The risk injury to the recurrent laryngeal nerve (RLN) is inherent to any surgical procedure involving the central compartment of the neck. For surgeons, the best strategy to prevent nerve injury is to be familiar with the normal anatomy—including its variations—and most importantly, the anatomical relationships of the RLN and parathyroid glands.

Both the right and left RLN originate as braches of the vagus nerve in the thorax. In the right side the recurrent nerve emerges posteriorly as the vagus crosses the subclavian artery, while in the left side it does so as the vagus crosses over the aortic arch. After circumventing subclavian artery and aortic arch and respectively, both nerves ascend along the tracheoesophageal groove towards the laryngeal inlet. In contrast with the near-vertical path of the left RLN, the right nerve has a more oblique course, explained by its relatively lateral point of inflection. As the RLN ascends in the neck, it becomes intimately related to the thyroid gland and to the inferior thyroid artery (ITA) . In roughly 65–70 % of the cases the nerve courses deep to ITA, in 20–25 % of the cases is superficial to the vessel, and it courses between the ITA branches in approximately 5 % of the cases [17], as shown in Fig. 46.2. In light of variable relationship between the RLN and the ITA, we recommend against using this vessel as the sole anatomical landmark for the identification of the nerve. Also, an anatomical study suggests that the ITA is absent in 6 % of the population [18], further underscoring this concept.

During its cervical course, the RLN branches prior to its point of entry into the larynx in 20–65 % of the cases [19–21], commonly in an anterior and a posterior branch. In this setting, most authors agree that anterior branch contains the majority of the motor fibers—both abductor and adductor—while the posterior branch is predominantly sensory [22]. The surgeon must be able to promptly identify the presence of RLN branching during the course of the dissection, as this anatomical variation has been associated with a twofold increase in the risk of RLN injury [23].

Intraoperative electrophysiologic recurrent laryngeal nerve monitoring (EMG) can be a useful tool in the identification of the RLN, particularly in challenging situations such as reoperative parathyroidectomy. While nerve monitoring has not proven to decrease the incidence of RLN injury, it has a well-documented prognostic role. In a recent study involving almost 1000 at-risk nerves, Genther et al. report a sensitivity of 95.5 % and a specificity of 99.2 % of EMG for identification of immediate postoperative vocal cord paralysis in patients undergoing thyroid- or parathyroidectomy [24].

Is important for the surgeon to clearly assess and document the patient’s vocal status pre- and postoperatively, as patients with a well-compensated vocal cord paresis or paralysis can present with a normal voice. The author’s preference is to visualize the larynx through an indirect laryngoscopy preoperatively in all patients as this is a noninvasive procedure that allows for documentation of the vocal cord function, and serves as a reference for future examinations. If the patient presents with any vocal impairment and/or the vocal cords can’t be properly visualized with this technique, a flexible fiberoptic laryngoscopy should be considered [22]. The same approach is recommended postoperatively, where functional manifestations of an acute RLN injury are not always obvious and may take some time to develop. Immediately after denervation, the balance of adductor and abductor musculature causes the vocal cord to migrate to a paramedian position. In this location the contralateral vocal cord may often compensate for the deficit, resulting mild symptomatology. In this context, patients often complain of a “weak” or raspy voice which not uncommonly is attributed to endotracheal intubation [25]. As the cord lateralizes—over the period of days to weeks—progressive hoarseness and vocal fatigue ensue, and patients develop a characteristic “breathy” voice that reflects the presence of an uncompensated glottic gap.

Postoperatively, surgeons should maintain a high index of suspicion for RLN injury. Should a patient present with a vocal cord paralysis, he or she should be counseled and promptly referred for specialized care. The chances for spontaneous recovery of the nerve function greatly depend on the mechanism and severity of the injury. Neurapraxia usually results from traction- or thermal injury to the nerve, and it has a better chance of spontaneous recovery than those cases where the nerve was transected. The treatment of unilateral vocal cord paralysis includes operative and nonoperative management and depends on the functional impact, patient’s vocal needs, and estimated changes for spontaneous recovery. Vocal cord medialization or thyroplasty are commonly performed in patients in whom recovery not anticipated based on the temporal profile and/or electromyographic findings.

Bilateral vocal cord paralysis is an extremely rare occurrence in the context of parathyroidectomy, but still worth noting given its life-threatening implications. In this scenario, both vocal cords migrate to paramedian position causing an acute airway obstruction that clinically presents as stridor. This usually becomes obvious as soon as the patient is extubated, but may go unrecognized until the patient is in the recovery room. Bilateral vocal cord paralysis is a medical emergency, and the goal in this setting is to promptly secure the airway. This is most commonly achieved through endotracheal intubation, but the surgical team should ready to establish a surgical airway.

Is important to recognize that in 0.3–4 % of the cases the nerve has no nonrecurrent course and originates directly as a cervical branch of the vagus nerve, without entering the mediastinum [26] (Fig. 46.3). This anatomical variation is explained by an embryological involution of the fourth aortic arch which causes the subclavian artery to arise from directly from the aortic arch [27]. In these cases the right subclavian artery commonly has a retropharyngeal course (arteria lusoria) where it can cause organic esophageal obstruction that presents as dysphagia lusoria [28]. Left-sided nonrecurrent laryngeal nerves are extremely rare. They occur only in the context of situs inversus and patients present with a corresponding left retropharyngeal subclavian artery [28].

Overall, the risk of recurrent laryngeal nerve injury after parathyroidectomy has been reported to be below 1 % in most series regardless of the type of surgical approach [6, 11, 12, 14, 29, 30]. Few studies have directly compared the risk of RLN injury between surgical techniques. In a series of 1300 patients treated at a teaching hospital for benign primary hyperparathyroidism, Karakas et al. [31] reported an incidence of permanent vocal cord paralysis of 0.4 % for minimally invasive parathyroidectomies vs. 2 % for bilateral open exploration. However, other series have found comparable rates of RLN injury between neck exploration (0.7 %) and MIP (0.8 %) [12], suggesting that the surgeon’s experience might play a more significant role than the surgical approach utilized.

In a reoperative setting the presence of scar tissue, loss of anatomical landmarks and frequent need for more extensive dissection inherently increase the risk of RLN injury. A recent study describes a 9 % permanent vocal cord paralysis in patients undergoing revision surgery for persistent or recurrent hyperparathyroidism [3], almost a tenfold increase over the reported rate for primary surgery. Preoperative counseling, baseline laryngeal examination, and intraoperative EMG laryngeal monitoring should be considered in all patients undergoing a revision parathyroidectomy.

Biochemical cure is defined as eucalcemia and normalization of serum PTH at 6 months postoperatively. Persistent hyperparathyroidism is defined as a PTH elevation within 6 months of surgery, while recurrent hyperparathyroidism is defined as PTH elevation beyond 6 months postoperatively, following a period of normalization. Since most of the surgical failures are preventable, it is worth discussing the process of patient selection and technical aspects of the surgery.

Primary hyperparathyroidism is caused by a single adenoma in 85–95 % of the cases [32–36], and a second adenoma is present in 3–5 % of the patients [37]. The incidence of 4-gland hyperplasia ranges between 2 and 6 %, but has been reported to be as high as 15 % [35, 36]. Parathyroid localization allows the surgeons to differentiate single vs. multigland disease preoperatively. Those patients with localizing disease (80–90 %) are candidates for a unilateral (minimally invasive) parathyroidectomy. The options for preoperative localization include: neck ultrasound, Sestamibi-SPECT, CT scan with and without contrast (4DCT), and magnetic resonance imaging (MRI). These test are not mutually exclusive and can be combined in an attempt to increase the accuracy of localization. Sestamibi-SPECT is by far the most commonly utilized, and currently considered as part of the standard of care. However, 4DCT has been rapidly adopted as it has demonstrated better sensitivity than Sestamibi (88 % vs. 65 %) and better ability to identify multigland disease (85 % vs. 25 %) [38–40].

Bilateral neck exploration without preoperative localization has long been considered the “gold standard” for surgical treatment of primary hyperparathyroidism [37]. The advent of reliable localization studies led to the development of minimally invasive parathyroid surgery and has radically changed the practice patterns over the last decades. Currently, MIP is the preferred approach for primary hyperparathyroidism when a single adenoma can be localized preoperatively, with surgeons increasingly adopting this approach over bilateral exploration [41, 42]. Minimally invasive parathyroidectomy is based on the excision of a single, well-localized parathyroid adenoma and is applicable to 90 % of the patients presenting with sporadic primary hyperparathyroidism [43]. In addition to the localization studies, intraoperative parathyroid hormone monitoring (IOPTH) plays a role in identifying patients who may need a bilateral exploration. The main purpose of IOPTH is to identify patients with multigland disease—which account for 5–15 % of the patients [13]—during the course of the operation, In the presence of multigland disease, the sensitivity of Sestamibi drops from 97 to 61 % and the specificity from 93 to 84 % [44]. The “Miami” criteria are defined as IOPTH drop of ≥50 % from baseline at 10–15 min post-excision [45], with most experts agreeing that the post-excision IOPTH should be also be within normal limits [46]. If these criteria are not met after the resection of the suspected adenoma, further exploration is warranted. Multiple series have documented a slight increase in biochemical cure rate with the use of IOPTH from 95–97.5 to 97–99 % [12, 43, 47–50], although this difference has failed to reach statistical significance in any of the series.

At this stage, the decision of bilateral neck exploration vs. MIPS greatly depends on the surgeon’s preference and expertise, although recent evidence seems to support minimally invasive approaches. Randomized trials comparing both techniques—presented in Table 46.1—consistently show equivalent cure rates even at 5-years postoperatively [51]. In a similar fashion, surgical resection of parathyroid adenomas through an <2 cm incision has been associated with shorter operative time, decreased pain and length of hospital stay, and better cosmetic results [52].

Overall, the success rate of surgery for primary hyperparathyroidism ranges between 94 and 99 % [11, 12, 31, 32, 35, 50, 53]. However, these outcomes must be interpreted cautiously, as most series come from high-volume, expert surgeons in centers with access to high-quality imaging and perioperative support [37], and may not accurately reflect surgical outcomes in less experienced hands. Worldwide, most parathyroid surgery is not performed by high-volume surgeons. This is also the case in the United States, where 78 % of the parathyroidectomies are performed by surgeons for whom endocrine case volume accounts for less than 25 % of their practice [54]. Several studies have suggested that surgeon’s expertise and case volume is associated with better outcomes. In a study including 159 revision parathyroidectomies, Chen et al. [55] compared the surgical volume of the centers performing the initial failed operations and concluded that patients who underwent their initial procedure at low-volume centers (<50 parathyroidectomies/year) had almost a sevenfold increase in preventable operative failure, defined as missing an adenoma in a normal anatomical location. Similarly, a study based on the Scandinavian national registry comparing outcomes between high- and low-volume centers found biochemical cure rates of 90 % for endocrine surgery centers, 76 % for general surgery clinics, and only 70 % for centers performing less than 10 cases/year [56].

Invariably, the reasons for surgical failure include missing a single adenoma and failure to identify multigland disease. While preoperative localization studies collectively represent a major advance in the field, no technique can replace a thorough understanding of the role that embryology plays in the genesis of parathyroid adenomas. Every parathyroid surgeon should be able to perform a bilateral neck exploration and directly “look” for a missing adenoma in the most common locations. The superior parathyroid glands arise from the fourth branchial arch and have a relatively constant location, in the posterior aspect of the superior thyroid pole, adjacent to the cricothyroid junction and recurrent laryngeal nerve [34]. The inferior parathyroid glands arise from the third branchial arch and descent towards the thymus; while they are routinely located at the level of the inferior thyroid pole, they can be in any location within their embryological path. As such, their location is much more variable. A nomenclature system that uses mnemonic associations provides an easy way for uninitiated parathyroid surgeons to systematically explore common sites where adenomas could be missed [30] (Fig. 46.4).

Reoperative parathyroid surgery is challenging and should be reserved for experienced surgeons in high-volume centers. Cure rates following reoperative parathyroidectomy are significantly lower than for primary surgery, ranging from 83 to 96.8 % [5, 57–59], and reoperative parathyroidectomy is associated with a higher complication rate [2–5]. Reoperations are also significantly more expensive, with a cost that roughly doubles that of the initial surgery [60]. As the risk/benefit balance significantly differs from the initial parathyroidectomy, candidates for reoperative surgery should be carefully evaluated. In these cases multiple localization studies are routinely performed looking for concordant findings which suggest an area of “high probability” to identify the adenoma. With localization protocols currently available, blind neck re-explorations should virtually never be required [37]. Anatomically, the missed adenomas will almost invariable be located along the embryological path of descent of the parathyroids. This is demonstrated in Fig. 46.5 which shows the anatomical location of missed adenomas in a series of 130 reoperative parathyroidectomies [61]. Technical advances will continue to impact the management these patients. MRI-based, real-time intraoperative localization has been successfully tested in a small cohort of patients [62]. This, and similar techniques, will further add to the surgical armamentarium in the treatment of persistent and recurrent hyperparathyroidism.

In the context of minimally invasive surgery, conversion to bilateral exploration must not be viewed as a complication, but rather as part of a surgical continuum in an attempt to achieve biochemical cure. Failing to identify an abnormal parathyroid gland, or an insufficient drop in IOPTH following the resection of the suspected adenoma are probably the most common factors leading to the decision to convert from a minimally invasive approach. Other factors may also lead to the decision to convert to bilateral neck exploration, as reported by Norman et al. in a prospective series of 3000 consecutive patients. In this study, the authors identified the following intraoperative findings leading to open exploration: involvement of the recurrent laryngeal nerve, contralateral thyroid disease discovered, extensive scar tissue, abnormal ipsilateral gland, failure to identify ipsilateral gland and insufficient parathyroid hormone reduction [63]. Overall, there are many situations in which converting to bilateral neck exploration represents the most sensible approach and reflects appropriate surgical judgment. It is important for the surgeon to disclose the limitations of minimally invasive techniques, and to discuss the potential need for bilateral exploration in all cases.

Hematomas of the central compartment are most commonly associated with thyroid surgery, but this complication may present after parathyroidectomy, although with a very low incidence. In a study comparing bilateral cervical exploration vs. MIPS, 0.2 % of the patients presented with hematoma after open approach while 0.8 % had a hematoma after MIPS [12]. Udelsman reports a 0.2 % incidence in a cohort of 1,650 consecutive patients [14] while Miccoli describes a 0.27 % incidence in patients treated with video-assisted parathyroidectomy [11].

In spite of their rarity, tension hematomas of the central neck compartment represent a serious, and potentially life-threatening complication that is worth noting. Acute bleeding in a nondistensible surgical cavity significantly increases the pressure in the larynx and perilaryngeal structures. This leads to venous congestion of the airway, edema of the supraglottic structures, and neurapraxia of the RLN which results in bilateral vocal cord paralysis. Patients present with noisy breathing or laryngeal stridor, and characteristically adopt the tripod position trying to alleviate the pressure over the airway. A high index of suspicion is necessary as the diagnosis is based on clinical findings and patients can deteriorate rapidly. As early as the diagnosis is suspected, the surgical incision must be reopened to evacuate the hematoma. This maneuver usually alleviate the symptoms and stabilizes patient enough to proceed with a formal neck exploration.

Overall, the risk of wound infection is extremely low. Parathyroid surgery is considered a clean surgery, so the wound infection rate should not exceed 1 %. A recent study of 776 patients undergoing parathyroidectomy reports a 0.3 % incidence of postoperative wound infection [64]. Like any elective surgery, routine, single-dose antibiotic prophylaxis should be used for all patients.

In general, parathyroidectomy incisions are nearly invisible when fully healed. However, just like in any surgical procedure, there is low risk of adverse scarring that should always be disclosed to the patient. African Americans and patients with history of keloids or exuberant scars should be approached cautiously. A good practice is to ask the patient to reveal previous surgical scars to anticipate potential wound complications. Intraoperatively, the incision should be placed in a skin crease if at all possible. Care must be exercised with skin retraction, particularly in small incisions that provide limited exposure. Excessive retraction traumatizes the skin edges, leaving a short but noticeable scar in the neck. If the exposure is insufficient, is better to extend the incision than to risk an unsightly scar derived from excessive retraction. If a keloid scar is identified postoperatively, compression therapy, and intralesional corticosteroids should be initiated as early as possible.

Intravenous administration of methylene blue has been used to identify abnormal parathyroid glands in patients with primary hyperparathyroidism. In a recent series of almost 100 patients, intravenous methylene blue appropriately stained close to 80 % of the glands [33]. The use of methylene blue has been associated with serotonin syndrome, a rare form of encephalopathy most frequent in patients under treatment with selective serotonin reuptake inhibitors (SSRIs) drugs [65]. This condition is characterized by autonomic, neurological, and neuromuscular instability presenting in the postoperative period. Clinical suspicion is important to recognize this condition. The treatment usually involves support measures as most cases resolve spontaneously within days. Since depressive symptoms are common in patients with primary hyperparathyroidism, use of SSRI should be directly inquired and the use of methylene blue should be avoided in these patients [66].