possibly even hormonal changes related to menstruation.1 Currently, prevention of outbreaks of HSV is limited to oral antiviral therapy. However, targeting the delivery of activated virus from the nerve to the skin has not been examined.We have previously demonstrated the efficacy of BoNTA in improving psoriasiform skin inflammation in the KC-Tie2 mouse model of psoriasis3 and have attributed the improvement to blockade of sensory nerve derived Substance P and CGRP. These preclinical findings were successfully translated to the treatment of a recalcitrant buttock psoriasis plaque in a patient where intradermal injection of AbobotulinumtoxinA (Dysport) successfully resolved the plaque.4 Interestingly, when this patient’s psoriasis recurred 8 months after treatment, an HSV outbreak was noted on the contralateral buttock.In the current case, BoNTA injection prevented labial HSV outbreaks at the site of treatment. However, outbreaks did occur at untreated sites, suggesting that the prophylactic effect by BoNTA was specific to the region directly around the injection sites.Additional off-label uses of BoNTA include treatment for non-histaminergic itch,5-7 inverse psoriasis of the axilla and inframammary regions,8,9 and with doses of toxin between 50-100 total units/site. Here, we report prophylactic improvement in HSV outbreaks in the perioral region following intradermal treatment with 4 units of onabotulinumtoxinA (BOTOX®) or 15 units of abobotulinumtoxinA (Dysport®). At presentation the patient had monthly herpes labialis outbreaks for 5-6 years, and prophylactic BoNTA suppressed fulminant outbreaks across a period of 1.7 years. The timing of HSV relapse was aligned with the timing of glabellar line improvement and reappearance following intramuscular injection of BoNTA. To our knowledge, this is the first report of preventative efficacy in an HSV patient and identifies a novel use for BoNTA in prophylaxing against herpes labialis outbreaks.The effectiveness of BoNTA in preventing HSV labialis outbreaks highlights the active role that peripheral nerve networks play in influencing the frequency and severity of HSV reactivation. The dynamic interactions between sensory nerve termini and infected cell targets have been investigated in biopsy tissue during natural HSV-2 reactivation in humans.10In HSV-2 affected skin, the axonal nerve endings for releasing reactivated HSV viral particles are shown to sprout upward and form direct contacts with basal keratinocytes, the peripheral targets of HSV. These close interactions between nerve endings and basal keratinocytes implicate that the direct delivery of HSV viral particles to peripheral target cells might be required to achieve optimal and productive viral replication in the periphery. Additionally, HSV infection of keratinocytes has recently been shown to actively modify cutaneous nerve networks, promoting directional nerve fiber growth and branching toward the basal keratinocytes in local tissue.11This modification of the peripheral nerve networks observed in vivo in humans involves the production of IL17c by keratinocytes upon HSV infection and the functional interactions between IL17c and its receptor IL17RA/RE expressed on the nerve termini. Higher nerve fiber ending density has been associated with HSV affected skin as compared to uninvolved normal control skin. Together, these findings emphasize that the skin-innervating nerve networks, and their active communication with peripheral cell targets, shape the pathogenesis of HSV diseases in humans.The mechanisms by which BoNTA prevents HSV infection remain unclear. We hypothesize that similar mechanism of BoNTA-mediated blockade of synaptic vesicle release might occur. Specifically, that vesicles carrying HSV are prevented from being released into the cutaneous region innervated by nerve endings. The critical step during HSV reactivation is to release the reactivated virus particles from axon terminals to infect peripheral target cells, the basal keratinocytes. This egress step has been associated with axon varicosities.12,13Decreased Labial Herpes Simplex Virus Outbreaks Following Botulinum Neurotoxin Type A Injection: A Case Report
October 2018 | Volume 17 | Issue 10 | Case Reports | 1127 | Copyright © October 2018
Erin Gilbert MD PhD,a Jia Zhu PhD,b Tao Peng PhD,b and Nicole L. Ward PhDc,d
aBrooklyn, New York, NY bDepartment of Laboratory Medicine, University of Washington and Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA cDepartments of Dermatology and Neurosciences, Case Western Reserve University, Cleveland, OH dThe Murdough Family Center for Psoriasis, University Hospitals Cleveland Medical Center, Cleveland, OH
possibly even hormonal changes related to menstruation.1 Currently, prevention of outbreaks of HSV is limited to oral antiviral therapy. However, targeting the delivery of activated virus from the nerve to the skin has not been examined.We have previously demonstrated the efficacy of BoNTA in improving psoriasiform skin inflammation in the KC-Tie2 mouse model of psoriasis3 and have attributed the improvement to blockade of sensory nerve derived Substance P and CGRP. These preclinical findings were successfully translated to the treatment of a recalcitrant buttock psoriasis plaque in a patient where intradermal injection of AbobotulinumtoxinA (Dysport) successfully resolved the plaque.4 Interestingly, when this patient’s psoriasis recurred 8 months after treatment, an HSV outbreak was noted on the contralateral buttock.In the current case, BoNTA injection prevented labial HSV outbreaks at the site of treatment. However, outbreaks did occur at untreated sites, suggesting that the prophylactic effect by BoNTA was specific to the region directly around the injection sites.Additional off-label uses of BoNTA include treatment for non-histaminergic itch,5-7 inverse psoriasis of the axilla and inframammary regions,8,9 and with doses of toxin between 50-100 total units/site. Here, we report prophylactic improvement in HSV outbreaks in the perioral region following intradermal treatment with 4 units of onabotulinumtoxinA (BOTOX®) or 15 units of abobotulinumtoxinA (Dysport®). At presentation the patient had monthly herpes labialis outbreaks for 5-6 years, and prophylactic BoNTA suppressed fulminant outbreaks across a period of 1.7 years. The timing of HSV relapse was aligned with the timing of glabellar line improvement and reappearance following intramuscular injection of BoNTA. To our knowledge, this is the first report of preventative efficacy in an HSV patient and identifies a novel use for BoNTA in prophylaxing against herpes labialis outbreaks.The effectiveness of BoNTA in preventing HSV labialis outbreaks highlights the active role that peripheral nerve networks play in influencing the frequency and severity of HSV reactivation. The dynamic interactions between sensory nerve termini and infected cell targets have been investigated in biopsy tissue during natural HSV-2 reactivation in humans.10In HSV-2 affected skin, the axonal nerve endings for releasing reactivated HSV viral particles are shown to sprout upward and form direct contacts with basal keratinocytes, the peripheral targets of HSV. These close interactions between nerve endings and basal keratinocytes implicate that the direct delivery of HSV viral particles to peripheral target cells might be required to achieve optimal and productive viral replication in the periphery. Additionally, HSV infection of keratinocytes has recently been shown to actively modify cutaneous nerve networks, promoting directional nerve fiber growth and branching toward the basal keratinocytes in local tissue.11This modification of the peripheral nerve networks observed in vivo in humans involves the production of IL17c by keratinocytes upon HSV infection and the functional interactions between IL17c and its receptor IL17RA/RE expressed on the nerve termini. Higher nerve fiber ending density has been associated with HSV affected skin as compared to uninvolved normal control skin. Together, these findings emphasize that the skin-innervating nerve networks, and their active communication with peripheral cell targets, shape the pathogenesis of HSV diseases in humans.The mechanisms by which BoNTA prevents HSV infection remain unclear. We hypothesize that similar mechanism of BoNTA-mediated blockade of synaptic vesicle release might occur. Specifically, that vesicles carrying HSV are prevented from being released into the cutaneous region innervated by nerve endings. The critical step during HSV reactivation is to release the reactivated virus particles from axon terminals to infect peripheral target cells, the basal keratinocytes. This egress step has been associated with axon varicosities.12,13
