Introduction

Pain in the parotid region occurring with the first bite of a meal was first described by Gardner in 1955. He described patients presenting with this pain after excision of the superior cervical ganglion [1]. Truax later reported a case of “gustatory pain” following carotid endarterectomy in 1989 [2]. The actual term “first bite syndrome” was not used until 1998 when Netterville used the term to describe facial pain with eating that occurred in 9 patients from a series of 46 who had undergone vagal paraganglioma resection.

First bite syndrome (FBS) is described as severe sharp or cramping pain in the parotid region that occurs with the first bite of each meal and improves with subsequent bites [3]. This is seen most typically in the post-surgical setting following surgery in the parotid or parapharyngeal region, with larger series reporting an incidence of FBS in 9.6% to 33% of patients in the first few weeks following surgery [4•, 5]. Though this syndrome is well known in surgical settings, it is not commonly included in the differential for sharp paroxysmal facial pain in neurology literature. In the authors’ clinical experience, this lack of knowledge has led to inaccurate diagnoses of “atypical trigeminal neuralgia” with subsequent unnecessary neurosurgical consults.

It is critical for neurologists to recognize FBS and differentiate it from other causes of facial pain. It is equally important to understand the relevant anatomy in order to anticipate commonly associated neurologic features (e.g., great auricular neuropathy and Horner’s syndrome). The fact that FBS has been reported as the presenting symptom of malignancies in the parapharyngeal space and parotid gland [6, 7, 8••, 9, 10] underscores the need for clinicians to recognize this syndrome even outside of post-surgical settings. This manuscript will review the relevant anatomy of FBS, current understanding of the pathophysiology, and guidelines for clinical evaluation and treatment.

Anatomy and Pathophysiology

An understanding of the anatomy of the parotid gland and surrounding structures is required to discuss the current theories regarding the pathophysiology of FBS (see Fig. 1). The parotid gland is bordered by the zygomatic arch superiorly, the sternocleidomastoid muscle inferiorly, and the parapharyngeal space posteriorly [11]. The glossopharyngeal nerve (cranial nerve IX) carries preganglionic parasympathetic fibers to the otic ganglion. Postganglionic parasympathetic fibers travel to the parotid gland via the auriculotemporal nerve, which is a branch of the trigeminal nerve. From the superior cervical ganglion of the sympathetic chain, postganglionic sympathetic fibers exit to travel with the external carotid artery to the parotid gland [11].

Fig. 1
figure 1

Parotid gland innervation and surrounding structures. The parotid gland is bordered by the zygomatic arch superiorly and the sternocleidomastoid muscle inferiorly. The sympathetic innervation is supplied by postganglionic sympathetic fibers from the superior cervical ganglion. The parasympathetic innervation is supplied by postganglionic parasympathetic fibers from the otic ganglion traveling to the parotid gland via the auriculotemporal nerve. The inset on the right shows the great auricular nerve which supplies sensation to the lower ear and along the mandible. Its superficial location wrapping around the sternocleidomastoid muscle makes it prone to injury following head/neck surgeries. From Duvall JR, Robertson CE. Clinical Reasoning: a misdiagnosis of atypical trigeminal neuralgia. Neurology 2019; 93(3): 124-131. Image used with permission of Mayo Foundation for Medical Education and Research, all rights reserved

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The parotid gland itself is composed of secretory units surrounded by myoepithelial cells, which are innervated by both parasympathetic and sympathetic nerves [11, 12]. The dual innervation of myoepithelial cells is suspected to have a synergistic effect on parotid gland function, both contributing to myoepithelial contraction and saliva secretion [12]. Parasympathetic stimulation expels a large volume of watery saliva while sympathetic stimulation expels a small volume of thick saliva [12]. Furthermore, parasympathetic stimulation results in vasodilation and increased blood flow while sympathetic stimulation results in vasoconstriction and decreased blood flow [2].

When FBS was described by Gardner, he proposed pain was a result of unopposed parasympathetic activity with vasodilation and stretching of intraparotid sensory fibers. However, subsequent resection of parasympathetic fibers did not result in complete pain relief; therefore, he ultimately attributed the mechanism to autonomous or residual innervation of postganglionic sympathetic fibers after superior cervical ganglionectomy [1]. Netterville, in contrast, attributed the mechanism to damage of sympathetic fibers supplying the parotid gland with resultant hypersensitivity of denervated sympathetic receptors. He theorized that during eating, parasympathetic stimulation might cross-stimulate these sympathetic receptors resulting in extreme contraction of myoepithelial cells and associated pain [3].

In support of Netterville’s hypothesis, there have been numerous reports of FBS occurring in the setting of suspected surgical injury or irritation to postganglionic cervical sympathetic chain fibers [13,14,15,16,17,18,19,20,21,22,23]. Furthermore, botulinum toxin injections have proven to be an effective treatment in some cases [24,25,26,27,28], which may also support his proposed pathophysiology. Both sympathetic and parasympathetic nerves contribute to myoepithelial cell contraction by suspected diffusion of norepinephrine and acetylcholine from nearby nerve terminals to cell surface receptors [12]. Botulinum toxin causes decreased parasympathetic acetylcholine release by inhibiting vesicular docking, which is thought to subsequently result in less cross-stimulation of sensitive, denervated sympathetic receptors [26].

In 2011, Deganello reported one of the first cases of FBS caused by a deep parotid malignancy in the absence of any surgical procedure. Initially, he wondered if the tumor had infiltrated the sympathetic fibers along the external carotid artery, contributing to denervation hypersensitivity of the sympathetic network. However, the FBS resolved after tumor and external carotid artery resection, requiring an alternative explanation. He theorized that there is a delicate balance between sympathetic and parasympathetic innervation of the parotid gland, and FBS may occur when this balance is disrupted [8••]. While in some cases this may involve sympathetic denervation with parasympathetic cross-stimulation of sympathetic receptors, in other cases, this may involve irritative stimulation of the sympathetic fibers and concomitant denervation of the parasympathetic system, with sympathetic cross-stimulation of parasympathetic receptors [8••]. This concept of imbalanced sympathetic/parasympathetic innervation has been used to explain additional nonsurgical cases, including a recent case report of FBS after trigeminal radiosurgery with suspected isolated parasympathetic denervation [29].

Whether there is predominantly sympathetic damage or isolated parasympathetic damage, autonomic imbalance would potentially explain why not all parotid region postoperative patients develop the syndrome. Perhaps there is damage or loss of sympathetic innervation to the parotid gland, but in some patients, this is not a significant enough amount to disrupt the balance of the autonomic nervous system. In contrast, given that the effect of the parasympathetic nerves on the parotid gland is more significant [12], it seems likely that even minor damage to this system could contribute to imbalance. This theory is supported by frequent resolution of FBS as a result of spontaneous nerve regeneration with time and total parotidectomy [7, 8••, 10], both of which may resolve the imbalance of autonomic innervation.

Complications from Injury to Nearby Anatomic Structures

Other recognized neurologic complications of parotid, parapharyngeal space, and high cervical surgeries include Horner’s syndrome and great auricular neuropathy. Injury to sympathetic fibers from the superior cervical ganglion traveling with the internal carotid artery to the eye can result in ipsilateral Horner’s syndrome [3, 18]. The great auricular nerve supplies sensation to the lower ear and along the mandible (see Fig. 1). Given its superficial location wrapping around the sternocleidomastoid, it is also prone to injury during surgery leading to numbness or persistent neuropathic pain in the region [11].

Case Vignettes from Our Institution

Case 1

A 41-year-old male underwent a left carotid body tumor resection diagnosed pathologically as paraganglioma. In the immediate postoperative period, he had a left Horner’s syndrome. Approximately ten days after surgery, he developed symptoms consistent with FBS and great auricular neuropathy. He described a severe pain and spasm similar to “biting into a lemon” in the left parotid region with the first bite of each meal that subsided with subsequent bites. Pain could also be precipitated by salivating or thinking about eating. He also described persistent numbness and tingling in the distribution of the left great auricular nerve. The patient had mild improvement in FBS symptoms with gabapentin 600 mg BID but no improvement with ibuprofen, acetaminophen, cyclobenzaprine, or botulinum toxin injections. His symptoms have persisted for 3 years postoperatively. Additional treatment recommendations were made recently, but have not yet been implemented.

Case 2

A 60-year-old male underwent transoral robotic surgery with left partial pharyngectomy and neck dissection for squamous cell carcinoma of the left palatine tonsil. In the immediate postoperative period, he developed symptoms consistent with FBS. He described severe paroxysmal pain in the left preauricular and jaw region with the first bite of each meal. The neurologic exam was normal. He reported improvement in pain beginning 4 weeks postoperatively but continued to be bothered by pain occurring with each meal. Approximately 4 months postoperatively, the patient received injections of 25 units of botulinum toxin into the left parotid gland. He reported significant pain relief beginning 2 weeks after injection. He was able to enjoy eating with only subtle associated spasm-like pain with his first bite. The patient presented for repeat botulinum toxin injections 1 year after initial injection with ongoing good pain control.

Diagnosis

FBS is a clinical diagnosis based on characteristic history and examination. As FBS presents similarly to many other facial pains and there are no currently available criteria to guide clinicians, we have proposed diagnostic criteria for FBS to be incorporated into ICHD-3 [30] (see Table 1). FBS should be suspected when a patient presents with pain in the preauricular and jaw region with the first bite of each meal. Severe sharp or spasm-like pain is maximal with the first bite and diminishes within seconds to minutes with subsequent bites. Pain is typically triggered by salivation, which may include smelling food or thinking about eating. History commonly reveals preceding head/neck surgery, but not always.

Table 1 Proposed diagnostic criteria for first bite syndrome
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It is important to elicit precipitating factors in the history in order to differentiate FBS from other disorders causing neuralgic pain. Trigeminal neuralgia is frequently precipitated by cutaneous stimuli along the region of the trigeminal nerve [31], and the absence of a cutaneous trigger should alert the clinician to the possibility of other disorders. Glossopharyngeal neuralgia is typically precipitated by swallowing, coughing, talking, or yawning [30]. Great auricular neuralgia is typically precipitated by turning the head, touching the neck, or neck positions during sleep [32]. In contrast, pain triggered by salivation or smelling food should raise suspicion for a disorder of the salivary glands or ducts. If the pain is typically only in the first bites of eating, the possibility of FBS should be entertained and additional surgical/procedural history should be gathered.

A history of recent upper neck or parotid surgery supports the diagnosis of FBS, with numerous postsurgical etiologies reported to date (see Table 2). Surgeries that involve parapharyngeal space dissection, deep lobe parotidectomy, sympathetic chain sacrifice, and external carotid artery ligation have been associated with a higher incidence of FBS [4•, 15, 43]. Timing of symptom onset after surgery ranges from days to months, with a mean of 97 days reported in a large retrospective cohort study [4•, 15]. There have also been reports of FBS as the presenting symptom of head/neck malignancy as summarized in Table 3, including one case associated with chemotherapy treatment for Hodgkin lymphoma [56]. Therefore, any patient presenting with FBS in the absence of a surgical procedure requires additional evaluation.

Table 2 Postsurgical etiologies of first bite syndrome
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Table 3 Neoplastic etiologies of first bite syndrome
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Evaluation

Initial evaluation includes a detailed history and examination including cranial nerves, oral cavity, temporomandibular joint and neck. On examination, bedside provocation of salivation with a sour candy may precipitate characteristic pain. Horner’s syndrome may be present ipsilaterally as a consequence of injury to the sympathetic nerve fibers. Sensation of the face should be normal, unless they have co-occurring great auricular neuropathy. As the great auricular nerve supplies sensation to the lower ear and along the mandible, patients may have numbness, paresthesia, or burning pain in this region (see Fig. 1).

If there is no history of surgery, imaging with either a CT or MRI with contrast of the skull base and neck should be considered to evaluate for malignancy. In the right clinical context, PET-CT could also be considered to evaluate for an FDG-avid lesion. If imaging is initially unrevealing, there should be a low threshold for repeat/surveillance imaging as FBS has been followed by a diagnosis of parapharyngeal space and parotid gland malignancy from one to nine years after presentation [6, 7, 8••, 9, 10].

Treatment and Prognosis

There is no consensus regarding treatment of FBS, as evidence is limited to case reports/series and is sometimes conflicting. In some cases, exact dosing, time after symptom onset, and duration of medication trial are not included. In many of these reports, multiple therapies have been trialed simultaneously or treatment may have been initiated several months after the onset of symptoms when spontaneous improvement might occur, making it difficult to conclude the effectiveness of any individual therapy. Furthermore, many reports outlining ineffective treatments either used subtherapeutic doses [34] or described trials in patients who have failed multiple therapies [48•] raising the possibility that they are more refractory at baseline than a typical FBS patient. Despite these limitations, some treatments have demonstrated partial or complete effectiveness is greater than one patient, and these are summarized in Table 4. Multiple neuropathic agents have demonstrated effectiveness, including carbamazepine, gabapentin, and/or pregabalin. Though the majority of cases demonstrated partial relief of pain with these, not all patients responded [10, 16, 34, 48•, 57]. Amitriptyline has been shown to be associated with symptom improvement in 4/6 cases [33, 39, 41]. Given the anticholinergic properties of amitriptyline with decreased salivation in the setting of suspected underlying autonomic nervous system pathophysiology as outlined above, in theory, we would expect a more robust response with this than other neuropathic agents. Clomipramine has also demonstrated partial effectiveness but only in one patient [33].

Table 4 Treatments of first bite syndrome with demonstrated effectiveness in >1 patient
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In 2008, Ali first demonstrated parotid gland botulinum toxin injections as a potentially effective treatment for FBS. He attributed the mechanism to the local blockade of acetylcholine release with subsequent myoepithelial cell paralysis and inhibition of painful, supramaximal contraction. He had one patient demonstrate complete relief of symptoms with injection of a total of 75 units dispersed diffusely throughout the parotid gland with focus on areas where most intense pain occurred [24]. After these promising results, multiple small series have evaluated the effectiveness of botulinum toxin injections in FBS as summarized in Table 4. All report partial or complete responses in the majority of patients with a total of 20 out of 24 patients demonstrating pain relief. There is no consensus regarding the location of injection and the number of sites injected or dose. However, at least one other small series described patients responding to a protocol resembling Ali’s, with 50-75 units injected using a “follow-the-pain” protocol, where injection sites were focused on areas of greatest pain reported by the patient [26]. The effect of botulinum toxin has been shown to wear off after approximately 4 months, with injections repeated at intervals between 6 weeks and 8 months [26, 28]. Interestingly, of the 24 patients reported to have been given botulinum toxin injections for FBS, the 4 patients without response were either injected with a dose in the lower end of the dosing range or the dose was not specified [10, 27, 28, 48•]. Except for mild discomfort during injection, there have been no complications or side effects reported [26]. Parotid gland injection of local anesthetic has only demonstrated transient relief, and other types of injections have not been reported [41].

In cases of FBS as the presenting symptom of malignancy, all patients had complete relief of symptoms following tumor resection [6, 7, 8••, 9, 10, 55]. In theory, however, persistence of FBS after resection seems possible in cases where ipsilateral parotid gland tissue is preserved with sympathetic or parasympathetic nerve injury or irritation. Four out of the 6 patients with improvement following resection also received postoperative radiotherapy, which has been independently shown to be associated with improvement/resolution of FBS [16, 33, 54]. It seems possible that the adjuvant postoperative radiotherapy prevented FBS through functional impairment of myoepithelial cells [54].

The prognosis of FBS is unclear. In the largest retrospective cohort study to date evaluating 499 postsurgical FBS patients, 4% had spontaneous complete resolution, and 69% had spontaneous partial resolution [4•]. Improvement or resolution of symptoms was reported over a wide range of 2 to 24 months after symptom onset [15].

Summary of Recommendations

Given the severe pain reported by patients and its impact on quality of life [25, 43], we recommend initiation of treatment with a neuropathic agent including carbamazepine, gabapentin, pregabalin, or amitriptyline while monitoring for symptom improvement. Doses should start small and be titrated slowly to doses typically used for other neuropathic pain. Based on the currently available literature, if there is no relief with one neuropathic agent at therapeutic doses for 3 months, we recommend a trial of parotid gland botulinum toxin injections. We do not recommend the use of over-the-counter analgesics or opioids as these treatments have been reported as ineffective in multiple cases [2, 16, 24, 39, 53, 54]. We also do not routinely recommend a trial of acupuncture as this was associated with partial effectiveness in only 50% of cases (2/4) [24, 39, 44].

Lastly, we must continue to collaborate with our surgical colleagues to minimize the risk, increase knowledge, and explore surgical treatment options of FBS. There has been one case report of complete resolution of pain with laser ablation of the tympanic plexus; however, other efforts at surgical intervention including tympanic neurectomy have been ineffective thus far [16, 24, 48•].

Conclusion

FBS is most commonly caused by upper neck or parotid surgery due to injury or irritation of postganglionic cervical sympathetic chain fibers resulting in an imbalance of parotid gland autonomic innervation. However, it may also be the presenting symptom of head/neck malignancy. It is critical for clinicians to recognize FBS and be able to differentiate it from other paroxysmal facial pains. Treatment options are limited, however, patients can be reassured that the majority of patients have improvement in symptoms within 24 months.