Evidence for BMS as a Peripheral Neuropathy

BMS is associated with unique histopathologic findings and alterations of levels of salivary neuropeptides. Lauria and colleagues evaluated the innervation of the epithelium of the anterolateral tongue in 12 patients with BMS present for at least 6 months using 3-mm punch biopsies of the region. In addition, samples were obtained from 9 normal patients as a control. Immunohistochemical and confocal microscopy colocalization studies were performed with cytoplasmatic, cytoskeletal, Schwann cell, and myelin markers for pathologic changes. Of note, BMS patients showed a significantly lower density of epithelial nerve fibers than controls, with a trend toward correlation with the duration of symptoms. There was no correlation between density of fibers and severity of symptoms. Epithelial and subpapillary nerve fibers also showed diffuse morphologic changes reflecting axonal degeneration, demonstrating that BMS is associated with a small-fiber sensory neuropathy or axonopathy of the tongue and that biopsy can be used to assess the diagnosis. The investigators note that these findings correlate with histologic findings in burning disorders of the lower limbs, and that the nociceptive stimulation of these fibers may be contributory to the accompanying dysguesia. A recent study by Borelli and colleagues examined the levels of salivary neuropeptides in 20 BMS patients and matched controls, and found significantly increased nerve growth factor peptide and tryptase activity in saliva of BMS subjects. Conversely, levels of substance P were shown to be significantly lower while neutrophil markers were unchanged. The investigators felt these substances might be useful biomarkers for diagnosis and monitoring of BMS.

There are alterations in trigeminal nerve function in BMS patients. Two studies by Jaaskelainen and colleagues examined alteration in function of the trigeminal nerve among BMS patients. Their 1997 article reported on 11 patients with BMS for at least 1 year and 10 healthy controls. Following a thorough neurologic and laboratory evaluation to rule out any other contributory factors, the patients underwent electrophysiologic evaluation of the blink reflex and jaw reflex, and needle electromyographic evaluations of facial and masticatory muscles were performed on those with abnormal blink reflexes. Although all other testing was normal, there was a significant abnormality noted in the blink reflexes of patients with BMS, suggestive of trigeminal dysfunction. A follow-up study in 2002 confirmed the findings of abnormal blink reflexes in 52 BMS patients, and correlated them with quantitative thermal thresholds in 46 of the patients. Seventy-six percent of patients tested had thermal sensory abnormalities, the majority of those some variety of hypoesthesia. Less than 10% of all patients had entirely normal electrophysiological testing of the trigeminal nerve. Some potential mechanisms include neuropathy due to causes such as injury during procedures in the mouth and throat, and viral-induced neuropathy.

Evidence for BMS as a Central Neuropathy

Central neuropathic mechanisms are also felt to be involved in BMS. Albuquerque and colleagues demonstrated differences in perception of trigeminal pain between BMS and normal patients on functional magnetic resonance imaging (fMRI) in a 2006 study. In follow-up to their aforementioned work in trigeminal abnormalities in BMS, Jaaskelainen and colleagues evaluated the nigrostriatal dopaminergic pathway in 10 BMS patients and 14 controls using modified positron emission tomography (PET). Findings of decreased uptake in the right putamen indicated decreased dopaminergic inhibition in BMS patients. Another study by the same group in 2003 found alterations consistent with a decline in endogenous dopamine levels in the putamen in BMS patients.

Evidence for BMS as a Phantom Pain

The role of dysguesia as a primary or secondary phenomenon in BMS remains a point of investigation. Whereas some have felt dysguesia is a secondary event arising from trigeminal dysfunction, others question if loss of taste might be an inciting event, playing a primary role in the etiology of some cases of BMS. It is hypothesized that BMS represents a central oral phantom pain secondary to damage to the gustatory system and disinhibition of central nociceptive regions. Other taste phantoms may also be associated with a similar etiology. Other supporting evidence is that anesthesia of the chorda tympani has been demonstrated to increase the contralateral pain response to capsaicin, and that overlap exists between brain regions involved in taste and pain perception. Supertasters, those with a genetic alteration causing increased number of fungiform papillae and an ability to taste the bitter compound phenylthiocarbamide, may be at increased risk. BMS patients may also have a higher likelihood of taking medications interfering with taste. Evidence that BMS is a form of oral phantom pain is both tantalizing and revealing, given the challenges experienced in treating the most common phantom sensation in otolaryngology, namely, tinnitus. Like tinnitus, BMS has an association with psychopathology and central and peripheral factors, as well as limited success with current medical therapies and a need for careful counseling of those affected.

Evidence for BMS as Variable Disorder with Subcategories

One recent effort to investigate a central versus peripheral origin for BMS was a double-blind, randomized crossover trial comprising 20 patients with BMS. The patients underwent lidocaine and saline injection of the lingual nerve, and although the group overall showed no significant difference in response, central (n = 7) and peripheral (n = 13) subgroups were identified. In the peripheral group, there was a significant decrease in burning with lidocaine injection compared with saline, whereas the central group had a nonsignificant trend toward worse burning with lidocaine. In addition, the peripheral group had a trend toward improved response to clonazepam, and had significantly less evidence of concomitant psychiatric issues on a validated survey. The 2 groups identified in this small study should be considered in the design of future treatment trials.

Contributions of Psychiatric and Hormonal Disturbances

Several studies have investigated relationships between BMS and psychiatric disease. Indeed, for several years BMS was felt by some to be primarily psychological in origin, although studies were unable to demonstrate a link between its onset and a stressful life event. Similar to other chronic pain patients, one group found an Axis I diagnosis in more than 50% of BMS patients, with depression predominating. Anxiety, when present, had an additional marked impact. Another study assessed Axis II diagnoses in 70 BMS patients compared with a normal population and a group of patients with somatoform disorders. Whereas only 24% of the normal group had a personality disorder, 86% of the BMS patients and 88% of the somatoform patients had an Axis II disorder, although interestingly Cluster A predominated among BMS patients whereas somatoform patients had a higher incidence of Cluster B disorders. Other potential psychogenic factors may include obsessive-compulsive disorder, depression, anxiety, and cancerophobia. Psychopathology may also increase the likelihood of the patient’s presentation and worsen the severity of the complaint, as is the case in chronic pain in general. So while considerable psychiatric comorbidity is present among BMS patients, this is felt to be usually a concurrent or secondary factor rather than its primary cause.

Menopause also has a definite but unclear relationship with BMS. As mentioned earlier, up to 90% of patients with BMS are perimenopausal women. Suggested explanations for this finding have included age-related changes, estrogen-related decreased perception of bitter tastes, coexistence of depression and anxiety, and subtle mucosal changes. Pisanty and colleagues relate the lack of evidence regarding the effects of estrogens on oral mucosa. Woda and colleagues recently proposed that at menopause, the drastic decrease in gonadal steroids leads to altered production of neuroactive steroids, resulting in neurodegenerative changes of small nerve fibers of the oral mucosa and/or some brain areas involved in oral somatic sensations. These investigators posit that these neuropathic changes become irreversible and precipitate the burning pain, dysguesia, and xerostomia associated with BMS, which all involve small nerve fibers.

Distinguishing BMS from Secondary Oral Burning

One difficulty in assessing the literature regarding BMS is that it is often unclear whether local and systemic underlying conditions have been adequately assessed and excluded. Danhauer and colleagues examined patients with BMS and compared them with patients who had oral burning derived from other clinical abnormalities. These investigators concluded that although the 2 categories of patients may initially present with similar clinical and psychosocial features, they are distinguishable with careful diagnosis that often enables successful management of symptoms for each group. Failure to rule out secondary oral burning will result in inappropriate management strategies. Because of this, it is important to understand the potential causes of secondary oral burning and symptom presentation. In BMS, complaints of oral burning may decrease when eating or chewing; symptoms are typically bilateral in presentation and may be present at multiple oral sites. Secondary oral burning related to mucosal changes may be localized to areas of mucosal lesions, and is typically increased with eating, particularly spicy or acidic foods. Secondary oral burning associated with systemic conditions may be bilateral.

One classification divides etiology of secondary oral burning into factors related to the mouth (such as decreased salivary production), systemic factors, and psychological conditions. Another article by Cerchiari and colleagues goes into further detail and includes etiologic categories of local, systemic, psychogenic, and idiopathic. In cases identifying local or systemic factors, the definition of idiopathic BMS is not met. Local factors might include parafunctional behaviors such as tongue movements or habits causing mucosal irritation, dental disease or galvanism, allergic reactions to dental materials, dentures, or other local factors, stomatitis, and infectious conditions such as candidiasis. Possible systemic causes of secondary oral burning include salivary dysfunction, endocrine disturbances, nutritional disorders such as vitamin B complex, folate, iron, or zinc deficiencies, gastrointestinal disease including gastritis, reflux, or Helicobacter pylori infection, medication-related causes, other distinct cranial neuropathies, and possibly primary psychiatric disease.

Evidence for BMS as a Peripheral Neuropathy

BMS is associated with unique histopathologic findings and alterations of levels of salivary neuropeptides. Lauria and colleagues evaluated the innervation of the epithelium of the anterolateral tongue in 12 patients with BMS present for at least 6 months using 3-mm punch biopsies of the region. In addition, samples were obtained from 9 normal patients as a control. Immunohistochemical and confocal microscopy colocalization studies were performed with cytoplasmatic, cytoskeletal, Schwann cell, and myelin markers for pathologic changes. Of note, BMS patients showed a significantly lower density of epithelial nerve fibers than controls, with a trend toward correlation with the duration of symptoms. There was no correlation between density of fibers and severity of symptoms. Epithelial and subpapillary nerve fibers also showed diffuse morphologic changes reflecting axonal degeneration, demonstrating that BMS is associated with a small-fiber sensory neuropathy or axonopathy of the tongue and that biopsy can be used to assess the diagnosis. The investigators note that these findings correlate with histologic findings in burning disorders of the lower limbs, and that the nociceptive stimulation of these fibers may be contributory to the accompanying dysguesia. A recent study by Borelli and colleagues examined the levels of salivary neuropeptides in 20 BMS patients and matched controls, and found significantly increased nerve growth factor peptide and tryptase activity in saliva of BMS subjects. Conversely, levels of substance P were shown to be significantly lower while neutrophil markers were unchanged. The investigators felt these substances might be useful biomarkers for diagnosis and monitoring of BMS.

There are alterations in trigeminal nerve function in BMS patients. Two studies by Jaaskelainen and colleagues examined alteration in function of the trigeminal nerve among BMS patients. Their 1997 article reported on 11 patients with BMS for at least 1 year and 10 healthy controls. Following a thorough neurologic and laboratory evaluation to rule out any other contributory factors, the patients underwent electrophysiologic evaluation of the blink reflex and jaw reflex, and needle electromyographic evaluations of facial and masticatory muscles were performed on those with abnormal blink reflexes. Although all other testing was normal, there was a significant abnormality noted in the blink reflexes of patients with BMS, suggestive of trigeminal dysfunction. A follow-up study in 2002 confirmed the findings of abnormal blink reflexes in 52 BMS patients, and correlated them with quantitative thermal thresholds in 46 of the patients. Seventy-six percent of patients tested had thermal sensory abnormalities, the majority of those some variety of hypoesthesia. Less than 10% of all patients had entirely normal electrophysiological testing of the trigeminal nerve. Some potential mechanisms include neuropathy due to causes such as injury during procedures in the mouth and throat, and viral-induced neuropathy.

Evidence for BMS as a Central Neuropathy

Central neuropathic mechanisms are also felt to be involved in BMS. Albuquerque and colleagues demonstrated differences in perception of trigeminal pain between BMS and normal patients on functional magnetic resonance imaging (fMRI) in a 2006 study. In follow-up to their aforementioned work in trigeminal abnormalities in BMS, Jaaskelainen and colleagues evaluated the nigrostriatal dopaminergic pathway in 10 BMS patients and 14 controls using modified positron emission tomography (PET). Findings of decreased uptake in the right putamen indicated decreased dopaminergic inhibition in BMS patients. Another study by the same group in 2003 found alterations consistent with a decline in endogenous dopamine levels in the putamen in BMS patients.

Evidence for BMS as a Phantom Pain

The role of dysguesia as a primary or secondary phenomenon in BMS remains a point of investigation. Whereas some have felt dysguesia is a secondary event arising from trigeminal dysfunction, others question if loss of taste might be an inciting event, playing a primary role in the etiology of some cases of BMS. It is hypothesized that BMS represents a central oral phantom pain secondary to damage to the gustatory system and disinhibition of central nociceptive regions. Other taste phantoms may also be associated with a similar etiology. Other supporting evidence is that anesthesia of the chorda tympani has been demonstrated to increase the contralateral pain response to capsaicin, and that overlap exists between brain regions involved in taste and pain perception. Supertasters, those with a genetic alteration causing increased number of fungiform papillae and an ability to taste the bitter compound phenylthiocarbamide, may be at increased risk. BMS patients may also have a higher likelihood of taking medications interfering with taste. Evidence that BMS is a form of oral phantom pain is both tantalizing and revealing, given the challenges experienced in treating the most common phantom sensation in otolaryngology, namely, tinnitus. Like tinnitus, BMS has an association with psychopathology and central and peripheral factors, as well as limited success with current medical therapies and a need for careful counseling of those affected.

Evidence for BMS as Variable Disorder with Subcategories

One recent effort to investigate a central versus peripheral origin for BMS was a double-blind, randomized crossover trial comprising 20 patients with BMS. The patients underwent lidocaine and saline injection of the lingual nerve, and although the group overall showed no significant difference in response, central (n = 7) and peripheral (n = 13) subgroups were identified. In the peripheral group, there was a significant decrease in burning with lidocaine injection compared with saline, whereas the central group had a nonsignificant trend toward worse burning with lidocaine. In addition, the peripheral group had a trend toward improved response to clonazepam, and had significantly less evidence of concomitant psychiatric issues on a validated survey. The 2 groups identified in this small study should be considered in the design of future treatment trials.

Contributions of Psychiatric and Hormonal Disturbances

Several studies have investigated relationships between BMS and psychiatric disease. Indeed, for several years BMS was felt by some to be primarily psychological in origin, although studies were unable to demonstrate a link between its onset and a stressful life event. Similar to other chronic pain patients, one group found an Axis I diagnosis in more than 50% of BMS patients, with depression predominating. Anxiety, when present, had an additional marked impact. Another study assessed Axis II diagnoses in 70 BMS patients compared with a normal population and a group of patients with somatoform disorders. Whereas only 24% of the normal group had a personality disorder, 86% of the BMS patients and 88% of the somatoform patients had an Axis II disorder, although interestingly Cluster A predominated among BMS patients whereas somatoform patients had a higher incidence of Cluster B disorders. Other potential psychogenic factors may include obsessive-compulsive disorder, depression, anxiety, and cancerophobia. Psychopathology may also increase the likelihood of the patient’s presentation and worsen the severity of the complaint, as is the case in chronic pain in general. So while considerable psychiatric comorbidity is present among BMS patients, this is felt to be usually a concurrent or secondary factor rather than its primary cause.

Menopause also has a definite but unclear relationship with BMS. As mentioned earlier, up to 90% of patients with BMS are perimenopausal women. Suggested explanations for this finding have included age-related changes, estrogen-related decreased perception of bitter tastes, coexistence of depression and anxiety, and subtle mucosal changes. Pisanty and colleagues relate the lack of evidence regarding the effects of estrogens on oral mucosa. Woda and colleagues recently proposed that at menopause, the drastic decrease in gonadal steroids leads to altered production of neuroactive steroids, resulting in neurodegenerative changes of small nerve fibers of the oral mucosa and/or some brain areas involved in oral somatic sensations. These investigators posit that these neuropathic changes become irreversible and precipitate the burning pain, dysguesia, and xerostomia associated with BMS, which all involve small nerve fibers.

Distinguishing BMS from Secondary Oral Burning

One difficulty in assessing the literature regarding BMS is that it is often unclear whether local and systemic underlying conditions have been adequately assessed and excluded. Danhauer and colleagues examined patients with BMS and compared them with patients who had oral burning derived from other clinical abnormalities. These investigators concluded that although the 2 categories of patients may initially present with similar clinical and psychosocial features, they are distinguishable with careful diagnosis that often enables successful management of symptoms for each group. Failure to rule out secondary oral burning will result in inappropriate management strategies. Because of this, it is important to understand the potential causes of secondary oral burning and symptom presentation. In BMS, complaints of oral burning may decrease when eating or chewing; symptoms are typically bilateral in presentation and may be present at multiple oral sites. Secondary oral burning related to mucosal changes may be localized to areas of mucosal lesions, and is typically increased with eating, particularly spicy or acidic foods. Secondary oral burning associated with systemic conditions may be bilateral.

One classification divides etiology of secondary oral burning into factors related to the mouth (such as decreased salivary production), systemic factors, and psychological conditions. Another article by Cerchiari and colleagues goes into further detail and includes etiologic categories of local, systemic, psychogenic, and idiopathic. In cases identifying local or systemic factors, the definition of idiopathic BMS is not met. Local factors might include parafunctional behaviors such as tongue movements or habits causing mucosal irritation, dental disease or galvanism, allergic reactions to dental materials, dentures, or other local factors, stomatitis, and infectious conditions such as candidiasis. Possible systemic causes of secondary oral burning include salivary dysfunction, endocrine disturbances, nutritional disorders such as vitamin B complex, folate, iron, or zinc deficiencies, gastrointestinal disease including gastritis, reflux, or Helicobacter pylori infection, medication-related causes, other distinct cranial neuropathies, and possibly primary psychiatric disease.