Cull (1995)⁴¹	Scotland and Holland	69	Mean (SD): 51.6 (8.9), range: 40–79	46 (66.7%)	Frequency of abnormalities on CT or MRI
Gozke et al (2004)³²	Istanbul, Turkey	45	Mean (SD): 40.91 (7.69), range: 19–53	43 (95.5%)	Frequency of abnormalities on cranial MRI and their relationship to age, type of migraine, frequency of attacks, and duration of symptoms
Honningsvag et al (2016)³³	Nord-Trondelag county, Norway	864	Mean (SD): 58.5 (4.2), range: 50–66	452 (52.3%)	Intracranial abnormalities on MRI
Hungerford et al (1976)¹⁹	London, UK	53	mean: 42.7	36 (67.9%)	Abnormalities including atrophy or infarcts on CT
Jacome and Leborgne (1990)³⁹	Florida, USA	18	Mean: 30, range: 17–57	14 (77.7%)	Abnormalities on MRI and CT
Kahn et al (1993)²⁵	Chicago, USA and Winnipeg, Canada	1111	Chicago women: mean: 46.6, range: 18–100	Chicago group: 587 (68.3%)	Abnormal findings including chronic, acute and extracranial findings on CT
			Chicago men: mean: 45.8, range: 18–93	Winnipeg group: not specified
			Winnipeg group: not specified
Kuhn and Shekar (1990)⁴²	Illinois, USA	74	Mean: 28, range: 9–39	59 (79.7%)	Abnormalities on MRI or CT
Masland et al (1978)²⁷	Arizona, USA	136	Not specified	Not specified	Abnormalities on CT
Mathew et al (1977)²³	Houston, USA	29	For those with abnormal CT scans (10/29): mean: 34.9, range: 18–50	23 (79.3%)	Abnormalities including ventricular enlargement or low density areas on CT
Mullally and Hall (2018)³⁸	Boston, USA	100	Mean: 31.5, range: 18–56	86 (86.0%)	Prevalence of incidental brain abnormalities on MRI
Osborn et al (1991)³⁴	San Diego, USA	41	Mean: 29.8, range: 18–66	17 (41.5%)	White matter abnormalities on MRI
Paemelaire et al (2005)⁴⁷	Ghent, Belgium	244 total; 80 with definitive migraine diagnosis	Total: mean (SD): 38 (14)	Total: 171 (70%)	Frequency of abnormalities on MRA of circle of Willis
			Migraine with aura: male: 35 (10) female: 34 (11)	Migraine with aura: 10 (59%)
			Migraine without aura: male: 44 (13) female: 35 (14)	Migraine without aura: 52 (83.0%)
Prager and Rosenblum (1991)³⁵	Chicago, USA	99	Mean: 40, range: 16–78	72 (72.7%)	White matter abnormalities on MRI and association with diagnosis, age, sex, and length of headache history or history of ergot use
Sargent et al (1979)²⁶	Topeka, USA	177	Range: 16–60	138 (78.0%)	Abnormalities on CT and association with age
Soges et al (1988)³⁶	Syracuse, USA	24	Mean: 36.8, range: 18–55	16 (66.7%)	Abnormalities on MRI
Valenca et al (2002)²⁸	Recife, Brazil	78	Not specified	Not specified	Frequency of abnormalities on CT
Wang et al (2001)³⁷	New York, USA	402	Range: 18–85	286 (71.1%)	Major abnormalities on MRI
Wang et al (2019)⁴⁰	China	1070 patients with primary headache; 1070 healthy controls	Headache: mean (SD): 40.1 (12.3)	Headache: 725 (67.8%)	Significant or non-significant abnormalities or normal on CT or MRI
Wang et al (2019)⁴⁰	China	1070 patients with primary headache; 1070 healthy controls	Controls: 40.2 (12.5)	Controls: 725 (67.8%)

Table 2. Studies Using CT Only for Evaluation
Study	Subjects	Results	Conclusions
Cala and Mastaglia¹⁸	94 subjects with migraine presenting with acute changes in headache pattern or focal neurological abnormalities	The majority of scans (69/94, 73%) were normal, but 2 were found to have unsuspected masses likely to be glioma. Other significant abnormalities included cerebral infarcts (6/94, 6%), and periventricular edema (transependymal cerebrospinal fluid flow or microangiopathy) (6/94, 6%)	CT is a useful screening test for patients with a change in symptoms or new exam findings
Mathew et al²³	29 total: 4 with hemiplegic migraine, 5 vertebrobasilar migraine, 11 migraine without aura, 9 migraine with aura. Many of the subjects had concerning signs or symptoms such as weakness, memory loss, ataxia, confusion, anxiety or tremor	Most of the patients (19/29, 66%) had normal CT scans. Abnormalities included 4 subjects with ventricular enlargement, in which 2 had associated parenchymal low density areas. Six patients had 1 or more areas of low density. In 3 patients these low-density abnormalities resolved 3 months later	The authors suggested these CT abnormalities represented edema from blood-brain barrier alterations rather than infarction
Cuetter and Aita²¹	435 subjects	Only 1 patient had a significant CT exam abnormality – showing a choroid plexus papilloma of the 4th ventricle. After surgery, there was no change in headache pattern	CT scanning provided "little diagnostic value in patients with classic migraine"
Akpek et al²⁴	592 subjects	40 (8%) had minor abnormalities: including: 16 with cerebral or cerebellar atrophy, 12 with chronic ischemia, 9 with possible pseudotumor cerebri, 3 with venous angioma, 2 with empty sella, 2 with ventricular asymmetry, 1 with basal ganglia calcifications, and 1 with a subcutaneous fibroma. No subject had major abnormalities	Patients with chronic headache and a normal exam do not need urgent imaging
Kahn et al²⁵	1111 subjects	10.8% were abnormal. Abnormalities included: acute infarction (44, 4.0%), primary neoplasm 18, (1.6%), subarachnoid hemorrhage 14 (1.3%), subdural hematoma 12 (1.1%), metastatic neoplasm 12 (1.1%), vascular abnormalities such as aneurysm or AVM 11 (1.0%), hydrocephalus 9 (0.8%). Extracranial abnormalities included sinusitis or skull metastasis	CT scans are most useful for identifying serious causes of headache in those with risk factors such as thunderclap headache, abnormal exams, old age, elderly, fever, neurological exam changes and seizure
Masland et al²⁷	136 subjects	19 (14%) had abnormalities including: 14 with cerebral atrophy, 2 with evidence of small infarcts, 1 with AVM, 1 with astrocytoma, 1 with meningioma, and 1 had a saccular aneurysm of the anterior communicating artery. CT scans did not show abnormalities during migraine attacks, including 2 patients with complicated migraine. The 2 patients with severe intracranial pathology also had recent clinical changes including progressive hemiparesis and focal seizure	CT during migraine and in those with uncomplicated migraine is unlikely to change management. However, CT is effective in detecting significant neurologic disease in patients with new clinical changes
Hungerford et al¹⁹	53 subjects	Almost ½ of subjects (25/53, 47%) had abnormalities on imaging, including 6 with generalized atrophy, 8 with focal atrophy, 6 with infarcts and 5 with other abnormalities. Of the 13 patients with "permanent neurological sequelae," 11 had CT abnormalities	In retrospect, some of these patients likely had secondary causes of headache such as stroke or reversible cerebral vasoconstriction syndrome
Sargent et al²⁶	138 patients with headache, 82 with migraine	Of the patients with migraine, 20 of 82 had an abnormality such as generalized or focal atrophy	The average age of migraine patients with an abnormal CT was 42.29 years compared to 33.33 years with a normal CT (P < .001) suggesting age is a risk factor for CT abnormalities
Valenca et al²⁸	78 subjects: 34 with migraine, 35 with tension-type, and 9 with both disorders	While many subjects had abnormal CT findings (38.5%), most were considered incidental. Abnormalities included inflammatory sinus disease (19.2%), cysticercosis (3.9%), unruptured cerebral aneurysm (2.6%), basilar impression (2.6%), intracranial lipoma (2.6%), arachnoid cyst (2.6%), empty sella (2.6%), intracranial neoplasm (2.6%), and colloid cyst (1.3%)	The authors concluded CT abnormalities are common but do not usually change management

Table 3. Studies Using MRI Only for Evaluation
Study	Subjects	Results	Conclusions
Jacome and Leborgne³⁹	Diagnosis of "non-epileptiform basilar artery migraine." (21) Exclusion criteria included objective abnormalities such as an abnormal neurological exam or EEG, as well as a diagnosis of epilepsy on anti-epileptic treatment	Of these 18 subjects, 6 had mild cortical sulci enlargement. One had moderate ventricular enlargement and focal T2 signal abnormalities in the centrum semiovale. Another subject had basal ganglia calcifications, and another cerebellar vermis hypoplasia. Two had 1 single T2 white matter lesion. Six of the 12 subjects had a CT study prior to MRI which did not show the MRI abnormalities. Six of the 18 subjects had both normal CT and MRI	The authors concluded MRI was more sensitive than CT for abnormalities. Neither CT nor MRI demonstrated a biomarker for the disorder, with the exception of the patient with cerebellar hypoplasia. The authors also mentioned the white matter abnormalities were not typical for demyelinating disease
Cooney et al³¹	185 consecutive patients with migraine in the same department. Their goal was to correlate MRI abnormalities such as white matter lesions with patient demographics and clinical features	Only 30 of the 185 (16%) had white matter abnormalities. These abnormalities were more common in patients over age 50 but did not correlate with clinical features such as length of disease, sex or migraine subtype. Only 6% of subjects who were under age 50 and had no significant medical problems such as hypertension, heart disease, or diabetes mellitus had white matter abnormalities (24)	The authors suggested white matter abnormalities may not be migraine related, and may be incidental findings related to other clinical variables such as age
Gozke et al³²	45 patients with migraine: 20 with aura and 25 without	White matter foci were noted in 13/45 subjects (28.8%) and significantly more common in those with aura (8/20, 40%) compared to those without (5/25, 20%). There was a non-significant difference for longer mean migraine duration in those with white matter foci. There was 1 patient each with frontoparietal cortical atrophy and heterotopy – felt to be incidental findings	The authors concluded that "there are no specific MRI findings peculiar for migraine" but that white matter foci are common, especially in those with aura
Honnigsvag et al ³³	Population-based cross-sectional study which included adults aged 50–65 who had participated in previous Nord-Trøndelag Health Studies (HUNT)	Patients with any headache disorder had a higher rate of any intracranial abnormality overall (29% vs 22%), including major (11% vs 10%) and minor (17% vs 13%) categories. However, when white matter hyperintensities were removed from the analysis, this association disappeared. Persons with migraine were not more likely to have cysts, aneurysm, cerebral infarctions, meningioma, or microhemorrhages. There were a large number of significant abnormalities in both headache and headache-free groups including venous angioma, multiple sclerosis, carotid disease, AVM, and pituitary tumor but there was no significant difference between headache and headache-free groups	The author concluded that persons with migraine are more likely to have white matter hyperintensities. Other neuroimaging abnormalities do not appear more common in those with migraine
Osborn et al³⁴	41 Subjects, with a mean age of 29.8 years	White matter lesions were detected in 5 of the 41 patients (12%) but were less common in those under 40 years old (5.5%). One of the patients with complicated migraine had white matter lesions, but no other significant abnormalities were seen
Prager and Rosenblum³⁵	77 subjects with migraine	White matter abnormalities were common in subjects with (44%) and without (47%) aura, and more common with advancing age	White matter changes are common in migraine and more common in older patients
Mullally and Hall³⁸	100 subjects with migraine and a normal neurological examination, including 41 with chronic migraine	Most scans were normal (82%) but 17% had insignificant abnormalities. One patient had a serious abnormality: a meningioma that eventually required surgery and radiation therapy.	Given that the prevalence of this tumor in the general population is similar, the authors concluded brain MRI should not be performed as part of the evaluation of migraine without a clear clinical indication
Soges et al³⁶	24 subjects: 17 migraine with aura, 7 migraine without aura. The authors did not clearly define migraine or specify how secondary causes of headache were ruled out	T2-weighted studies demonstrated white matter lesions more frequently in those with aura (4/7, 57%) than those without aura (7/17, 41%). In addition, among those with aura there were large cortical abnormalities similar to infarcts in three patients and multiple bilateral focal white matter lesions in one patient	The authors noted the cortical lesions correlated with neurological deficits, but the periventricular changes were not
Wang et al³⁷	402 subjects referred for headache by a neurologist. Headache types included: migraine (161 subjects), tension-type (71), mixed (27), atypical (64), or other (79)	The study focused on major abnormalities of possible clinical significance, not white matter abnormalities. Major abnormalities were significantly less common in those with migraine than in other types of headache. The only abnormality among the migraine subjects was a petrous apex cholesterol cyst in a 58 year old woman	If anything, patients with migraine are less likely to have significant neuroimaging abnormalities than those with non-migraine headaches

Table 4. Studies Using Either MRI or CT for Evaluation
Study	Subjects	Results	Conclusions
Cull⁴¹	69 subjects, with "late-onset migraine" after age 40. The majority (86%) had were migraine with aura. When available, carotid ultrasound and laboratory testing was also reviewed	Most subjects (93%) had normal neuroimaging. Four of the subjects had evidence of a previous cerebral infarction, and 3 had evidence of mild-moderate carotid atheroma on ultrasound scanning. However, none of the subjects had findings which would change clinical management such as brain cancer or a vascular malformation	Routine neuroimaging of late-onset migraine is unlikely to be of value in patients with a normal exam and no worrisome clinical features
Kuhn and Shekar⁴²	17 subjects with migraine with aura. Included both pediatric and adult subjects (age 9–39, mean 28)	In 19 of the 74 subjects (26%) MRI revealed multiple foci of bright signal on T2 MRI which were not detected on CT. Focal or generalized ventricular enlargement or sulcal prominence was present in 26 subjects both on CT and MRI. One patient with homonymous hemianopsia had an occipital lobe infarct – seen on both MRI and CT	MRI is more sensitive for detecting lesions than CT, but not brain atrophy
Clarke et al⁴³	167 subjects with migraine	Only 2 (1.2%) had significant abnormalities and both had known secondary causes of headache. One abnormality was a Chiari malformation in a patient with a history of Moya-Moya disease and extracranial-intracranial bypass surgery. The other presented with blurred vision and early morning headache with known Dandy-Walker syndrome and was found to have a blocked shunt	The authors concluded it is best to selectively image in patients with exam abnormalities or worrisome signs or symptoms
Wang et al⁴⁰	1070 subjects with headache, including 665 with migraine, and 1070 controls. Subjects with red flags raising concern for headache or abnormal exam findings were excluded	None of the 382 subjects undergoing CT had significant abnormalities. Of the 688 subjects receiving MRI, only 4 subjects with headache had significant imaging abnormalities (0.58%), including 3 of the migraine subjects (0.67%). Abnormalities included 2 subjects with hydrocephalus and 2 with tumors of the throat and nose. There were 5 abnormalities in the healthy controls (0.73%) which was not significantly different	Neuroimaging in patients with migraine or other primary headache who do not have exam abnormalities or red flags is unneeded and a poor use of health care resources

Table 5. Study Quality Assessment Using a Modified Newcastle Ottawa Scale for Cross-Sectional Studies ¹⁵
Study	Selection												Comparability		Outcome						Quality Score
Study	1a	1b	1c	1d	2a	2b	3a	3b	3c	4a	4b	4c	1a	1b	1a	1b	1c	1d	2a	2b	Quality Score
Akpek et al²⁴		*				*	*					*					*			*	1
Cala and Mastaglia¹⁸		*				*	*					*						*		*	1
Clarke et al⁴³		*				*		*		*							*			*	1
Cooney et al³¹		*				*			*	*			*	*	*				*		5
Cuetter and Aita²¹		*				*	*				*							*		*	1
Cull⁴¹			*			*			*			*						*		*	0
Gozke et al³²			*			*			*	*								*	*		2
Honningsvag et al³³	*					*		*		*			*	*	*				*		6
Hungerford et al¹⁹			*			*			*			*						*		*	0
Jacome and Leborgne³⁹			*			*			*			*						*		*	0
Kahn et al²⁵		*				*	*				*		*				*		*		3
Kuhn and Shekar⁴²		*				*			*			*						*		*	0
Masland et al²⁷			*			*			*		*							*		*	0
Mathew et al²³				*		*			*		*						*			*	0
Mullally and Hall³⁸		*				*			*	*							*			*	1
Osborn et al³⁴		*				*			*		*						*			*	0
Paemelaire et al		*				*	*			*								*	*		3
Prager and Rosenblum³⁵		*				*	*					*	*	*				*		*	3
Sargent et al²⁶		*				*		*			*						*			*	0
Soges et al³⁶				*		*			*			*						*		*	0
Valenca et al²⁸			*			*			*	*								*		*	1
Wang et al³⁷		*				*	*					*	*	*				*	*		4
Wang et al⁴⁰		*				*		*		*			*	*	*					*	4

Maximum scores: Selection = 5, Comparability = 2, Outcome = 3, Total Quality Score = 10.

Authors and Disclosures

Randolph W. Evans, MD, Rebecca C. Burch, MD, Benjamin M. Frishberg, MD, Michael J. Marmura, MD, Laszlo L. Mechtler, MD, Stephen D. Silberstein, MD and Dana P. Turner, MSPH, PhD

Department of Neurology, Baylor College of Medicine, Houston, TX, USA (R.W. Evans); John R. Graham Headache Center, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA (R.C. Burch); The Neurology Center, Carlsbad, CA, USA (B.M. Frishberg); University of California at San Diego School of Medicine, San Diego, CA, USA (B.M. Frishberg); Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA (M.J. Marmura and S.D. Silberstein); Dent Neurologic Institute, Headache Center, Buffalo, NY, USA (L.L. Mechtler); Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA (D.P. Turner).

Address all correspondence to
R.W. Evans, Department of Neurology, Baylor College of Medicine, 1200 Binz #1370, Houston, TX 77004, USA, email: revansmd@gmail.com

Conflict of Interest
Randolph W. Evans, MD: Speaker's Bureau: Allergan, Amgen, Novartis, Teva, and Biohaven Pharmaceuticals. Consultant/Advisory Boards: Alder, Amgen, Eli Lilly, Novartis, and Teva. Received publishing royalties or fees from Elsevier, MedLink Neurology, Medscape Neurology, Oxford University Press, UpToDate, Jaypee Brothers. Rebecca C. Burch, MD: None. Benjamin M. Frishberg, MD: Speaker for Lilly, Biogen, Sanofi-Genzyme, EMD-Serono, Alexion, Allergan, Celgene. Investigator for Lilly, Allergan, Lundquist, Electrocore. Michael J. Marmura, MD: Advisory boards for Antres Pharma, Alder, Valeant, Supernus, Promius and Theranica, Research support as a principal investigator from Allergan, Teva, GammaCore. Speaker bureaus for GammaCore, Amgen and Eli Lilly. Laszlo L. Mechtler, MD: Dent Neurologic Institute, SUNY Buffalo, and Roswell Park Cancer Institute. Stephen D. Silberstein, MD: Consultant and/or advisory panel member for Abide Therapeutics; Alder Biopharmaceuticals; Allergan, Inc.; Amgen; Avanir Pharmaceuticals, Inc.; Biohaven Pharmaceuticals; Cefaly; Curelator, Inc.; Dr Reddy's Laboratories; Egalet Corporation; GlaxoSmithKline Consumer Health Holdings, LLC.; eNeura Inc.; electroCore Medical, LLC; Impel NeuroPharma, Inc.; Lilly USA, LLC; Medscape, LLC; Novartis, Inc.; Satsuma Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Teva Pharmaceuticals; Theranica; and Trigemina, Inc.; Dana P. Turner, MSPH, PhD: None.

Appendix 1: Search Strategy

MEDLINE (Pubmed)

The search was run in December 2016 and August 2018. Equivalent search strategies were run in Web of Science and Cochrane Central Register of Controlled Trials on the same dates.

Search	Query
#1	Search "Migraine Disorders" [Mesh] or "Cluster Headache" [Mesh] or Migrain * [tiab] or Cluster headache * [tiab] or Cluster type headache * [tiab] or Cluster like headache*[tiab]
#2	Search "magnetic resonance imaging" [MeSH] or "Tomography, X-Ray Computed" [Mesh] or "Neuroimaging" [Mesh] or "Diagnostic Imaging" [Mesh:NoExp] or "Radiography" [subheading] or MRI [tiab] or Magnetic resonance imaging [tiab] or CT [tiab] or Computed tomography [tiab] or Computerized tomography[tiab] or Computer assisted tomography [tiab] or Neuroimag * [tiab] or Imaging [tiab]
#3	Search "Diagnosis" [Mesh:NoExp] or "Diagnostic Imaging" [Mesh:NoExp] or "Delayed Diagnosis" [Mesh] or "Diagnosis, Differential" [Mesh] or "Early Diagnosis" [Mesh] or "diagnosis" [Subheading:NoExp] or "Sensitivity and Specificity" [Mesh] or "physiopathology" [Subheading] or Diagnos* [tiab] or Specificity [tiab] or Predictive value * [tiab] or PPV [tiab] or NPV [tiab] or Likelihood Ratio * [tiab] or Testing [tiab] or Test [tiab] or Tests [tiab] or Tested [tiab]
#4	Search (#1 and #2 and #3)
#5	Search (#1 and #2 and #3) Filters: Publication date from 1973/01/01
#6	Search (#1 and #2 and #3) Filters: Publication date from 1973/01/01; English
#7	Search "Meeting Abstracts" [Publication Type] or "Case Reports" [Publication Type] Filters: Publication date from 1973/01/01; English
#8	Search (#6 not #7) Filters: Publication date from 1973/01/01; English

Neuroimaging for Migraine: The American Headache Society Systematic Review and Evidence-Based Guideline

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