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Migraine headaches triggered by palpation of chronic facial folliculitis: a peripheral and central interaction in migraine

Objective To report a case of severe migraine without aura (MwoA) headaches triggered by palpation of the folliculitis around a unilateral nosewing and the folliculitis was chronic before effective treatment for migraine, and to discuss its underlying mechanisms. of


Background
Multiple studies have shown that peripheral mechanisms may be involved in migraine generation and there are few case reports supporting this speculation. But a clinical case demonstrating a reciprocal action between migraine headache and peripheral pathology has never been reported.

Methods
A case of new onset migraine headache triggered by palpation of the regional facial folliculitis which was chronic but responsive to an effective treatment for migraine was reported. We brie y reviewed the peripheral mechanisms of migraine and the reciprocal action between migraine headache and peripheral pathology.

Results
A 45-year-old man with chronic folliculitis around the left nosewing of which palpation, each time, would trigger an episode of headache ful lling the criteria for MwoA by the International Classi cation of Headache Disorders 3rd edition (ICHD-3). And the episode of headache would be solely triggered by palpating the facial folliculitis. His chronic folliculitis around the left nosewing did not relieve after treatment with only antibiotics but resolved in the setting of no triggered migraine headache after treatment with sodium valproate.

Introduction
High occurrence of tenderness of pericranial areas, such as shoulder, neck, sternocleidomastoid, anterior temporal and occipital insertions, in migraine patients has been recognized for long time. And many of these tenderness areas are trigger points for migraine attack. This implicates that peripheral mechanisms may be involved in the pathogenesis of migraine [1]. There have been several case reports showing that petrous apicitis can present with headache as one of the main presentations, some of which had a phenotype of migraine features [2][3][4]. Recently, Alyssa Mancini described a patient with petrous apicitis developed a new onset of migraine without aura (MwoA) headaches which resolved after treatment with mastoidectomy and long course of antibiotics [5]. This indicates that in ammatory alterations of trigeminal nerve bers innervated on petrous apex can initiate and sustain the recurrence of migraine headaches. But an interactive association between migraine and chronic facial folliculitis has never been reported. Here, we describe a case of severe MwoA headaches triggered by palpation of the facial folliculitis around a unilateral nosewing in a man whose facial folliculitis resolved after effective treatment for migraine. We also discuss the probable peripheral mechanisms responsible for triggering migraine headaches under the condition of facial folliculitis around a unilateral nosewing, and how the central mechanisms affect the peripheral in ammatory pathology in migraine.

Case Presentation
A 45-year-old man came to our department with complaints of severe headache which was triggered by face washing or shaving contacting on the facial folliculitis around the left nosewing for the past 8 months. The headache was solely triggered by contacting on the folliculitis due to face washing and shaving or by hand palpation of the folliculitis, and the folliculitis contact or palpation each time could initiate a severe headache. Before the occurrence of severe headache, an abrupt and transient sharp stabbing pain radiated from the area of left nosewing to around area of the left face immediately after contacting or palpating the folliculitis. The headache was unilateral, left-sided, and located in the left frontal, temporal and parietal regions or sometimes the whole left hemisphere. The head pain was throbbing, pulsating and sometimes stabbing in feature and 8-10/10 in intensity on average. The headache was accompanied with nausea, vomiting sometimes, photophobia, phonophobia and irritability, and was aggravated by head movement, walking and physical activity but alleviated mildly by lying down and rest. The headache would last for half day or relieve after an overnight sleep. He had ever taken Ibuprofen 0.2 g and 0.4 g, indometacin 25 mg and 50 mg, and these analgetic agents only mildly decreased the pain severity but not the pain duration. On the other hand, he complained the incurable facial folliculitis around the left nosewing though he had used different antibiotic ointment prescribed by different dermatologists. Folliculitis with purulent heads disappeared in one small area and reoccurred in other small areas, but the chronic recurrence of folliculitis with purulent heads were restricted within the regional skin area surrounding the left nosewing. His pain presentation was treated as trigeminal neuralgia as there was an abrupt and transient sharp stabbing pain radiating from the area of the left nosewing to around area of the left face prior to the severe unilateral headache and there was triggering events of face washing and shaving or hand palpating which usually evoke the attacking of trigeminal neuralgia. Thus, he was given, by physicians, carbamazepine (0.2-0.3 g twice a day), or oxcarbazepine (0.3-0.6 g twice a day) but the pain was not alleviated.
When the patient came to our department, neurological and physical examinations, and brain magnetic resonance imaging (MRI) revealed normal. Blood routine test and other investigations including erythrocyte sedimentation rate and venereal disease screen were all in normal range. On regional skin around the left nosewing, small purulent heads were found and some keloids with different degrees of pigmentation which as described by the patient as antecedent purulent heads (Fig. 1). Basing on the headache presentations and the normal examinations apart from regional skin ndings, the patient was treated as migraine headaches, as it met the diagnostic criteria for MwoA by the International Classi cation of Headache Disorders 3rd edition (ICHD-3) except for the triggering event [6]. The patient accepted prophylactic treatment with sodium valproate (500 mg twice a day) without using antibiotic ointment for two months. During the rst week of the migraine treatment, the migraine headaches could still be triggered by the purulent head palpation, but pain severity and duration was dramatically decreased. One week after the migraine treatment with sodium valproate, the purulent heads on the skin around nosewing faded away and no headache was triggered by palpation of the left nosewing skin or by other contact like face washing. In the next two-month migraine treatment and half-year follow-up, the patient had no headache attack and no regional skin purulent infection occurred around the left nosewing.

Discussion
Migraine headache attacks can be triggered by many factors through trigeminal nerve (TN) or non-TN pathways. Many factors including odor stimulation, stress, menstruation, weather change and sunlight have been identi ed as trigger factors for migraine attacks through non-TN pathway [7][8][9]. On the other hand, clinical observational studies have shown that some pericranial tenderness areas existing in migraine patients are trigger points for migraine attack through TN or spinal nerve pathways [1]. Case studies have shown that petrous apicitis can initiate and sustain the recurrence of migraine headaches through TN pathway [5]. Here, we report, for the rst time, that migraine headaches were triggered exclusively by palpation of a purulent infection on a regional skin innervated by the second branch (V2) of TN. This case indicates that TN terminal stimulation provoked a migraine headache attacking under the condition of skin infection in the area innervated by TN terminals, while a TN terminal stimulation by palpating or pressing the symmetrical area without skin infection on the other side of the face did not evoke headache attacking. This is consistent with the report that noxious craniofacial stimulation to TN terminals has an amplifying effect on migraine headache induced by glyceryl trinitrate [10]. Currently, there is no literature report showing that TN stimulation can directly evoke migraine headache attacking though TN block is effective in the treatment of episodic and chronic migraine [11]. Thus, it might be proposed that TN stimulation itself is not enough to initiate a migraine or trigger a migraine headache attack, but, under certain condition causing increased sensitivity of TN or central system, TN stimulation can initiate a migraine or trigger a migraine headache attack.
On the other hand, migraine patients are found to be infrequently but not uncommonly accompanied with facial symptoms including facial pain associated with TN [12]. And trigeminal neuralgia development is at high risk in patients with migraine [13]. Recently, episodic migraine patients were detected with TN microstructural changes under magnetic resonance imaging study [14], and this microstructural changes were presented with disrupted myelin sheaths under electron microscopic study [15]. These literature reports indicate that migraine attacking may affect the TN with presentations on face, especially on the area innervated by the V2 of TN [12]. All these previous reports show migraine patients may have peripheral sensory presentations associated with TN or involvement of TN itself, a peripheral presentation of medication-resistant skin infection associated with migraine has never been reported. Here, we report, for the rst time, that antibiotic medication-resistant chronic facial infection on the regional skin innervated by V2 of TN was ceased by an effective treatment of migraine, indicating that migraine processing in the central nervous system can in uence skin immunomodulation through TN.
Folliculitis is a type of uncomplicated skin and skin structure infection (uSSSI) which includes cellulitis, simple abscesses, impetigo, erysipelas and folliculitis. The common pathogenic bacteria of uSSSI are staphylococcus aureus and streptococcus pyogenes [16]. Recently, a study of necrotizing fasciitis demonstrated that streptococcus pyogenes secretes streptolysin to directly activate nociceptor neurons inducing pain during infection. The activated neurons in spinal ganglion, in turn, release the calcitonin gene-related peptide (CGRP) from the neuronal ber terminals into the infected tissues, which inhibits the neutrophil recruiting and phagocytic killing of streptococcus pyogenes [17]. On the other hand, multiple studies have indicated that abundant CGRP secreted by trigeminal ganglion (TG) neurons interacts with adjacent neurons and satellite glial cells within TG to perpetuate both peripheral and central sensitization [18], and it is supposed with multiple evidences that central sensitization increase the propensity of either an external or an internal stimulus to trigger a migraine headache attack [18]. Thus, in our patient, it might be proposed that purulent infection around the nosewing may cause an activation of TG nociceptor neurons, the activated TG neurons secretes CGRP to sensitize the TN and brain and a migraine headache attack can be triggered by an external stimulus, a palpation of the skin, which may not be enough to generate a migraine attack in normal condition. Meanwhile, the activated TG neurons release CGRP from the TN terminals into the infected facial skin tissues causing a chronic infection as CGRP inhibits the phagocytic killing of pathogenic bacteria.
In conclusion, a bidirectional relationship between migraine headaches and chronic infection of regional skin innervated by TN terminals can be determined by the triggering role of TN stimulation under a condition of chronic regional skin infection, and by the maintaining role of migraine headaches in the chronic regional skin infection. This peripheral and central interaction in migraine might be associated with neuropeptide CGRP released from TG neurons.

Declarations Ethics Approval and consent to participate
The case study was approved by the Research Ethics Committee of the Anhui Medical University prior to study initiation. The patient provided written informed consent before the study procedure.

Consent for Publication
The patient provided written informed consent for publication of this article.  Facial folliculitis around the left nosewing. On regional skin around the left nosewing, small purulent heads of folliculitis were found (B) and some keloids with different degrees of pigmentation which as described by the patient as antecedent purulent heads (Square a and b on image A). B is the image magni ed from square c on image A.