Definition and Etiology

Orchitis is defined as inflammation of the testicle, [1] and may be due to infectious or non-infectious causes. Infectious etiologies can be bacterial or viral, and the most common offending organism varies based on patient age. In 20–40% of cases of infectious orchitis, infection spreads contiguously from the epididymis to the testis [2]. In men younger than 35 years old, the most common organisms are the sexually transmitted pathogens C. trachomatis and N. gonorrhea, whereas in prepubertal boys and men older than 35, causative bacterial organisms are more frequently derived from urinary sources including E. coli and P. mirabilis [3, 4]. Other organisms include atypical pathogens such as brucellosis (B. melitensis), Cryptococcus (C. neoformans), and tuberculosis (M. tuberculosis) which may originate in the upper genitourinary tract. Orchitis has also been reported in men who have been treated with intravesicular bacillus Calmette-Guerin (BCG) therapy for bladder cancer, which may present with subacute symptoms and hypoechoic lesions on ultrasound [5].

Viral orchitis is disseminated by hematogenous route or may represent a direct viral infection via the epididymis [6]. The mumps virus is the most common viral etiology of orchitis, involves both testicles in 15–30% of cases, and can lead to oligospermia and male factor infertility if contracted after the onset of puberty [7]. Childhood vaccination is the best way to prevent mumps orchitis and its sequelae [8]. Enteroviruses and adenoviruses have been implicated in culture-negative epididymoorchitis, [9] and most recently the Zika virus has been associated with orchitis and testis damage leading to infertility in animal models [10].

Non-infectious causes of orchitis may be autoimmune, drug-induced, or ischemic. Autoimmune orchitis is associated with the presence of antisperm antibodies, and may be associated with male factor infertility. Primary autoimmune orchitis is typically asymptomatic and associated with isolated infertility, whereas secondary autoimmune orchitis usually presents with acute symptomatic orchitis and may be associated with other autoimmune diseases including rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus, and others [11]. Drug-induced orchitis has also been reported with immune checkpoint inhibitors [12]. A rare etiology of non-infectious orchitis is segmental testicular infarction. Cases of segmental testicular infarction have been reported in the setting of embolus, drug-induced or autoimmune vasculitis, sickle cell disease, polycythemia, intimal fibroplasia of the spermatic artery, trauma, and intermittent testicular torsion, though the majority of cases are idiopathic [13–17].

Similar to orchitis, epididymitis is defined as an inflammation of the epididymis [1] and can be caused by a variety of conditions including infection, autoimmunity, trauma, vasculitis, and other idiopathic inflammation. Acute epididymitis is thought to be due at least in part to retrograde flow of urine into the ejaculatory ducts, through the vas deferens and to the epididymis. This theory is supported by the fact that 56% of older men diagnosed with acute bacterial epididymitis have concomitant benign prostatic hyperplasia with bladder outlet obstruction, urethral stricture disease, or prostate cancer. Dysfunctional voiding has been identified in 10% of patients with non-infectious epididymitis. However, reflux of urine cannot be the isolated etiology of epididymitis, as patients who have undergone vasectomy can also present with epididymitis. This is thought to be due to congestion and inflammation from obstruction and formation of sperm granulomas which results in a local reaction surrounding nerves and vasculature [18]. Epididymitis in children is often an inflammatory process following an acute viral infection [9].

The infectious etiologies of epididymitis are similar to those of orchitis. In sexually active men younger than 35, C. trachomatis and N. gonorrhoeae are the most frequent causative organisms in acute epididymitis, whereas E. coli is the most common infectious pathogen in men older than 35 [19]. Other bacterial pathogens less commonly seen include U. urealyticum, Corynebacteria species, Mycoplasma species, and M. polymorpha [20], as well as B. melitensis, M. tuberculosis, and C. neoformans [2]. M. tuberculosis can cause a chronic infectious epididymitis, thought to be due to hematogenous spread [21].

Non-infectious etiologies of epididymitis may include sarcoidosis, Behcet’s disease, or certain drugs. Behcet’s disease is an idiopathic multiorgan vasculitis, which may result in chronic vasculitis and subsequent chronic epididymitis with periodic exacerbations [22]. Men undergoing treatment with intravesical BCG for bladder cancer may develop tuberculous epididymitis. Amiodarone has been shown to cause a drug-induced epididymitis in 11% of patients on high-dose amiodarone, due to anti-amiodarone HCL antibodies which attack the epididymal lining [22–24].

Chronic epididymitis presents with varying degrees of chronic epididymal discomfort lasting longer than 3 months, which may or may not be associated with other clinical signs of infection or inflammation [25]. It may be classified into one of three categories, including inflammatory epididymitis, obstructive epididymitis, or chronic epididymalgia. Inflammatory chronic epididymitis is defined as pain and discomfort associated with swelling, induration, or other physical exam findings consistent with inflammation, due to infectious, granulomatous, drug-induced, or idiopathic etiologies. Obstructive chronic epididymitis results from obstruction of the epididymis or vas deferens due to congenital, acquired, or iatrogenic causes. Chronic epididymalgia is defined as pain or discomfort with a normal physical exam and no identifiable etiology [25].

In the pediatric population, epididymoorchitis is a rare presentation of the acute scrotum. There are several theories for the etiology of this condition in children, including reflux of infected urine into the ejaculatory duct, chemical irritation from reflux of sterile urine, as well as direct infection or hematogenous spread of infection. Dysfunctional voiding has been identified in children with acute epididymoorchitis, with common findings including elevated post-void residuals and meatal stenosis. Epididymitis in children may also be caused by posterior urethral valves, or direct insertion of an ectopic ureter into the urethra adjacent to the ejaculatory ducts or into the seminal vesicle, resulting in reflux of urine and recurrent acute epididymitis. An ectopic ureter may also cause external compression and obstruction of the epididymis [26–29]. Evaluation of urinary tract anomalies in children with recurrent epididymoorchitis should be considered [6, 30].

Clinical Signs and Symptoms

The typical symptoms of orchitis include scrotal pain, swelling, tenderness, and skin fixation over the testicle. Relief of pain with elevation of the testicle, or Prehn’s sign, has been described in epididymoorchitis [31]. However, this is nonspecific and nondiagnostic and cannot reliably distinguish epididymoorchitis from testicular torsion.

In addition to causing pain, orchitis can cause an irreversible effect on spermatogenesis, impacting the quality and number of spermatozoa. In the acute setting, sperm concentration can decrease for 3–6 months and typically recovers spontaneously. However, some studies have shown that azoospermia may persist in 10% of patients, and oligospermia with alterations in sperm quality persists in 30% of men following an episode of orchitis [32]. In cases of chronic orchitis, lymphocytic infiltration and seminiferous tubule damage can be seen on testicular biopsies of subfertile men [33].

Symptoms of acute epididymitis can be similar to those of orchitis, and usually include pain and swelling which develops over several days. A patient may also have a positive urine culture, fever, skin erythema, leukocytosis, a reactive hydrocele, or involvement of the ipsilateral testis [18]. Patients who undergo urinary tract instrumentation or intermittent catheterization are at higher risk of developing infectious epididymitis, especially if the urine is infected at the time of instrumentation [34, 35]. As discussed above, patients with chronic epididymitis can have epididymal tenderness with or without palpable abnormalities or abnormalities on scrotal ultrasound [36]. Chronic epididymitis may be associated with erectile dysfunction, neurological diseases, and musculoskeletal complaints [18]. These men have been shown to have a greater number of sexual partners, a more frequent history of sexually transmitted disease, and have more frequent unprotected intercourse when compared to controls [25]. Children with epididymitis often present with an acute scrotum and sonographic hyperemia on Doppler, with or without leukocytosis, fever, positive urine culture, or pyuria [37].

Chronic epididymitis has been associated with male factor infertility. This has been associated with oligoasthenospermia and alterations in spermatozoa DNA integrity [38]. A recent study evaluated antisperm antibodies using the mixed antiglobulin reaction test and found significant antisperm antibodies in patients with clinical and ultrasound features suggestive of chronic epididymitis. This data further supports epididymitis as a potential underlying etiology of male factor infertility [39]. Other etiologies of epididymitis, such as sarcoidosis and tuberculosis, can lead to obstructive azoospermia via granulomatous epididymal deposits or extrinsic compression of epididymal ducts [40, 41].

Diagnostic Evaluation

A thorough history and physical examination are the most valuable aspects of the diagnostic evaluation of men with acute scrotal pain and swelling. Microscopic examination of a first-void urine specimen should be obtained. Patients younger than 35 years of age should undergo gram stain of urethral secretions and if ≥2 white blood cells (WBCs) per oil-immersion field are visualized, or if they are found to have ≥10 WBCs per high-powered field (HPF) or a positive leukocyte esterase test on microscopic examination of a first voided urine specimen, further evaluation for an infectious etiology should be pursued. To confirm the presence of N. gonorrhea or C. trachomatis, nucleic acid amplification or urine PCR may be performed. In patients older than 35 years of age, presence of leukocyte esterase or ≥10 WBCs/HPF on a first voided urine should prompt a urine gram stain and culture [42]. Children, adolescents who are not sexually active, and patients older than 35 years of age, should provide a midstream urine specimen. Patients with indwelling ureteral stents, recent anal intercourse, or recent urinary tract instrumentation should undergo urine culture. Patients found to have N. gonorrhea or C. trachomatis should undergo testing for other sexually transmitted infections including HIV and syphilis [42].

Ultrasound is utilized primarily to evaluate the acute scrotum with the intent to rule out testicular torsion, and should be reserved for patients in whom the diagnosis of epididymoorchitis is unclear. Ultrasound is not needed to make the diagnosis of epididymitis or to direct therapy [42]. In men with epididymoorchitis, ultrasound typically reveals an enlarged, hypoechoic, heterogeneous epididymis, or the epididymis may appear hyperechoic in the presence of hemorrhage. Scrotal wall thickening, reactive hydrocele, or pyocele may also be seen. Color Doppler may show increased blood flow, or hyperemia, to the epididymis or testis [43–45] (Fig. 18.1).

In patients with clinical orchitis, scrotal ultrasound should be considered as testicular malignancy has been reported to masquerade as orchitis [46], and at least 10% of men with a testicular malignancy will initially be incorrectly diagnosed with an acute inflammatory process or testicular torsion [47]. Additionally, a history of prior epididymoorchitis has been shown to be associated with an increased incidence of testicular cancer [48]. High-frequency transducer sonography (7.5–10 MHz) is considered the best imaging modality for evaluation of scrotal pathology [2]. Incidental testicular microlithiasis is a relatively common finding in up to 19% of scrotal ultrasounds performed for a variety of reasons [49], and has been hypothesized as an etiology of orchitis in some case reports [50, 51]. In the absence of risk factors for testicular malignancy, microlithiasis is not associated with an increased risk of testicular cancer [49].

Segmental testicular infarction appears as a wedge-shaped hypoechoic lesion in the testis and may be difficult to distinguish from a malignant process. Testicular tumor markers should be obtained in this setting to assist in the diagnosis. Arterial infarctions are more often visualized as wedge-shaped lesions in the upper poles of the testes, whereas venous infarctions (more commonly seen in epididymitis or germ cell tumors) appear in a more rounded pattern. Absence of vascularity on color Doppler ultrasound may also suggest infarction rather than a malignant lesion [17]. If the diagnosis remains unclear, T2-weighted and post-enhanced magnetic resonance imaging (MRI) has been shown to be useful [52].

Children with acute epididymitis and positive urine cultures should undergo renal ultrasound and VCUG. Ultrasound examination of the kidneys and urinary bladder without VCUG is adequate for children with acute epididymitis and a negative urine culture [37].

Treatment of Infectious Orchitis

The Center for Disease Control and Prevention (CDC) recommends a course of doxycycline 100 mg orally twice per day for 10 days, along with a single intramuscular injection of ceftriaxone 250 mg in young men in whom sexually transmitted infection is suspected, or a 10 day course of a fluoroquinolone in men in whom an enteric organism is suspected [19]. If sexually transmitted infection is suspected, treatment of sexual partners is recommended as well. Patients with severe bacterial orchitis should be admitted and treated with intravenous antibiotics including aminoglycosides, cephalosporins, or combinations of both, until culture results are available and sensitivity-specific adjustments can be made. Rarely, severe epididymoorchitis can result in testicular ischemia, abscess, or chronic pain, and orchiectomy may be required [53, 54].

Treatment of Acute Epididymitis

If the patient appears toxic, has systemic symptoms (fevers or leukocytosis, necrotizing fasciitis, testicular infarction) or has significant comorbidities (immunosuppression, uncontrolled diabetes mellitus), then hospitalization is warranted where close observation, supportive care, parenteral antibiotics, and fluid resuscitation can be administered as needed [18, 42].

Treatment of Chronic Epididymitis

Although there is no level-one evidence for the optimal treatment of chronic epididymitis, local supportive therapy including heat, nerve blocks, analgesics, tricyclic antidepressants, anticonvulsants such as gabapentin, and anti-inflammatory drugs are common practice and may offer some relief [18]. Other treatment options implemented for chronic epididymitis include phytotherapy, anxiolytics, narcotics, acupuncture, and steroid injection therapy [25]. Despite evidence that up to 75% of patients do not have an identifiable bacterial urinary tract infection in the setting of clinical epididymitis, antibiotics are still routinely given. Antibiotic administration does not decrease the duration of symptoms or the return to full activity in men without an identifiable bacterial pathogen and are overprescribed for epididymitis [18].

Surgical Treatment of Chronic Epididymitis

Surgical treatment for chronic epididymitis is poorly studied in clinical trials, with no level-one evidence to support the use of a specific surgical procedure. We do not advocate orchiectomy for chronic epididymoorchitis, but if orchiectomy is recommended, the patient should previously have failed conservative therapy and must be apprised of the risks and benefits of orchiectomy, including the risk of incomplete pain resolution. If orchiectomy is performed for chronic pain, an inguinal approach may have the greatest chance of pain relief [55].

Epididymectomy has been performed for chronic epididymitis, with varying improvement in pain symptoms. In one study, ten patients with chronic epididymitis underwent epididymectomy for intractable symptoms. Only one of these patients had significant improvement in pain [55]. Other authors have reported higher success rates. Chronic or recurrent epididymitis and persistent unilateral epididymalgia with point tenderness to the epididymis may be reasonable indications for epididymectomy [56]. A retrospective review of 32 men who underwent epididymectomy for chronic epididymitis showed that outcomes were best when the patient had a palpable epididymal abnormality on physical examination. Men in this study without a palpable abnormality but with sonographic changes had slightly worse outcomes, and those without either a palpable abnormality or a demonstrable ultrasound abnormality did not improve with epididymectomy [36].

Subinguinal microsurgical denervation of the spermatic cord may be offered for symptomatic relief of chronic scrotal pain in select patients. This has been shown to be effective in management of post-vasectomy pain syndrome of at least 3 months duration, and appears to be most successful in patients who experience temporary relief following cord block [57]. Recently Calixte et al. performed a large retrospective review of 860 cases of targeted robotic microsurgical denervation of the spermatic cord from 2008 to 2016, with a wide variety of underlying etiologies of chronic pain including trauma, prior inguinal hernia repair or other genitourinary surgery, varicocele, post-vasectomy, or idiopathic. Post-operative pain completely resolved in 49% of cases, decreased by 50% in 34% of cases, and persisted in only 17% of cases. Pain improved both subjectively and objectively, and pain improvement increased over time, to 83% of patients reporting reduction in pain by 4 years post-operatively [58].

Treatment of Purulent and Atypical Epididymitis

The diagnosis of purulent epididymitis is made with the combination of physical examination, ultrasound evaluation, and occasionally needle aspiration of the epididymis. Epididymectomy is performed when possible and orchiectomy is performed when an abscess or necrosis of testicular tissue is present. Common causative organisms include N. gonorrhea, C. trachomatis, and E. coli [59].

Corticosteroids should be utilized as first-line treatment for pain and swelling in sarcoid epididymitis. In the rare case where surgical exploration is undertaken, a frozen section should be obtained to prevent an unnecessary epididymectomy or orchiectomy [40, 60]. Patients with oligospermia should consider sperm baking in the setting of sarcoid epididymitis [61]. Similarly, treatment of Behcet’s disease is targeted at symptomatic relief, mainly with corticosteroids [62].

Treatment of epididymal tuberculosis should consist of a 6 month course of a standard anti-tuberculosis therapy, with 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol, followed by 4 months of isoniazid and rifampicin. In areas of high isoniazid resistance, ethambutol may be added to the continuation phase [63]. Men with BCG induced epididymitis are treated with isoniazid and rifampin, with or without pyrazinamide [64].

Brucellosis caused by infection with B. melitensis may result in epididymoorchitis in ~9% of cases [65, 66]. These patients should be treated with doxycycline and rifampin for 60 days [66, 67].

Epididymitis in children is often secondary to viral infections and should be treated conservatively with ice packs and analgesics [68].

Amiodarone-induced epididymitis is managed by lowering the dose of Amiodarone.

Treatment of Noninfectious Epididymoorchitis

Conservative therapy for patients with noninfectious epididymoorchitis includes nerve blocks, analgesics, scrotal elevation, bed rest, and non-steroidal anti-inflammatory medications [18].

Segmental testicular infarction may be managed conservatively. If tumor markers are negative and clinical suspicion for malignancy is low, it is reasonable to follow these patients with serial exams and imaging until the diagnosis becomes clear. In most cases, the infarcted lesion will gradually regress over 6–12 weeks [69]. However, in cases where it remains difficult to distinguish a segmental testicular infarction from a malignant lesion, radical orchiectomy should be pursued [17].

Differential Diagnosis of the Acute Scrotum

The differential diagnosis of the acute scrotum is broad and primarily includes acute epididymoorchitis, testicular torsion, and torsion of the testicular appendages. Alternative etiologies of acute scrotal pain may include testicular or paratesticular tumors, symptomatic distal ureterolithiasis, scrotal trauma, varicocele, incarcerated inguinal hernia, hyperactive cremaster muscle reflex with resultant testicular retraction, or other genital infections. A thorough history and physical examination is the key to making an accurate diagnosis. Leukocytosis or pyuria may or may not aid with differentiating the diagnosis. Additionally, while color Doppler ultrasound has traditionally been thought to have the highest sensitivity and specificity for differentiating testicular torsion from other etiologies of the acute scrotum, studies have shown that torsion is possible in the setting of preserved blood flow [70–72]. While Doppler ultrasound is not required if the clinical history and physical exam are consistent with a diagnosis of testicular torsion, any asymmetry or decrease in flow on Doppler ultrasound should prompt emergent surgical exploration.

The sensitivity of scrotal ultrasound to diagnose scrotal pathology is high, and as such, it is commonly used by primary care and emergency medicine physicians as well as urologists as an extension of the physical exam to confirm a diagnosis or rule out more serious pathology which may require surgical intervention. Kashanian et al. recently evaluated 7668 scrotal ultrasounds performed over a 12 year time period for scrotal or testicular pain and found that 80% of these ultrasounds revealed a normal or benign finding. A finding necessitating surgical intervention (including suspicious intratesticular lesion, testicular torsion, scrotal abscess, or infiltrative testicular process) was identified in only 2.2% of scrotal ultrasounds, with less than 1% of ultrasounds revealing an intratesticular lesion concerning for malignancy. The authors concluded that while scrotal ultrasound may identify benign scrotal pathology, the likelihood of finding serious or concerning medical pathology on ultrasound performed for pain alone remains low [73].

Clinical Signs, Symptoms, and Presentation of Torsion of the Testis and Appendages

Testicular torsion can be seen in patients of any age, but most commonly occurs in males between the ages of 12 and 18. Testicular torsion occurs in 3.8 per 100,000 men younger than 18 years annually, and accounts for 10–15% of cases of acute scrotum in children [74]. The incidence of bilateral testicular torsion (synchronous or metachronous) is 2% [75].

The most consistent presentation of testicular torsion is acute onset of severe testicular pain, which may be accompanied by nausea, vomiting, and even low grade fever. The hemiscrotum of the affected side is typically swollen, tender, and inflamed on physical examination, with a high-riding testis and absence of the cremasteric reflex. Barbosa et al. developed a validated scoring system, the “TWIST” score, using testicular swelling, firm testicle, absent cremasteric reflex, nausea/vomiting, and high-riding testis to determine the likelihood of a diagnosis of testicular torsion based on physical exam. Cutoff scores of two for low-risk and five for high-risk of testicular torsion were found to have 100% negative and positive predictive values with specificity of 97% and sensitivity of 54% [76].

Torsion of the spermatic cord can occur within the tunica vaginalis (intravaginal), or along with the tunica vaginalis (extravaginal). 10% of cases are familial, and 80% of intravaginal torsions are associated with a “bell-clapper” deformity, in which the tunica vaginalis inserts high in the scrotum, preventing full descent of the testis and allowing the testis and spermatic cord to rotate freely within the tunica vaginalis [74]. In the case of extravaginal torsion, the tunica vaginalis is incompletely tethered to the scrotal wall, which allows the spermatic cord and tunica vaginalis to rotate together within the scrotum [77] (Fig. 18.2).

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