Chronic Sciatica Induced by Endometriosis

examinations. The findings that endometrial-like tissue can develop at the sciatic nerve, offer new insights for better understanding and treating sciatic endometriosis. Many studies have reported that the symptoms could be alle-viated by surgically removing the endometriotic lesions. New evidence showed that in a rat model, sciatic endometriosis could cause neuropathic pain and local inflammation. Summary: This article is aimed to review reports about chronic sciatica induced by endometriosis, explore the possible mechanisms and come up with effective treatments.(Funded by the National Institutes of Health.) ABSTRACT


Pathophysiology and Pathogenesis
Retrograde menstruation, coelomic metaplasia and embryonic cell rests have been presented as the most reasonable hypotheses of pathogenesis of endometriosis (9), with retrograde menstruation phenomenon being the most well-accepted theory (1,10). For peritoneal endometriosis implants, it is generally considered to be implanted after endometrium fragments flow into peritoneal cavity along with retrograde mense (11,12,13). Referring to endometriosis of the sciatic nerve, a highly acknowledged concept is about an anatomic sign which was first described by Head as "pocket sign" -a peritoneal invagination, downward toward the greater sciatic notch, in the posterior part of the pelvis (14). The first case of endometriosis-induced sciatica was described by Schlincke in 1946 (15). There are two types of endometriosis of the sciatic nerve basically -deep infiltrating endometriosis of the rectovaginal septum with the involvement of the sciatic nerve roots, which can be seen as endopelvic endometriosis, and isolated endometriosis of the sciatic nerve. Some endometrial foci were found within the sciatic nerve itself -under the sheath, which is one of the rarest variations of the condition (16).
Endometriosis is also considered as a disease with dysfunction immune system. It was reported that endotoxin (LPS), a potential inflammatory mediator, concentration in menstrual fluid (MF) / peritoneal fluid (PF) was significantly higher in women with endometriosis than those without endometriosis. The elevated LPS promoted the growth of endometriotic cells at the ectopic site, contributing the development and maintenance of endometriosis (17). In endometrial lesions, infiltrating macrophages was considered as a consistent feature. With the activation of macrophages, a large amount of vascular endothelial growth factor (VEGF) was generated and initiated neovascularization in the new tissue (18).

Pain Symptoms
Symptoms of endometriosis are often described as infertility and chronic pain. The most essential problem is chronic pain, which can occur unpredictably, be related to the menstrual cycle or even continuous (1). Most of the endometriosis patients suffer from chronic pelvic pain (dysmenorrhea, chronic pelvic pain, dyspareunia -painful sexual intercourse, dysuria -painful urina-tion, dyschezia -painful defecation, et al.). Of patients who have endometriosis of the sciatic nerve, lesions of the ipsilateral sciatic nerve are reported as the primary cause of almost all the endometriosis-induced cyclic sciatica (9). Some case reports showed that those reproductive-age women with catamenial sciatica-like pain should consider sciatic nerve endometriosis and which were verified by histology and pathology as sciatic endometriosis. Cyclic sciatica caused by biopsy-proven endometriosis was first described in 1955 (19). Catamenial pain, weakness and sensory loss are presented as the most frequent symptoms of endometriosis of the sciatic, femoral or lumbosacral nerve roots (20).
It is estimated that 40% of women affected by endometriosis have leg pain, mostly cyclic sciatica-like pain appearing along with menstruation -catamenial sciatica-like pain with normal CT or MRI of the spine (21). Sciatica is traditionally defined as pain along the distribution areas of the sciatic nerve. Combined by L4, L5, S1, S2 and S3, the roots of sciatic nerve exit the spinal cord. Endometriosis lesions either form around the five roots or directly involve the peripheral sciatic nerve can cause irritation, which leads to sciatica. Due to the property of endometriosis as estrogen-dependent (22), this kind of sciatica is cyclic and catamenial, and it is considered as referred pain (23) and neuropathic pain (24,25,16), with the latter one thought by clinical doctors and researchers as endometrial foci is found around peripheral nerves and causes inflammation or damage to the nerves. Some researchers think most cyclic leg pain is referred, with endometrial lesions locating at posterolateral pelvic peritoneum irritate the roots of the sciatic nerve (23).
Having much likeliness with endometriosis of the bladder or bowel, endometriosis lesions involve the sciatic nerve are highly destructive which cause dysfunction of the sciatic nerve. Patients often complain having thigh pain even down to the posterior or lateral aspect of the calf to the foot, sometimes along with sensory loss, muscle weakness, and reflex alterations (26), depending on the extent of sciatic nerve damage. Also, women with sciatica are usually sent to orthopedic or neurology departments, causing the delay of diagnosis (27). Thus, we should pay much more attention to this kind of disease that is hard to diagnose and easy to be neglected (28), and come up with effective treatment plans before the damage becomes irreversible.

Pain Mechanisms
Several mechanisms of pain in endometriosis have been described as inflammatory, nociceptive or neuropathic mechanisms, and there is evidence that all three of these mechanisms are relevant to pelvic pain that endometriosis-associated ( Figure 1) (29).
For intrapelvic endometriosis, endometrial fragments which shed into the pelvic cavity adhere to the peritoneal surface, sometimes even invade into the abdominal wall, causing local and systematic inflammation, which can lead to unpredictable, catamenial or continuous pain. Several serum protein markers like c-reactive protein (CRP) and serum amyloid A (SAA) have already been found increasing in some patients have stage III and IV endometriosis (30). There is a wide-accepted theory of the etiology of endometriosis is dysfunction of immune cells, which is studied mostly in peritoneal fluid (31,32). With nature killer (NK) cells' defect activity and a decreased cytotoxicity to endometrial cells, it is thought to promote implantation of endometrial tissue as a tissue graft (33). It has The table demonstrated the possible contributors for endometriosis in general. An increase in genetic mutation or a history of endometriosis in family members, a history of menstrual issues and other factors like smoking and alcohol consumption can also cause the development of endometriosis. The risk is presented as the direction of the arrow (upward=increase of risk; downward=decrease of risk).
Nociceptive pain includes 4 basic stepstransduction, transmission, modulation and perception (27). The nerves that primarily consider as nociceptors are C and Aδ fibers. Endometriotic foci were found innervated mainly by sensory C and sensory Aδ, which can be nociceptors for noxious stimuli -endometriotic lesions (46). There are also studies verify that sensory and sympathetic nerves invade the ectopic endometrial tissue both in rat model (47) and in human researches (48)(49)(50)(51)(52). The ectopic foci can develop sensory and sympathetic nerve supply, connecting itself with the central nervous system. Chen et al. found that when autologous uterus tissue was implanted onto sciatic nerve of rat established sciatic endometriosis and caused pain and local inflammation, and by surgically removing the endometriosis lesion could reverse the painlike symptoms (53). Some clinical studies also showed that after surgically remove the foci, there was obvious alleviation of pain (54,55).
Neuropathic pain is pain produced by damage to or dysfunction of neurons in the peripheral or central nervous system. Growth-associated protein (GAP) -43 is a marker molecule for neural outgrowth and regeneration, which is moderately to strongly expressed in endometriosis-associated nerve fibers, supporting the possibility of neuropathic pain (56). In rectovaginal septum endometriotic nodules, a high proportion of the nerves are found, and there is a significant correlation between nerves and ectopic endometrium tissue, which may invade the nerve perineurially (47). Sometimes endometriosis patients feel an increased level of pain due to central sensitization but not peripheral nerves damage (48,57).
With the many possible causes of leg pain in women with endometriosis, it is unknown that if it's due to one or more peripheral nerve directly affected or co-existing pathologies (21). Sometimes intrapelvic inflammatory endometriomaespecially deep infiltrating endometriosis of the rectovaginal septum can affect the nerve and axon nearby -like a neuritis, and cause leg pain (58). Assume that cytokines produced by inflammation of endometriosis lesion can also irritate nearby nerves as nociceptive pain generators. During each menstrual cycle, with ectopic endometrium cells affected by level changes of estrogen and progesterone, foci in or around the sciatic nerve undergoes hemorrhage into the surrounding tissues and can cause considerable inflammation (16). However, there are few reports about mechanisms how lesions directly involve the peripheral sciatic nerve outside the pelvic cavity causing leg pain. Chen et al. (53) found that sciatic endometriosis caused robust local inflammation and sciatic nerve damage at the affected area, which contributed to sciatica. There were elevated pro-inflammatory cytokines at the ectopic site. The local inflammation and the compression from the endometrial cyst caused nerve damage, and then induced neuropathic pain. At the same time, the inflammatory cytokines could be stimulators damaging the surrounding tissues and cause nociceptive pain. However, there was no evidence of newly grown nerve fibers in the endometrial cyst tissue.
Moreover, it is well-accepted that changes in the central nervous system also contribute to chronic pain in endometriosis patients (59,60). However, there is a lack of further studies regarding sciatic endometriosis specifically.

Diagnosis and Management
Diagnosis often relies on typical sciatica beginning just a few days before menstrual cycles and lasting almost the whole menses, with no low back pain experienced. With the hemorrhage of endometrium-like tissue going on, the MRI can be presented as a specific diagnosis of sciatic endometriosis and is recommended for evaluation of endometriosis-induced sciatica when the pain level appears differently during the menstrual cycle or with patients who have a history of endometriosis (61). MRI findings of sciatic nerve endometriosis are mostly described as a mixed sig-  nal(s) in the sciatic nerve -usually between the sciatic notch and greater trochanter, with hemorrhage within the mass. Lesions can be surgically removed during surgical exploration, then proved as endometrial tissues histologically and pathologically. Management of endometriosis mainly includes treatment for infertility and treatment for chronic pain (Figure 2). Both medical and surgical approaches can be used in women with endometriosis. Medical therapy can always be an essential part of this estrogen-dependent disease, for instance, GnRH agonists, danazol, gestrinone, and oral contraceptives and progestins. The goal is to achieve a respectively stable hormone milieu and to reduce the endometrial cells proliferation. In the USA, most patients receive a surgical treatment within the first year of diagnosis. Associated with chronic pain and infertility (1), to treat those patients and maintain life quali-ty is costly (US$706 per month) (62).
Treatment for infertility can be divided into two parts. One is surgically removing ectopic endometrium tissue and to resume the normal relationships of pelvic organs. The other one is overlooking the abnormal pelvic environment and perform in vitro fertilization (IVF), which retrieve oocytes directly from the ovaries and place the embryo in the uterine cavity (22). Also, in cases of endometriosis of the sciatic nerve, conservative surgery which only removes endometrium tissue from the nerve can be successful for whom want to keep reproductive function (63). However, medical treatment has no effect on infertility in women with endometriosis (22). For pain management, GnRH-agonist has been studied more than other medical treatments (64). Recent studies show that without postoperative hormonal therapy, recurrence of pain symptoms is becoming what puzzle both doctors and patients Volume 5 Number 6 November, 2018

Figure 2. Retrograde Endometrial Tissues Adhere to Ectopic Sites and Form Endometriosis.
Endometriosis causes both infertility and chronic pain. Specifically, sciatic endometriosis causes cyclic or ongoing sciatica due to local inflammation and/or nerve damage induced by ectopic endometrium infiltration. Current treatments regarding the symptoms of endometriosis focus on surgically removing ectopic tissue, which can treat most cases of endometriosis, and IVF for infertility or medication for pain management.
the most (65). Sometimes pain recurs without lesions grow back. Nafarelin, a GnRH agonist, using 6 months after surgical treatment, can delay the recurrence of pain symptoms (66). According to some research findings, long-term oral contraceptive pills can reduce the recurrent of pain induced by endometriosis (67).
It is often difficult to assess the efficacy of both medical and surgical treatments. There is also no significant superiority of one over the other. However, since different endometriosis patients might possess different types of pain, there is evidence that medical treatment is sometimes preferable in specific cases. For example, GnRH agonist was found more effective than oral contraceptives targeting dysmenorrhea (68). A prospective study with 2-5 years follow-up showed that a majority of endometriosis patients benefited from laparoscopic excision surgeries, and only 36% of them would require further surgery because of recurrence of endometriosis which was confirmed histologically (69). Taken the recur-rence of endometriosis into consideration, it is necessary to combine medical treatment after an excision surgery as a long-term plan. It has shown that six months of GnRH application after laparoscopic surgery generated a greater relief from endometriosis-induced pain and a delay of a necessity of further treatment (70).
Brought out are also psychosocial consequences as depression, anxiety, decreased quality of life and work efficiency (71,72), which can' t be ignored and should be treated as well. Endometriosis, as a chronic condition, often negatively affects patients intimate relationships as well (73). More commonly, researchers have found out endometriosis has a huge impact on patients working lives. Generally, women who are diagnosed as endometriosis have an average of 13% loss of work time, and the economic burden associated with treating endometriosis can be extremely high and comparable to other comorbidities with chronic nature (74). At last, endometriosis is also associated with higher rates of depression, anxi- ety and emotional distress (74,75).

Conclusions
In a nutshell, great progress has been made in recognizing, diagnosing and treating endometriosis (76,77). As early as in 1980, rabbits were used to perform autologous transplant to induce endometriosis (78), with also hamsters (79) and rats (80,53). Lots of studies have been focusing on using animal models to get to know better about endometriosis. However, for endometriosis of the sciatic nerve, the development, pathogenesis, pain mechanisms, and treatments are still not fully-known, let alone well-practiced in clinical use. In the future study, new animal mod-els of sciatic endometriosis should be established, so that researchers can dig into the mechanisms and come up with better, even more, individual treatment plans. In this regard, more efforts need to be made, both theoretical knowledge and clinical approaches, aiming at pain relief, reproductive ability regaining, and reducing expenditure on health care.
This study was supported in part by grants (NS045594, NS055860, and AR068989) from the National Institutes of Health.
The authors declare no conflicts of interest.