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 Table of Contents  
Year : 2021  |  Volume : 5  |  Issue : 1  |  Page : 1-8

Human tissue studies in primary headache disorders: A scoping review

1 Medical Student, School of Medicine, University of Jordan, Amman, Jordan
2 Medical librarian, Mayo Clinic Arizona, Arizona, United States
3 Neuropathologist, Independent Contractor, Arizona, United States
4 Department of Neurology, Mayo Clinic, Arizona, United States

Date of Submission23-Sep-2020
Date of Decision02-Feb-2021
Date of Acceptance03-Feb-2021
Date of Web Publication18-Jun-2021

Correspondence Address:
Jonathan Helmsley Smith
Mayo Clinic, 13400 E Shea Boulevard, Scottsdale, AZ 85259
United States
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijcpc.ijcpc_17_20

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Background: Despite the identification of structures with putative pathophysiological significance in primary headache disorders (e.g., posterior hypothalamus in cluster headache) there appears to be a paucity of human tissue studies examining the neuropathology of these regions.
Objective: To synthesize the extent and knowledge pertaining to direct human tissue analysis in primary headache disorders.
Methods: Scoping literature review.
Results: Of 2718 located articles, 15 were eligible for inclusion. These studies evaluated either migraine (9, 60%) or cluster headache (6, 40%). Approximately 75% were published before or during the era of the first edition of the International Classification of Headache Disorders. The most common study design was case-control (8, 53.3%), and the most commonly examined tissues equally included skin (3, 20%), muscle (3, 20%), and brain (3, 20%). Thematically, these manuscripts generally evaluated peripheral nervous and systemic pathology, as well as more targeted pathophysiological aspects, including mitochondrial and mast cell dysfunction.
Conclusions: While interest in this type of study design appears to be waning, histopathological evaluation of human tissue provides unparalleled opportunity to reveal novel pathophysiological insight. Considerations for future study design and reporting of work involving human tissue is suggested based on our review.

Keywords: Autopsy, biopsy, cluster, human tissue, migraine, neuropathology, primary headache

How to cite this article:
Amer MA, Almader-Douglas D, Smith VD, Smith JH. Human tissue studies in primary headache disorders: A scoping review. Int J Clinicopathol Correl 2021;5:1-8

How to cite this URL:
Amer MA, Almader-Douglas D, Smith VD, Smith JH. Human tissue studies in primary headache disorders: A scoping review. Int J Clinicopathol Correl [serial online] 2021 [cited 2021 Dec 3];5:1-8. Available from: https://www.ijcpc.org/text.asp?2021/5/1/1/318756

  Introduction Top

Primary headache disorders are defined as headache disorders not attributed to another disorder.[1] Primary headache disorders represent a diverse diagnostic group recognized by the International Classification of Headache Disorders, 3rd Edition (ICHD-3), typified by entities such as migraine, tension-type, and cluster headaches.[1] The pathophysiology of disorders such as a migraine and cluster headache has been established to have a neural mechanism on the basis of human neuroimaging and preclinical work,[2],[3] with risk susceptibility conferred in the case of migraine based on genetic[4] and acquired mechanisms.[5] However, the pathophysiological significance of nearly all targets identified in genome-wide association studies of migraine remains to be elucidated, with only a variant in the transient receptor potential cation channel subfamily M member 8 having a known role in nociception.[6] In addition, despite numerous advantages, preclinical work has important associated pitfalls, including an inability to model the numerous complexities of headache disorders.[7],[8]

The opportunity to gain direct and unbiased insights into primary headache disorders in humans exists in the form of direct human tissue analysis. However, the extent that this methodology has been utilized, as well as the quality and barriers encountered in executed studies has not been previously appraised. This approach has been utilized with success in allied fields, such as in the study of primary mood disorders and schizophrenia.[9],[10] In many circumstances in the field of headache medicine, distinct structures of pathophysiological significance have been identified by functional imaging techniques (e.g., posterior hypothalamus in cluster headache[11]), but with completely unknown histopathological correlate. Examples of structural neuroimaging abnormalities with unknown pathology include the ubiquitous stroke-like lesions and white matter hyper-intensities seen in migraine, as well as the microscopic consequences of iron deposition in the periaqueductal gray.[12],[13]

In this scoping review, we intended to synthesize the extent and knowledge pertaining to studies specifically analyzing human tissue with the intent to further understand primary headache disorders. The results are intended to document the current state-of-the-science with regard to the topic and establish a framework for future research directions.

  Methods Top

Overall design

The scoping review was not eligible for registration in the PROSPERO database due to the intent of synthesizing the extent, range, and characteristics of evidence on a particular topic. A core aim of a scoping-type review is to facilitate future study. The PRISMA extension for scoping reviews (PRISMA-ScR) was utilized in the preparation and execution of the current work before the initiation of the literature review.[14]

In contrast to a systematic review, a scoping review provides reporting independent of methodological quality or risk of bias.[14] However, limitations of the methodologies of included manuscripts will be commented upon in our reporting. Data reporting will be sub-divided by the corresponding primary headache diagnosis, using the categorization presented in the ICHD-3 as a framework.[1]

Search strategy and methods

An experienced medical librarian (DAD) conducted literature searches in the electronic databases PubMed (which includes Medline), Embase, Scopus, Web of Science, and the Cochrane Database of Systematic Reviews, and in ClinicalTrials.gov. A combination of keywords and subject headings were applied to retrieve broad results pertaining to analyzing human tissue of primary headache disorders. Representative search terms included “headache,” migraine, “biopsy,” “autopsy” and “physiopathology.” Detailed search methodology is available upon request to the corresponding author. The number of papers retrieved from the databases was 2718. EndNote software was used to automatically and then manually de-duplicate the list of papers, which identified 139 duplicates resulting in a net 2579 total papers. The searches were limited to English-language and human subjects of all ages. Investigators (MAA, JHS) ran a series of hand-searches and identified 7 additional citations.

Inclusion and exclusion criteria

The following inclusion and exclusion criteria were utilized in the screening of abstracts and then full texts:


  • All study designs
  • Human studies
  • All ages
  • The study must include a headache diagnosis corresponding to and established by current ICHD-3,[1] or prior versions[15],[16]
  • Studies predating the 1988 first edition of the ICHD will be included if a reasonable attempt to classify and/or describe the headache disorder is provided, or reference to an alternative diagnostic template. The inclusion of these studies will require agreement by two study investigators
  • For primary headache disorders, any tissue study was considered relevant that focused on understanding the biology of the disorder.


  • Animal studies
  • Human biochemical and genetic studies without histopathological analysis
  • Studies of cellular components from human blood samples[17]
  • Clinicopathological correlations of headache disorders not recognized by ICHD[18]
  • Human tissue studies of structures relevant to headache disorders, but sampled from healthy controls[19]
  • Studies in which the headache diagnosis cannot be confirmed by consensus agreement according to contemporary criteria.[20]

Screening and abstracting identified manuscripts

Following the application of our search strategy, two reviewers independently screened all titles and abstracts for more detailed review for study inclusion. Disagreements were resolved between reviewers by discussion, and involvement of a third reviewer, if needed. The agreed upon studies were each reviewed by two investigators for more in-depth evaluation of content to determine final study eligibility. A standardized data charting form will be utilized by the investigators abstracting the included manuscripts.

Abstracted data elements included: Publication year, country of origin, study design, patient age(s) and sex distributions, headache diagnosis, histopathological findings, and a qualitative description of study findings.

  Results Top

Characteristics of included studies

Manual review of full texts for eligibility resulted in 15 manuscripts for analysis [Figure 1]. The details of the manuscripts are summarized in [Table 1].
Table 1: Human tissue studies in primary headache disorders

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Figure 1: PRISMA flowchart

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Headache diagnoses were established with reference to ICHD-1 (6, 40%), ICHD-2 (3, 20%), or ICHD-3 (1, 6.7%). Five (33.3%) of the manuscripts were published before the first publication of ICHD in 1988, where inclusion was felt to be reasonable by agreement by the authors.

Diagnoses included migraine (9, 60%) and cluster headache (6, 40%). Among reports of migraine, diagnoses included migraine with and without aura (5, 55.5%), familial hemiplegic migraine (3, 33.3%), and chronic migraine (1, 11.1%). Among reports of cluster headache, 2 (33.3%) included patients with chronic cluster headache. All tissue studies of cluster headache included patients during an active cluster bout.

The study design was most commonly case-control (8, 53.3%), but also included case reports (3, 20%), case series (3, 20%), and one randomized controlled trial[21] with a histopathological primary endpoint.

Sources of samples included: Research volunteer (10, 66.6%), clinical samples (4, 26.6%), and necropsy/autopsy material (2, 13.3%).

Manuscripts evaluated biopsied or necropsy tissue from skin (3, 20%), muscle (3, 20%), brain (3, 20%), gastrointestinal mucosa (2, 13.3%), pericranial nerve (1, 6.7%), periosteum (1, 6.7%), nasal mucosa (1, 6.7%), and temporal artery (1, 6.7%).

Findings in human tissue studies of primary headache disorders


In patients with migraine, mild abnormalities in muscle reflecting mitochondrial oxidative dysfunction were observed.[22],[23] One of these series exclusively included 9 patients with migraine with aura, including 5 who had a presumed migrainous infarction.[23] In patients with familial hemiplegic migraine, muscle pathology was suggestive of mitochondrial oxidative dysfunction in two cases,[24] as well as demonstrating potential noninflammatory small vessel arteriopathy in another.[25]

In a case-control study, abnormalities predominantly in myelin were reported in a descriptive fashion in the zygomaticotemporal nerve obtained during so-called migraine surgeries.[26] Samples were obtained at least 5-mm from reported compression sites, and compared to nerve obtained from patients without migraine undergoing brow lift procedures.

In a more recent study of periosteal biopsy of the calvarium in patients with chronic migraine undergoing occipital nerve decompression, targeted transcriptomic analysis was compared with samples obtained from Parkinson's disease controls undergoing deep brain stimulation. The study controlled for medication exposures and Parkinson's – related genes. An upregulation of pro-inflammatory genes was identified, as well as a concomitant down-regulation of immune regulatory transcripts, suggesting an impact of extra-cranial pathophysiology in chronic migraine.[27]

Pradalier et al. evaluated duodenal biopsy samples in patients with migraines either self-reporting a food trigger or not, and did not identify differences in overall or Ig-subtyped plasmacytes.[28] Finally, in a larger case-control study, Helicobacter pylori was more common on gastric biopsies in patients with migraine (57.1%) versus control (33.3%).[29]

In a single case report of a patient with hemiplegic migraine, diagnostic brain and dural biopsies were obtained in the case also involving brain edema. Nonspecific reactive changes were observed in the brain.[30]

Cluster headache

In patients with cluster headache, mast cell degranulation was variably observed to be more common[31],[32] or not[33],[34] on the affected side, and mast cells to be overall more numerous[33] or not.[31] Data on preferential mast cell localization by nerve fibers were also conflicting based on qualitative observation alone.[31],[33] A case report describing necropsy of a patient cluster headache was generally unrevealing, noting an incidental (subacute) hypothalamic infarct without further characterization.[35] Finally, a single-blind randomized controlled trial of hyperbaric oxygen in cluster headache demonstrated semi-quantitative reduction in substance P immunoreactivity in the nasal mucosa as a primary outcome.[21]

  Discussion Top

In our scoping-type review, diverse manuscripts were identified focusing on the diagnostic entities of migraine and cluster headache. Thematically, these manuscripts generally focused on peripheral and systemic headache pathology, as well as more targeted pathophysiological aspects, including mitochondrial and mast cell dysfunction. Interest in this type of study design appears to be waning, as nearly three-quarters of the identified publications were in the pre-ICHD or ICHD first edition era. The level of evidence was variable, with 6 (40%) of the studies lacking a control group. However, notable exceptions existed, most recently including a well-controlled evaluation of the periosteal transcriptome in patients with chronic migraine,[27] as well as a single-blinded randomized control trial in cluster headache with a histopathological primary endpoint.[21] The value of human tissue studies as identified in our review is highlighted in the following examples, directly demonstrating peripheral pathology and mitochondrial abnormalities in migraine.

The relative roles of central and peripheral nervous system pathology in migraines remain controversial. Central trigeminovascular neuronal activation may follow cortical spreading depression,[36] and hypothalamic activation is seen in the premonitory phase of migraine,[37] findings both indicative of centrally-driven pathways. In a preclinical model, lignocaine injection into the trigeminal ganglion did not prevent activation of central trigeminal neurons following cortical spreading depression, indicating a dependence on a purely central pathway.[38] However, on the basis of anatomic work demonstrating branching of intracranial nociceptors into extracranial tissue through calvarial sutures, as well as the efficacy of onabotulinumtoxinA in chronic migraine prevention, an extracranial “origin” of migraine has been hypothesized.[39] Further, neuroimaging using an inflammatory radiotracer has demonstrated extra-axial inflammatory signals in the meninges in migraine, also consistent with long-standing preclinical work modeling peripheral neurogenic inflammation.[40] In our review, human tissue studies were consistent with the involvement of peripheral trigeminovascular pathways;[26],[27] however, a temporal sequence of recruitment and contribution relative to central pathways cannot be deduced.

Prior work has also implicated a mismatch in cerebral metabolism and antioxidant capacity as a homeostatic imbalance that may trigger migraine.[41] This work has often implicated mitochondria as a putative substrate, consistent with identified spectroscopic abnormalities in brain mitochondrial metabolism and clinical efficacy of suggestive nutraceuticals (e.g., coenzyme Q10) in migraine prevention.[41] However, a recent mitochondrial genome-wide association study looking at 4021 migraine patients and 14,288 controls did not support a role for mitochondrial genetic variation in migraine pathophysiology.[42] In our review, the value of human tissue work is highlighted as being able to directly visualize mitochondrial abnormalities in patients with migraine.[22],[23],[24]

Strengths of human tissue research as suggested by identified references include the elimination of assumptions inherent in preclinical work, as well as the possibilities for study designs to be both hypothesis-generating[26] without a clear end-point, as well as hypothesis-testing, which was the case in the majority of studies. However, among hypothesis-testing studies, clearly defined primary outcome measures were rarely present, and not well defined, making the evaluation of the results challenging. Outcomes were often qualitative or semi-quantitative, likely susceptible to reporting biases. Putative abnormalities, such as mast cell degranulation, were noted in control samples in one study, highlighting the importance of including a control group.[33]

The source of samples and controls was also variable, most often derived from patient volunteers. Sources of samples come with advantages and disadvantages that investigators must consider, weighing ease and ethics of access, as well as the introduction of confounding biology. The voluntary use of superficial biopsies in controlled populations allows for a more rigorously controlled study design, whereas the use of clinical/surgical specimens may be more ethically acceptable, at the cost of some control over clinical covariates. Autopsy allows for in-depth evaluation of otherwise inaccessible targets, however, clinical correlates may be inadequate, and medical and neurologic confounders may be present. Krabbe[35] provides an indication of the potential yield of reviewing autopsy specimens, noting the death of 16/337 (5%) cluster headache patients over a 10-year interval. International brain banks exist with searchable databases that researchers can access. Notable examples include the National Institutes of Health NeuroBioBank (https://neurobiobank.nih.gov/specimens/) and UK Brain Bank Networks (https://mrc.ukri.org/research/facilities-and-resources-for-researchers/brain-banks/).

Limitations of this current manuscript include the probability that despite our best efforts, our search may not have been completely exhaustive given the broad scope of our review. In an effort to be methodologically rigorous, we also may have excluded manuscripts of potential relevance. For example, certain publications included relevant histopathological analysis, but case definitions could not be confirmed allow inclusion in our review, such as in a basic science study including analysis of a dorsal root ganglion from a possible migraine case.[43] In these cases, more deliberate efforts at inter-disciplinary collaboration may remedy such pitfalls. Finally, our prespecified inclusion/criteria did not allow the inclusion of human studies examining individual cellular elements from hematological samples.[17]

The analysis of human tissue with the intention of understanding headache neurobiology is ripe for future work. Our current review suggests that in addition to standardized reporting guidelines, additional requirements in the realm of human tissue studies would be relevant and useful [Table 2].
Table 2: Additional recommendations for reporting human tissue studies

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  Conclusions Top

In our scoping review, we identified a role for human tissue studies in primary headache disorders in providing direct evidence for the involvement of trigeminal nerves, as well as mitochondrial and mast cell dysfunction in headache pathophysiology.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1]

  [Table 1], [Table 2]


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