Upregulation of inflammatory gene transcripts in periosteum of chronic migraineurs: Implications for extracranial origin of headache.
Chronic migraine (CM) is often associated with chronic tenderness of pericranial muscles. A distinct increase in muscle tenderness prior to onset of occipital headache that eventually progresses into a full-blown migraine attack is common. This experience raises the possibility that some CM attacks originate outside the cranium. The objective of this study was to determine whether there are extracranial pathophysiologies in these headaches.



We biopsied and measured the expression of gene transcripts (mRNA) encoding proteins that play roles in immune and inflammatory responses in affected (ie, where the head hurts) calvarial periosteum of (1) patients whose CMs are associated with muscle tenderness and (2) patients with no history of headache.



Expression of proinflammatory genes (eg, CCL8, TLR2) in the calvarial periosteum significantly increased in CM patients attesting to muscle tenderness, whereas expression of genes that suppress inflammation and immune cell differentiation (eg, IL10RA, CSF1R) decreased.



Because the upregulated genes were linked to activation of white blood cells, production of cytokines, and inhibition of NF-κB, and the downregulated genes were linked to prevention of macrophage activation and cell lysis, we suggest that the molecular environment surrounding periosteal pain fibers is inflamed and in turn activates trigeminovascular nociceptors that reach the affected periosteum through suture branches of intracranial meningeal nociceptors and/or somatic branches of the occipital nerve. This study provides the first set of evidence for localized extracranial pathophysiology in CM. Ann Neurol 2016;79:1000-1013.
River Oaks Plastic Surgery Center, Houston, TX.
Carlton J
CJ
Perry
Headache Center of Greater Heights, Memorial Hermann Greater Heights Hospital, Houston, TX.
Pamela
P
Blake
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA.|Harvard Medical School, Boston, MA.
Catherine
0000-0002-7025-6760
C
Buettner
Harvard Medical School, Boston, MA.|Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA.
Efstathios
E
Papavassiliou
Harvard Medical School, Boston, MA.|Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Boston, MA.
Aaron J
AJ
Schain
Harvard Medical School, Boston, MA.|Division of Genomics, Proteomics, Bioinformatics, and Systems Biology, Beth Israel Deaconess Medical Center, Boston, MA.
Manoj K
MK
Bhasin
Harvard Medical School, Boston, MA.|Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Boston, MA.
Rami
R
Burstein
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002509:Cephaloridine / Q000494:pharmacology; D002908:Chronic Disease; D005215:Fasting; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D007530:Isoflurane / Q000494:pharmacology; D037181:Lectins, C-Type / Q000235:genetics; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000235:genetics*; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics; D010521:Periosteum / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics; D053574:Receptors, Interleukin-1 Type II / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics; D055815:Young Adult
D015415:Biomarkers; C482593:CLEC4D protein, human; C508592:IL1R2 protein, human; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D053574:Receptors, Interleukin-1 Type II; D000072000:NF-KappaB Inhibitor alpha; D007980:Levodopa; D007530:Isoflurane; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D002509:Cephaloridine