Evidence-Based Guidelines for Migraine Headache:
Overview of Program Description and Methodology
Douglas C. McCrory, MD, MHSc
Assistant Professor, Department of Medicine, Assistant Research Professor, Center for Clinical
Health Policy Research, Duke University Medical Center, Durham, NC
Research Associate, Center for Health Services Research in Primary Care
Durham Veterans Affairs Medical Center, Durham, NC
David B. Matchar, MD
Professor of Medicine and Director, Center for Clinical Health Policy Research,
Duke University Medical Center, Durham, NC
Rebecca N. Gray, DPhil
Center for Clinical Health Policy Research, Duke University Medical Center,
Durham, NC
Jay H. Rosenberg, MD, FAAN
Department of Neurology, Southern California Permanente Medical Group, and Clinical Professor
of Neurology, Voluntary Faculty, UCSD School of Medicine,
San Diego, CA
Stephen D. Silberstein, MD, FACP
Professor of Neurology, Thomas Jefferson University, and Director of Jefferson Headache
Center, Philadelphia, PA
US Headache Consortium:§
American Academy of Family Physicians
American Academy of Neurology
American Headache Society
American College of Emergency Physicians*
American College of Physicians-American Society of Internal Medicine
American Osteopathic Association
National Headache Foundation
§The US Headache Consortium participants: J. Keith Campbell, MD; Frederick G. Freitag, DO; Benjamin
Frishberg, MD; Thomas T. Gilbert, MD, MPH; David B. Matchar, MD; Douglas C. McCrory, MD, MHSc; Donald
B. Penzien, PhD; Michael P. Pietrzak, MD, FACEP; Nabih M. Ramadan, MD; Jay H. Rosenberg, MD; Todd D.
Rozen, MD; Stephen D. Silberstein, MD, FACP; Eric M. Wall, MD, MPH; William B. Young, MD.
*Endorsement by ACEP means that ACEP agrees with the general concepts in the guidelines and believes that the
developers have begun to define a process of care that considers the best interests of patients with migraine
headache
Copyright © by the American Academy of Neurology: Licensed to the members of the US Headache Consortium
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Overview of Program Description and Methodology
Background
In June 1998, Duke University’s Center for Clinical Health Policy Research (CCHPR), in
collaboration with the American Academy of Neurology (AAN), completed a series of Technical
Reviews on migraine sponsored by the Agency for Health Care Policy and Research (AHCPR) in
Washington, DC. The AHCPR Technical Reviews systematically reviewed controlled trials of
treatments for migraine published in English from 1966 through 1996. Four topics were covered:
self-administered drug treatments for acute migraine (migraine is defined in Table 1); parenteral
drug treatments for acute migraine; drug treatments for the prevention of migraine; and behavioral
and physical treatments for migraine.1-4 The Education and Research Foundation of the AAN later
funded an additional report on diagnostic testing for headache patients, an update on sumatriptan
and other 5-HT1 agonists, and a report on butalbital-containing compounds for migraine and
tension-type headache. These supplemental reviews employed the same methodology that was
used in the original AHCPR Technical Reviews.
A multidisciplinary panel was convened by a consortium of professional organizations to
develop clinical practice guidelines in the primary care setting based on the reviews described
above. The US Headache Consortium, as the panel was called, produced four guidelines, each
related to a distinct set of management decisions: diagnostic testing (primarily neuroimaging
studies), pharmacological management of acute attacks, migraine-preventive drugs, and
behavioral and physical treatments for migraine. This article describes the methods used to
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identify and synthesize evidence in the ACHPR Technical Reviews and to develop the clinical
practice guidelines.
Program Objective
The objective of the US Headache Consortium was to develop scientifically sound,
clinically relevant practice guidelines on headache, for use in the primary care setting. Practice
guidelines are systematically developed statements to assist practitioner and patient decisions
about appropriate health care for specific clinical circumstances. For the guidelines on chronic
headache, these included diagnostic approach, acute and preventive pharmacologic treatment, and
non-pharmacological measures.
Methods used in the AHCPR Technical Reviews
Treatment Reviews
The following is a brief description of the methods used to prepare the AHCPR Technical
Reviews that formed the basis for the US Headache Consortium’s clinical practice guidelines on
the treatment of migraine. Further details can be found in the methodology sections of the
AHCPR Technical Reviews.1-4
The reviews examined the effects of various treatments for migraine on headache pain
and/or frequency. In the case of drug treatments, tolerability was also investigated. To be
considered for inclusion, studies were required to be prospective, controlled trials of treatments
for migraine (all medication treatment trials used only level one evidence which by definition also
included blinding). Allocation to treatment groups had to be randomized or quasi-randomized
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(i.e., based on some nonrandom process unrelated to the treatment selection or expected
response). Concurrent cohort comparisons and other nonexperimental designs were excluded.
Control groups could receive no intervention, placebo or (in the case of behavioral and physical
treatments) sham intervention, usual care, or a specified alternative drug or nondrug treatment.
Only trials conducted on adults and published in English were considered.
Relevant controlled trials were identified through computerized searches of the
MEDLINE, PsycINFO, and CINAHL databases, by searching the reference lists of review articles
and included studies, by searching books on headache, and by consulting experts in the field. The
search strategy used the MeSH term “headache” (exploded) and a published search strategy for
identifying randomized controlled trials.5
Identified citations were screened for inclusion based on specific criteria concerning
patient population, intervention, study design, and type of outcome data reviewsed (see Table 2).
Trials passing this screen were evaluated for methodological quality using the scale developed by
Jadad and colleagues.6 Data on study design, patient population, interventions, efficacy outcomes,
and adverse events were abstracted onto specially designed forms.
The efficacy outcomes analyzed and the methods of analysis used varied among reviews
(see Table 2). In general, however, when outcomes were reported in dichotomous form, the
reviewers required that the threshold for distinguishing between success and failure be clinically
significant. For example, the reviewers interpreted a 50% or greater decrease in headache
severity or frequency as meeting this criterion. Dichotomous data meeting this definition were
used to calculate odds ratios. Outcomes reported on a continuous scale (e.g., mean headache
severity or frequency scores) were used to calculate standardized mean differences or effect sizes
whenever variance data were also reported.
5
In some cases, calculated efficacy measures yielded conclusions that were more
conservative than those reached by the original investigators. This occurred most often when the
original analyses used individual patient data (e.g., in trials using a crossover design or an
ANOVA analysis) rather than comparisons of group means or proportions. In these cases, the
original analyses were described in a narrative format, along with the reasons for the discrepancy
from our results.
Where similar trials provided data, meta-analysis of efficacy measures was performed. The
identity and rates of adverse events were recorded and statistically compared. A summary in
narrative format was used for additional data that met selection criteria but were not reported in
sufficient detail to contribute to the quantitative synthesis.
Diagnostic Review
Investigators reviewed English-language studies published from 1966 through August 1998
that estimated the sensitivity, specificity, or predictive value of the clinical history, physical exam,
or laboratory, radiological, or other tests for identifying significant intracranial abnormalities in
patients presenting with nonacute headache. Studies that assessed observer variation or
reproducibility of diagnostic tests for patients with nonacute headache were also included. Trials
were identified through computerized searches of MEDLINE and by examining the reference lists
of review articles, searching books on headache, and consulting experts in the field. The search
paired a strategy that identified studies on the operating characteristics of diagnostic tests
(modified from a strategy developed by the editorial staff of the Journal of the American Medical
Association’s “Rational Clinical Examination Series”)7 and a strategy that identified headachespecific terms.
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Articles were included in the analysis if they provided original data for 20 or more subjects
with nonacute headache and met at least one of the following criteria:
•
compared clinical history, physical examination, laboratory, radiological, or other
tests with a neuroimaging test as a reference standard.
•
described the results of a neuroimaging study in a consecutive series or random
sample of patients.
For studies meeting these criteria, a general internist confirmed the relevance of each
study, abstracted data from it, and assigned it a quality score. Study quality was graded using the
methods accepted by the Journal of the American Medical Association’s “Rational Clinical
Examination Series” for methodological levels of evidence for grading diagnostic studies7 (Table
3). Studies that did not address primary headache disorders, involved emergency patients only, or
did not include enough data to perform analysis (e.g., did not provide the data necessary to
construct a 2-by-2 table) were excluded. Studies were also excluded if the underlying cause of
headache was known, if the study was performed in the acute treatment setting, or if the condition
was a "new onset" headache.
The analysis focused first on the effectiveness of the clinical evaluation (history and
physical examination) for detecting intracranial anatomical abnormalities among patients
presenting with nonacute headache in the primary care setting. The clinical evaluation of the
patient was treated as a screening test that might predict abnormalities on imaging. Computerized
tomography (CT) and magnetic resonance imaging (MRI) were treated as confirmatory “gold
standard” or “reference standard” tests.
With the assistance of two board-certified neurologists, the reviewers classified all the
neuroimaging outcomes reported in the included studies as either “significant abnormalities,”
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“abnormalities possibly related to headache,” “insignificant abnormalities,” or “normal” (see Table
4). The analysis focused exclusively on significant abnormalities.
To describe the efficiency of the screening tests, sensitivity and specificity were combined
to create likelihood ratios. The pretest odds of disease were multiplied by the likelihood ratio to
calculate the post-test odds. Values greater than one increase the odds of disease, while values
less than one diminish the odds, and values approaching one have an increasingly small impact on
changing the odds of disease beyond the baseline prevalence. Confidence intervals were
constructed around the likelihood ratios, assessing whether the 95% limits included or excluded
the indeterminate value of one. For tests yielding continuous outcomes only, standard statistical
methods were used to compare means between groups with and without significant abnormalities
on neuroimaging. When several studies provided estimates of a single parameter, these estimates
were tested for homogeneity. If studies were clinically and statistically homogeneous, a summary
estimate was calculated using a fixed-effects meta-analysis.
Peer Review of Technical Reviews
All of the AHCPR Technical Reviews underwent an external peer review process and were
modified to incorporate substantive and editorial changes suggested by reviewers.
Methods used in Developing the Clinical Practice Guidelines: Assembly of the US
Headache Consortium
The AAN invited organizations whose constituents treat or represent headache patients,
to nominate representatives to the US Headache Consortium. Seven organizations participated:
the American Academy of Family Physicians, American Academy of Neurology, American
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Headache Society, American College of Emergency Physicians, American College of Physicians,
American Osteopathic Association, and National Headache Foundation. The multidisciplinary US
Headache Consortium provided a balance of practicing generalist physicians, headache specialist
physicians, and other health professionals from relevant disciplines, and was supported by
individuals with expertise in administration, writing and editing, and in the methodology of
evidence synthesis and guideline development.
Values
In formulating guideline recommendations, the US Headache Consortium considered data
on relief of headache symptoms, functional status, quality of life, and tolerability of treatment.
Cost of treatment was not explicitly considered in the guideline development process.
The US Headache Consortium strove to base all of its recommendations on high-quality
evidence. Only for compelling issues were recommendations made based on expert judgment.
Consensus Development
No formal or explicit techniques were used to reach consensus among members of the US
Headache Consortium. Starting with the AHCPR Technical Reviews on a given topic, a subgroup
of members prepared summary evidence tables, wrote narrative descriptions of the evidence, and
formulated specific treatment recommendations. These guideline documents were reviewed and
voted on by the entire US Headache Consortium. Recommendations required consensus, defined
as unanimous agreement. Topics on which consensus could not be reached were described in the
guidelines as areas of disagreement. Evidence not considered in the AHCPR Technical Reviews
was incorporated if recommended by the US Headache Consortium; such data were reviewed and
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graded for quality by the project methodologist. This evidence included studies published after the
Technical Reviews were completed and studies on topics outside the scope of the AHCPR
Technical Reviews.
Grading Recommendations
Recommendations were graded according to the level of evidence supporting them. The
grading system adopted by the Consortium rates the aggregated evidence, including the number of
studies and the consistency of their findings, thereby implicitly acknowledging that trials of the
same treatment sometimes yield conflicting results.
Recommendations in the Treatment Guidelines were graded according to the following
scale, adapted from a previous AHCPR Guideline:8
A. Multiple well-designed randomized clinical trials, directly relevant to the recommendation,
yielded a consistent pattern of findings.
B. Some evidence from randomized clinical trials supported the recommendation, but the
scientific support was not optimal. For instance, few randomized trials existed, the trials that
did exist were somewhat inconsistent, or the trials were not directly relevant to the
recommendation. An example of the last point would be the case where trials were conducted
using a study group that differed from the target group for the recommendation.
C. The US Headache Consortium achieved consensus on the recommendation in the absence of
relevant randomized controlled trials.
This scale was adapted for recommendations about diagnostic testing as follows:
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A. Multiple well-designed clinical studies, in cohorts of patients directly relevant to the
recommendation, yielded a consistent pattern of findings.
B. Some evidence from clinical studies in appropriate cohorts of patients supported the
recommendation, but the scientific support was not optimal. For instance, either few studies
existed or the studies that did exist were small or somewhat inconsistent.
C. The US Headache Consortium achieved consensus on the recommendation in the absence of
clinical studies or based on studies that were conducted using a study group that differed from
the target group for the recommendation.
Validation
After approval by the US Headache Consortium members, Guideline drafts were reviewed
by the appropriate representative of each of the Consortium’s member organizations. None of
these reviewers had been directly involved in the preparation of the Technical Reviews or
Guideline recommendations. The US Headache Consortium responded to all comments from the
reviewers, and revised versions of the Guidelines were resubmitted to each member organization’s
governing body for approval. The Guidelines have not been field-tested in clinical use.
Acknowledgments
The authors and US Headache Consortium wish to thank Starr Pearlman, PhD, and
Joanne Okagaki for their help in preparing this manuscript and for their administrative support.
We also wish to acknowledge the scientific advice of Drs. Jes Olesen, Jean Schoenen, Helene
Massiou, Peer Tfelt Hansen, F. Cankat Tulunay, and Kai Jensen.
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Funding and Support
The Evidenced-Based Guidelines for Migraine Headache were supported by: Abbott
Laboratories, AstraZeneca, Bristol Myers Squibb, Glaxo Wellcome, Merck, Pfizer, Ortho-McNeil
and the AAN Education & Research Foundation, along with the seven participant member
organizations.
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References
1.
Gray RN, McCrory DC, Eberlein K, Westman EC, Hasselblad V. Self-Administered Drug
Treatments for Acute Migraine Headache. Technical Review, 2.4. February 1999. (Prepared for
the Agency for Health Care Policy and Research under Contract No. 290-94-2025. Available
from the National Technical Information Service; NTIS Accession No. 127854.)
2.
Gray RN, McCrory DC, Eberlein K, Westman EC, Hasselblad V. Parenteral Drug
Treatments for Acute Migraine Headache. Technical Review, 2.5 February 1999. (Prepared for
the Agency for Health Care Policy and Research under Contract No. 290-94-2025. Available
from the National Technical Information Service; NTIS Accession No. 127862.)
3.
Gray RN, Goslin RE, McCrory DC, Eberlein K, Tulsky J, Hasselblad V. Drug Treatments
for the Prevention of Migraine Headache. Technical Review, 2.3. February 1999. (Prepared for
the Agency for Health Care Policy and Research under Contract No. 290-94-2025. Available
from the National Technical Information Service; NTIS Accession No. 127953.)
4.
Goslin RE, Gray RN, McCrory DC, Penzien D, Rains J, Hasselblad V. Behavioral and
Physical Treatments for Migraine Headache. Technical Review, 2.2. February 1999. (Prepared
for the Agency for Health Care Policy and Research under Contract No. 290-94-2025. Available
from the National Technical Information Service; NTIS Accession No. 127946.)
5.
Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews.
Br Med J. 1994;309(6964):1286-1291.
6.
Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized
clinical trials: is blinding necessary? Controlled Clin Trials. 1996;117(1):1-12.
7.
Holleman DR, Simel DL. Does the clinical examination predict pulmonary airflow
obstruction? JAMA. 1995;273:313-319.
8.
Fiore MC, Bailey WC, Cohen SJ, et al. Smoking Cessation. Clinical Practice Guideline No
18. Rockville, MD: US Department of Health and Human Services, Public Health Service,
Agency for Health Care Policy and Research. AHCPR Publication No. 96-0692. April 1996.
9.
Headache Classification Committee of the International Headache Society. Classification
and diagnostic criteria for headache disorders, cranial neuralgias, and facial pain. Cephalalgia.
1988;8(suppl 7):1-96.
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Table 1
International Headache Society (HIS) diagnostic criteria for migraine
without and with aura9
1.1
A.
B.
C.
D.
E.
Migraine without aura:
At least 5 attacks fulfilling B-D.
Headache attacks lasting 4-72 hours* (untreated or unsuccessfully treated).
Headache has a least two of the following characteristics:
1.
Unilateral location
2.
Pulsating quality
3.
Moderate or severe intensity (inhibits or prohibits daily activities)
4.
Aggravation by walking stairs or similar routine physical activity
During headache at least one of the following:
1.
Nausea and/or vomiting
2.
Photophobia and phonophobia
At least one of the following:
1.
History, physical- and neurological examinations do not suggest one of the
disorders listed in groups 5-11
2.
History, physical- and/or neurological examination do suggest such disorder, but it
is ruled out by appropriate investigations
3.
Such disorder is present, but migraine attacks do not occur for the first time in
close temporal relation to the disorder
1.2
A.
B.
Migraine with aura:
At least 2 attacks fulfilling B
At least 3 of the following 4 characteristics:
1.
One or more fully reversible aura symptoms indicating focal cerebral cortical and/or brain stem dysfunction
2.
At least one aura symptom develops gradually over more than 4 minutes or, 2 or
more symptoms occur in succession
3.
No aura symptom lasts more than 60 minutes. If more than one aura symptom is
present, accepted duration is proportionally increased
4.
Headache follows aura with a free interval of less than 60 minutes. (It may also
begin before or simultaneously with the aura)
C.
At least one of the following
1. History, physical- and neurological examination do not suggest one of the disorders
listed in groups 5-11
2. History and/or physician and/or neurological examination do suggest such disorder,
but it is ruled out by appropriate investigations
3. Such disorder is present, but migraine attacks do not occur for the first time in close
temporal relation to the disorder
____________________
* In children below age 15, attacks may last 2-48 hours. If the patient falls asleep and wakes up
without migraine, duration of attack is until time awakening.
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Table 2: Important characteristics of AHCPR Technical Reviews on migraine diagnosis and treatment
Diagnostic
Patient
population
Intervention
Study design
Quality
assessment
Patients presenting
with nonacute
headache in primary
care setting
Data from history and
physical examination
(including neurological
exam) or from
laboratory,
radiographic, or other
studies (e.g., EEG)
Studies correlating
historical, physical
exam, or laboratory
findings to reference
standard test (CT or
MRI); must be able to
construct 2-by-2 table
4-point scale
developed by
Holleman and Simel
(1995)
Acute (including
parenteral)
Adults with migraine
Preventive
Adults with migraine
Behavioral/
Physical
Adults with migraine
Active: Drug treatments
aimed at the relief of
symptoms of individual
episodes of migraine
Active: Drug treatments taken
regularly during headache-free
intervals and intended to prevent
the occurrence of episodes of
migraine
Active: Behavioral or physical
treatments aimed at the
prevention of attacks of migraine
or the relief of symptoms of
individual attacks
Control: Placebo, no
intervention, usual care, or a
specified alternative drug or
nondrug treatment
Control: No intervention,
placebo or sham intervention,
usual care, or a specified
alternative drug or nondrug
treatment
Prospective, controlled trials;
allocation to treatment
randomized or quasi-randomized
Control: Placebo, no
intervention, usual care, or
a specified alternative drug
or nondrug treatment
Prospective, controlled
trials; allocation to
treatment randomized or
quasi-randomized
Prospective, controlled trials;
allocation to treatment
randomized or quasirandomized
5-point scale developed by
Jadad, Moore, Carroll, et
al. (1996)
5-point scale developed by
Jadad, Moore, Carroll, et al.
(1996)
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5-point scale developed by
Jadad, Moore, Carroll, et al.
(1996)
Outcomes
data
Identification of
significant intracranial
abnormalities
Preferred efficacy
outcomes (in descending
order): (1) headache relief
or change in headache
intensity; (2) post-treatment
headache intensity; (3)
functional disability or
headache duration
Preferred efficacy outcomes (in
descending order): (1) headache
index; (2) headache frequency;
(3) headache intensity
Preferred efficacy outcomes (in
descending order): (1) headache
index; (2) headache frequency;
(3) headache intensity
Data obtained directly from
patient and recorded daily (e.g.,
in headache diary)
Data obtained directly from
patient and recorded daily (e.g.,
in headache diary)
Data obtained directly from
patient
Adverse event data
recorded
Outcomes analyzed posttreatment (8-12 wks or
immediately after treatment,
whichever was later); follow-up
(last available time point for
which dropout rate was < 20%,
with data reported for all
groups)
Outcomes analyzed posttreatment (8-12 wks or
immediately after treatment,
whichever was later); follow-up
(last available time point for
which dropout rate was < 20%,
with data reported for all groups)
Odds ratio (dichotomous)
or effect size (continuous)
Adverse event data recorded
Odds ratio (dichotomous) or
effect size (continuous)
Outcomes analyzed at 1-2
hours
Summary
efficacy
measures
Likelihood ratio
positive, likelihood
ratio negative
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Odds ratio (dichotomous) or
effect size (continuous)
Table 3: Scale for grading quality of diagnostic studies7
Level I evidence: Independent, blind comparison with a “gold standard” of anatomy,
physiology, diagnosis, or prognosis among a large number of consecutive patients suspected of
having the target condition.
Independent: Neither the test result nor the gold standard result was used to select
patients for the study.
Blind: Test and gold standard each applied and interpreted without knowledge of the
result of the other.
Gold standard: The results of biopsy, angiography, autopsy, plain radiographs, sonogram,
physiological study, follow-up, therapeutic response, etc., that established the true
anatomy, physiology, diagnosis, or outcome of the target condition.
Target condition: The anatomical or physiological state, disease, syndrome, prognosis, or
therapeutic response that the sign or symptom identifies.
Large number: Sufficient numbers of patients to have narrow confidence limits on the
resulting sensitivity, specificity, or likelihood ratio.
Level II evidence: Independent, blind comparison with a “gold standard” among a small
number of consecutive patients suspected of having the target condition.
Small number: Insufficient numbers of patients to have narrow confidence limits on the
resulting sensitivity, specificity, or likelihood ratio.
Level III evidence: Independent, blind comparison with a “gold standard” among
nonconsecutive patients suspected of having the target condition.
Level IV evidence: Included studies which did not meet criteria for at least Level III evidence.
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Table 4: Classification of abnormalities found on neuroimaging
Classification of
abnormalities
Significant abnormalities
Abnormalities possibly related
to headache
Insignificant abnormalities
Definition
Related to headache and requiring definite action. Examples
include acute cerebral infarct, acute cerebral edema, acute
cerebral hemorrhage (subarachnoid, intra-parenchymal, or extraaxial), neoplastic disease, hydrocephalus, and vascular
abnormalities (e.g., aneurysm or arteriovenous malformation).
Possibly related to headache; may require definite action.
Examples include metastases to the calvarium, acute or chronic
sinusitis, and abnormalities of the nasal cavity.
Unrelated to headache or requiring no action. Examples include
developmental venous anomaly, cerebral or cerebellar atrophy,
subcortical (lacunar) infarction, old cortical infarction, and
normal variants (e.g., cavum septum pellucidum, physiological
calcifications).
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