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Neuropathic

Persistent genital arousal disorder: a special sense neuropathy

Oaklander, Anne Louisea,b; Sharma, Saurabhc,*; Kessler, Katiec; Price, Bruce H.a,c

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doi: 10.1097/PR9.0000000000000801
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Abstract

1. Introduction

The anatomy and physiology—and thus the innervation—of sexual arousal are dimorphic, but it has been studied almost exclusively in male patients, and the peripheral and spinal pathways and neurotransmitters mapped primarily in rodents.15,16,27 Studies mapping human arousal are rare and mostly conducted in spinal cord–injured or multiple sclerosis patients.1,20 Veterans Administration and other investigators have studied effects of myelopathies, radiculopathies, neuropathies, and various medications on male arousal,20 but research in female patients is nearly nonexistent. Women's complaints of inappropriate arousal are typically attributed (by predominantly male evaluators) to psychopathology or misinterpreted as beneficial.4

Here, we begin neurological investigation of persistent genital arousal disorder (PGAD), a largely female-reported syndrome of out-of-context sexual arousal and/or orgasm. PGAD has been mostly investigated by psychologists. With physicians and neuroscientists largely unaware of it, medical causality has not been systematically investigated.14 Feigenbaum and Komisaruk established the firmest association to date, with sacral Tarlov cysts. These form exclusively on and can damage sensory ganglia and roots.2,11 Some cases are attributed to brain effects of serotonergic and dopaminergic drugs,5,22 and sexologists have hypothesized that other neurological problems may be associated, mentioning restless leg syndrome, fibromyalgia, genital sensory hyperesthesia, neuropathic pain, and sensory neuropathy, but we are unaware of previous neurologically focused investigations.7,8,17,19,22–24,26

2. Methods

A lack of standardized nomenclature (synonyms include persistent sexual arousal syndrome and restless genital syndrome) and billing codes precluded systematic case ascertainment, so we reviewed records from our university–hospital neurology practices for PGAD mentions and solicited additional referrals regardless of whether neurological symptoms were present. The review board waived consent, although we obtained verbal consent to anonymous publication. All genders and ages were eligible; inclusion required neurological evaluation of diagnosed or suspected PGAD, and some patients were reinterviewed. We analyzed demographics, medical histories and examinations, results about localization, etiology, and treatment.

3. Results

All participants were female, and on average 53.4 years old on December 31, 2018 (Table 1). Ages at PGAD onset ranged from puberty to postmenopausal. We identified 2 patterns of arousal—episodic and sustained. Eighty percent of patients reported daily transient sexual arousals (minutes/few hours) with 40% reporting longer, lesser near-continuous arousals for days-years (2 had both). All PGAD illnesses began as anorgasmic but almost always progressed to include spontaneous orgasms. Patient 4, with ≤30 arousals daily, had 2 unprovoked orgasms in front of a hospital teaching-conference audience. Almost all patients tried masturbation to terminate arousals, and this helped 20%.13 Patient 10 masturbated 4 to 5 times daily despite the lack of pleasure, to obtain a few hours relief. Patient 3 induced several orgasms each afternoon to quell symptoms until the next morning. Five reported no postorgasm refractory relief, and patient 6 avoided all vulvar contact because of allodynia.

Table 1
Table 1:
Patient characteristics.
Table 1-a
Table 1-a:
Patient characteristics.
Table 1-b
Table 1-b:
Patient characteristics.

Chronic PGAD always terminated sexual relations. All 6 partnered patients initially sought sex during their arousals, but all of their partners came to perceive their approaches as too frequent and/or “mechanical,” and terminated sexual relations, although all marriages continued. Among the 3 patients who were virgins at PGAD onset, 2 remained abstinent and 1 tried intercourse only once, an encounter abrogated by vulvodynia. Every patient reported that PGAD caused new or worse depression and anxiety. Onset in childhood was bewildering, causing confusion, shame, and fear. All patients considered themselves disabled from PGAD and associated symptoms, and most had curtailed daily activities. At presentation, only 20% of patients' physicians recognized their symptoms as PGAD, so most self-diagnosed online. Before onset, all were functioning well and none had major psychiatric diagnoses, yet several reported psychiatric attribution and treatment—for example, with sex therapy and electroconvulsive treatments.

Eighty percent of patients first sought care for their other pelvic symptoms and only mentioned PGAD after establishing trust. Among medical consultations, neurological evaluations were the most productive. They documented colocalizing somatosensory symptoms in 90%, including perineal, buttock, or leg pain and/or sensory loss. Neurological testing was also productive, with 78% (6/8) of sacral magnetic resonance imaging studies revealing radiculopathy, 2/2 nerve-conduction studies diagnostic for sensory polyneuropathy along with 2/5 lower-leg, PGP9.5-immunolabeled skin biopsies. Among 2 composite autonomic function tests, 1 was abnormal, the other borderline. Abnormal urodynamic and anorectal manometry testing confirmed myelopathy in the spina bifida patient. Four electroencephalograms in 2 patients were unremarkable, including one capturing 4 spontaneous orgasms.9

Psychiatric treatment was universally ineffective, including 7 psychiatric hospitalizations and 17 electroconvulsive therapy sessions for patient 10. Gynecological and urological treatments, including medications, injections, and electrotherapies, were also ineffective. Local anesthetics and/or corticosteroid injections never had lasting benefit, but a few gave temporary relief, suggesting the potential for diagnostic localization of hyperexcitable sensory nerves as with neuropathic pain conditions. Genitofemoral nerve blocks gave transient relief to 2/3, but pudendal nerve blocks were ineffective or worsened symptoms in 5/5. All epidural corticosteroid injections worsened symptoms. One intravaginal botulinum toxin administration was ineffective.

By contrast, neurological treatment was effective in 80% of patients. Gradual duloxetine taper (patient 5) and Tarlov-cyst resection (patient 2; Fig. 1) were curative. Immunoglobulins (2 grams/kg/4 weeks) improved patient 8's PGAD and motor symptoms dramatically. Another Tarlov-cyst patient found intrathecal pressure reduction helpful, whereas surgical resection was ineffective for another.

Figure 1.
Figure 1.:
Magnetic resonance imaging identifying sacral Tarlov cysts (patient 1). (A) Sagittal view. Green arrows depict trilobed, multiseptate T2 hyperintense, T1 hypointense nonenhancing Tarlov perineurial cysts in the left L5-S1, left S1-S2, and left S2-S3 neural foramina (right S1-S2 cysts were also present and seen on other images). (B) Coronal view. Green arrows depict multiseptated T2 hyperintense, T1 hypointense perineurial cysts in the same patient. The largest cyst, at left L5-S1, tracks along the course of the L5 nerve root and measures 6 cm in greatest dimension.

4. Discussion

This report associates PGAD with disorders and lesions of the lower spinal cord, roots, and nerves that control sexual arousal and orgasm. Genital sensory innervation is mostly through the dorsal nerve of the clitoris/penis, a branch of the pudendal nerve that enters the cord through S4 dorsal roots to excite T12-S1 dorsal-horn interneurons (lamina VI and X27)1,16 and send axons up the dorsal columns and gracile fasciculus to affect the brain widely.3,12 In female rats, electrophysiological recordings link pelvic contractions to rhythmic pudendal nerve firing, with L4 spinal cord injury increasing this firing.1 Autonomic mapping in mice identifies hypogastric sympathetic afferents entering at L2,16 with efferents exiting the T12-L2 ventral roots and white rami to synapse paravertebrally then send postganglionic fibers through gray rami to the hypogastric nerve. Parasympathetic efferents arise from S2-5, exit as splanchnic nerves through the inferior hypogastric plexus to synapse in ganglia in pelvic organ walls, and increase pelvic blood flow and other arousal responses.

Given our patients' lesion localizations, etiologies, and colocalizing neurological signs and symptoms, we propose that at least some PGAD cases arise from lesions affecting the sacral sensory networks that transmit sexual arousal—that it is a disorder of special sensation akin to neuropathic pain and itch. To reflect this, we propose congruent Greek-derived neurophysiologic nomenclature. For sexual arousal after nonsexual stimulation, we suggest “allodiegersis” (allo/άλλο) for “other” plus diegersis/διέγερσης (sexual arousal), analogous to “allodynia” for pain and “alloknesis” for itch. For spontaneous sexual arousal or orgasm without physical or mental stimulation, we propose “aftodiegersis” from aftomato/αυτοματο (unprovoked) and diegersis/διέγερσης (sexual arousal). A genitopelvic nosology has been developed,19 but adding conventional neurological nomenclature could improve general medical awareness, care, and research.

Our findings will have clinical implications if confirmed because most PGAD patients now linger medically undiagnosed and untreated. Patient-initiated internet sites document thousands of (usually female) questioners. Therefore, this small series, although among the largest of examined patients, cannot fully represent PGAD nor provide accurate prevalences, causes, or treatment outcomes because of referral bias. However, it offers an interim clinical framework. It independently identifies sacral dorsal root Tarlov cysts as causal2,11 and strengthens associations with sensory polyneuropathy. It adds another case associated with lumbosacral disc herniation and proposes cauda equina malformation and sensory CIDP as potential new causes. It associates PGAD with abrupt duloxetine withdrawal, given that duloxetine resumption was curative, extending reported associations beyond initiation of libido-promoting drugs (eg, dopaminergics) and abrupt discontinuation of libido-inhibitors (eg, serotonergic antidepressants).5,6,8,22 It is unknown whether the synapses involved in drug-associated PGAD are central or peripheral. In patient 8, the fact that immunoglobulin treatment resolved not only motor CIDP symptoms but also reduced PGAD-symptomatic days from 30 to 4/month and stopped spontaneous orgasms suggests potentially broader associations between PGAD and sensory polyneuropathy, and potential effectiveness of standard neuropathy treatment for PGAD. Patient 4 developed isolated PGAD with only L5-S1 disc herniation identified. Given her L5 foraminal but not central stenosis, if this contributed, impingement of entering clitoral afferents was a more likely source than the conus medullaris.16 Given the high prevalence of disc herniations, her PGAD may be unrelated, but the associations of PGAD with sacral radiculopathy from Tarlov cysts convey plausibility.

Female over-representation of published PGAD is high—we know of only 5 to 6 unique male cases (including 1 with L5-S1 disc herniation and 2 with small-fiber polyneuropathy).8,10,21,24 Conceivably, male patients merely seek treatment less often, but we propose 3 biological contributors. A total of 90% to 95% of symptomatic Tarlov-cyst patients are women, because of their thinner meninges and tilted pelvis containing more-vertical nerve roots more exposed to CSF pressure waves. In addition, female patients represent 3/4 of many small-fiber neuropathy cohorts,13 and 2/3 of US antidepressant users.18 Female patients thus have a higher risk of associated neurologic conditions.

For lesion localization, 3-mm-cut sacral MRI and tests for neuropathy were highly useful. Pudendal nerve conduction should be measured more often, particularly with glove electrodes now standard. Brain MRI and EEG were futile.23 Regarding treatment, skilled neurosurgeons report good outcomes for Tarlov-cyst resection.2 Medical management of PGAD symptom should include gradual tapering of causal medications, and perhaps considering libido-dampening drugs. For nerve and nerve-root lesions, tricyclics, ion-channel blockers, and antiepileptics—effective for neuropathic pain and itch—deserve consideration. Neurological evaluation and treatment should precede psychotherapy, electroconvulsive therapy, or clitoridectomy.25

Disclosures

The authors have no conflict of interest to declare.

Supported in part by NIH R01NS093653 and K24NS059892 (to A.L.O.) and Sydney R. Baer Jr. Foundation (to B.H.P.).

Presented in abstract form to the 2018 meeting of the International Association for the Study of Pain.

Acknowledgements

The authors appreciate the referral of two patients by neurourologist Dr. Elise De and the assistance of Dr. Marinos Dalakas with Greek terminology.

References

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Keywords:

Neuropathic pain; Pelvic pain; Tarlov cysts; Peripheral neuropathy; Spinal cord; C-fibers

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.