Effect of multiple injections of botulinum toxin into painful masticatory muscles on bone density in the temporomandibular complex.

BACKGROUND: Adverse effects of masticatory muscle injections of Botulinum Toxin (Btx) have been noted in animal and, less dramatically, human studies. OBJECTIVE: Among women treated in multiple community-based private practices, to compare TMJ bone density and mandibular condylar volume between patients with myofascial TMJD receiving multiple masticatory muscle Btx treatments and similarly diagnosed women not receiving such treatment. METHODS: Cohorts consisted of women whose treatment charts indicated a diagnosis of myofascial TMJD: 35 received at least 2 Btx treatment cycles; 44 received none. Bone density at pre-specified regions of interest (ROI) was defined by grey scale values from Cone Beam CT, adjusting for a fixed density phantom included in each scan. Mean bone density and mandibular condyle volume were compared between groups. Dose-response effects were tested within the Btx-exposed group. RESULTS: The mean density of primary and secondary ROIs was similar between exposure groups, as was condylar volume. Among Btx-exposed women, increasing dose of Btx to the temporalis muscle was inversely proportional to the density of the trabecular area of the mandible body. Many Btx-exposed women received smaller doses of Btx to the masseter muscles than in most TMJD Btx clinical trials. CONCLUSION: Masticatory muscle injections of Btx failed to produce clinically significant TMJ bone-related changes. Should Btx receive regulatory approval for treatment of myofascial TMJD, a phase IV study is recommended to evaluate potential adverse effects of Btx on bone and muscle when administered at higher doses and/or for more treatment cycles.

Thermal temporal summation and decay of after-sensations in temporomandibular myofascial pain patients with and without comorbid fibromyalgia.

INTRODUCTION: Chronic myofascial temporomandibular disorders (TMD) may have multiple etiological and maintenance factors. One potential factor, central pain sensitization, was quantified here as the response to the temporal summation (TS) paradigm, and that response was compared between case and control groups. OBJECTIVES: As previous research has shown that fibromyalgia (FM) is diagnosed iñ20% of TMD patients, Aim 1 determined whether central sensitization is found preferentially in myofascial TMD cases that have orofacial pain as a regional manifestation of FM. Aim 2 determined if the report of after-sensations (AS) following TS varied depending on whether repeated stimuli were rated as increasingly painful. METHODS: One hundred sixty-eight women, 43 controls, 100 myofascial TMD-only cases, and 25 myofascial TMD + FM cases, were compared on thermal warmth and pain thresholds, thermal TS, and decay of thermal AS. All cases met Research Diagnostic Criteria for TMD; comorbid cases also met the 1990 American College of Rheumatology criteria for FM. RESULTS: Pain thresholds and TS were similar in all groups. When TS was achieved (~60%), significantly higher levels of AS were reported in the first poststimulus interval, and AS decayed more slowly over time, in myofascial TMD cases than controls. By contrast, groups showed similar AS decay patterns following steady state or decreasing responses to repetitive stimulation. CONCLUSION: In this case-control study, all myofascial TMD cases were characterized by a similar delay in the decay of AS. Thus, this indicator of central sensitization failed to suggest different pain maintenance factors in myofascial TMD cases with and without FM.

Development of a disease registry for autoimmune bullous diseases: initial analysis of the pemphigus vulgaris subset.

Pemphigus vulgaris (PV) is a rare, potentially life threatening, autoimmune blistering skin disease. The International Pemphigus and Pemphigoid Foundation (IPPF) has recently developed a disease registry with the aim to enhance our understanding of autoimmune bullous diseases with the long-term goal of acquiring information to improve patient care. Patients were recruited to the IPPF disease registry through direct mail, e-mail, advertisements, and articles in the IPPF-quarterly, -website, -Facebook webpage, and IPPF Peer Health Coaches to complete a 38-question survey. We present here the initial analysis of detailed clinical information collected on 393 PV patients. We report previously unrecognized gender differences in terms of lesion location, autoimmune comorbidity, and delay in diagnosis. The IPPF disease registry serves as a useful resource and guide for future clinical investigation.

Polysomnographic investigation of sleep and respiratory parameters in women with temporomandibular pain disorders.

STUDY OBJECTIVES: Temporomandibular pain disorders (TMD) and myofascial pain were linked to increased prevalence of insomnia and obstructive sleep apnea (OSA) on clinical grounds. However, the literature lacks an accurate polysomnographic (PSG) characterization of sleep abnormalities associated with TMD, given that prior studies included small or uncontrolled samples of TMD patients. The present investigation aims to objectively evaluate measures of sleep and respiratory disturbance in a large representative sample of TMD cases in comparison with matched controls. METHODS: Sleep, respiration, and limb movements were measured using a 2-night attended PSG protocol in 170 women-124 TMD cases with myofascial pain and 46 demographically matched controls. The second night data were compared between the groups using ANCOVAs. In TMD cases, the relationship between pain ratings and sleep parameters was analyzed using multiple regressions. RESULTS: In comparison to healthy controls, TMD cased evidenced a significant increase in stage N1 sleep (12.2% ± 7.6% vs. 9.2% ± 5.0%, p = 0.03), which was only mild relative to normative values. TMD cases also demonstrated mild but significant elevations in arousals associated with all types of respiratory events (6.0/h ± 6.1 vs. 3.5/h ± 3.3 p = 0.02) and in respiratory effort related arousals (RERAs, 4.3/h ± 4.3 vs. 2.6/h ± 2.7, p = 0.02). Myofascial pain predicted a lower sleep efficiency (p = 0.01), more frequent awakenings (p = 0.04), and higher RERA index (p = 0.04) among TMD cases. CONCLUSIONS: Myofascial pain in TMD is associated with mild elevation in sleep fragmentation and increased frequency of RERA events. Further research is required to evaluate the clinical significance of these findings.

A new treatment paradigm for trigeminal neuralgia using Botulinum toxin type A.

OBJECTIVES: To review the current data for the use of Botulinum toxin type A (BoNT-A) in trigeminal neuralgia (TN) and to describe the preferred injection technique of BoNT-A in TN. To propose a new treatment paradigm for TN incorporating the use BoNT-A. DATA SOURCES: MEDLINE and Google Scholar databases. REVIEW METHODS: The current data on BoNT-A for TN were reviewed and analyzed for outcomes. RESULTS: Seven studies examining the use of BoNT-A were identified: Two randomized double-blind, placebo-controlled studies and five prospective case series. All studies found BoNT-A to be an effective treatment in the majority of patients; and the results of the two randomized double-blind placebo-controlled study showed significant benefit over placebo. The majority of studies used an intradermal or subcutaneous injection technique. The most common side effect was transient facial paresis. CONCLUSIONS: BoNT-A offers a safe, effective, local treatment for TN that is nonablative in nature. BoNT-A should be considered in patients who have failed, become refractory to, or are unable to tolerate first-line pharmacologic treatments. LEVEL OF EVIDENCE: N/A.

EDNRB and DCC salivary rinse hypermethylation has a similar performance as expert clinical examination in discrimination of oral cancer/dysplasia versus benign lesions.

PURPOSE: Promoter hypermethylation has been recently proposed as a means for head and neck squamous cell carcinoma (HNSCC) detection in salivary rinses. In a prospective study of a high-risk population, we showed that endothelin receptor type B (EDNRB) promoter methylation in salivary rinses is a useful biomarker for oral cancer and premalignancy. EXPERIMENTAL DESIGN: Using that cohort, we evaluated EDNRB methylation status and 8 additional genes. Clinical risk assessment by expert clinicians was conducted and compared with biomarker performance in the prediction of premalignant and malignant disease. Methylation status of 9 genes was analyzed in salivary rinses of 191 patients by quantitative methylation-specific PCR. RESULTS: HOXA9, EDNRB, and deleted in colorectal cancer (DCC) methylation were associated (P = 0.012; P < 0.0001; P = 0.0005) with premalignant or malignant disease. On multivariable modeling, histological diagnosis was only independently associated with EDNRB (P = 0.0003) or DCC (P = 0.004) methylation. A subset of patients received clinical risk classification (CRC) by expert clinicians based on lesion examination. CRC, DCC, and EDNRB were associated with diagnosis of dysplasia/cancer on univariate (P = 0.008; P = 0.026; P = 0.046) and multivariate analysis (P = 0.012; P = 0.037; P = 0.047). CRC identified dysplasia/cancer with 56% of sensitivity and 66% of specificity with a similar area under curve [AUC; 0.61, 95% confidence interval (CI) = 0.60-0.81] when compared to EDNRB and DCC combined AUC (0.60, 95% CI = 0.51-0.69), sensitivity of 46% and specificity of 72%. A combination of EDNRB, DCC, and CRC was optimal AUC (0.67, 95% CI = 0.58-0.76). CONCLUSIONS: EDNRB and/or DCC methylation in salivary rinses compares well to examination by an expert clinician in CRC of oral lesions. These salivary biomarkers may be particularly useful in oral premalignancy and malignancy screening in clinical care settings in which expert clinicians are not available.

Effect of contingent electrical stimulation on masticatory muscle activity and pain in patients with a myofascial temporomandibular disorder and sleep bruxism.

AIMS: To determine whether an intervention reduces oromotor activity and masticatory muscle pain in myofascial temporomandibular disorder (M/TMD) patients with high levels of masticatory muscle activity associated with sleep bruxism. METHODS: Fourteen women with M/TMD and prior polysomnographic evidence consistent with sleep bruxism participated in a 10-week single-group pre-test/ post-test mechanistic clinical trial. A 2-week period of baseline monitoring of individually biocalibrated electromyographic (EMG) events associated with sleep bruxism was followed by 6 weeks of EMG-event-contingent treatment via an innocuous electrical pulse to the skin overlying the temporalis muscle. Treatment was discontinued during 2-week follow-up monitoring. Each night before sleep, subjects recorded their average daily pain. RESULTS: Mixed-model analysis of variance showed a reliable reduction of EMG events during contingent stimulation treatment periods, but frequency of EMG events returned to baseline levels during follow-up (linear term, P = .002; quadratic term, P = .001). In contrast, nightly pain reports failed to show any systematic changes during treatment (linear and quadratic trends, both P > .10). CONCLUSION: Spontaneous pain severity and nighttime oromotor activity vary independently over nights, even in M/TMD patients selected for relatively high levels of both characteristics.

Sleep bruxism and myofascial temporomandibular disorders: a laboratory-based polysomnographic investigation.

BACKGROUND: Many dentists believe that sleep bruxism (SB) is a pathogenic factor in myofascial temporomandibular disorder (TMD), but almost all supportive data rely on patients' self-reports rather than on direct observation. METHODS: The authors administered a structured self-report interview to determine whether a large and well-characterized sample of patients with myofascial TMD (124 women) experienced SB more often than did matched control participants (46 women). The authors then used data from a two-night laboratory-based polysomnographic (PSG) study to determine whether the case participants exhibited more SB than the control participants. RESULTS: The results of independent sample t tests and χ(2) analyses showed that, although self-reported rates of SB were significantly higher in case participants (55.3 percent) than in control participants (15.2 percent), PSG-based measures showed much lower and statistically similar rates of SB in the two groups (9.7 percent and 10.9 percent, respectively). Grinding noises were common in both case participants (59.7 percent) and control participants (78.3 percent). CONCLUSIONS: Most case participants did not exhibit SB, and the common belief that SB is a sufficient explanation for myofascial TMD should be abandoned. CLINICAL IMPLICATIONS: Although other reasons to consider treating SB may exist, misplaced concern about SB's sustaining or exacerbating a chronic myofascial TMD condition should not be used to justify SB treatment.

Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.

Our scientific knowledge of bullous pemphigoid (BP) has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in BP. A major obstacle in sharing multicenter-based evidences for therapeutic efforts is the lack of generally accepted definitions for the clinical evaluation of patients with BP. Common terms and end points of BP are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. These recommendations from the International Pemphigoid Committee represent 2 years of collaborative efforts to attain mutually acceptable common definitions for BP and proposes a disease extent score, the BP Disease Area Index. These items should assist in the development of consistent reporting of outcomes in future BP reports and studies.

The International Pemphigus and Pemphigoid Foundation.

The International Pemphigus Pemphigoid Foundation (IPFF) was founded in 1997. The IPPF lists more than 4500 members. The IPPF provides peer health coaches to aid patients in the navigation of the health care system and recommends dermatologists and other specialists in their area who are experts in autoimmune bullous disease. The IPPF hosts the largest worldwide registry of pemphigus/pemphigoid patients with biospecimen collection opportunities are planned. Twice a year the IPPF hosts formal meetings with invited speakers.

Endothelin receptor type B gene promoter hypermethylation in salivary rinses is independently associated with risk of oral cavity cancer and premalignancy.

Endothelin receptor type B (EDNRB) and kinesin family member 1A (KIF1A) are candidate tumor suppressor genes that are inactivated in cancers. In this study, we evaluated the promoter hypermethylation of EDNRB and KIF1A and their potential use for risk classification in prospectively collected salivary rinses from patients with premalignant/malignant oral cavity lesions. Quantitative methylation-specific PCR was performed to analyze the methylation status of EDNRB and KIF1A in salivary rinses of 191 patients. We proceeded to determine the association of methylation status with histologic diagnosis and estimate classification accuracy. On univariate analysis, diagnosis of dysplasia/cancer was associated with age and KIF1A or EDNRB methylation. Methylation of EDNRB highly correlated with that of KIF1A (P < 0.0001). On multivariable modeling, histologic diagnosis was independently associated with EDNRB (P = 0.0003) or KIF1A (P = 0.027) methylation. A subset of patients analyzed (n = 161) without prior biopsy-proven malignancy received clinical risk classification based on examination. On univariate analysis, EDNRB and risk classification were associated with diagnosis of dysplasia/cancer and remained significant on multivariate analysis (EDNRB: P = 0.047, risk classification: P = 0.008). Clinical risk classification identified dysplasia/cancer with a sensitivity of 71% and a specificity of 58%. The sensitivity of clinical risk classification combined with EDNRB methylation improved to 75%. EDNRB methylation in salivary rinses was independently associated with histologic diagnosis of premalignancy and malignancy and may have potential in classifying patients at risk for oral premalignant and malignant lesions in settings without access to a skilled dental practitioner. This may also potentially identify patients with premalignant and malignant lesions that do not meet the criteria for high clinical risk based on skilled dental examination.

Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus.

Our scientific knowledge of pemphigus has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in pemphigus. A major obstacle in comparing therapeutic outcomes between centers is the lack of generally accepted definitions and measurements for the clinical evaluation of patients with pemphigus. Common terms and end points of pemphigus are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. This consensus statement from the International Pemphigus Committee represents 2 years of collaborative efforts to attain mutually acceptable common definitions for pemphigus. These should assist in development of consistent reporting of outcomes in future studies.

Dental care of patients with autoimmune vesiculobullous diseases: case reports and literature review.

Dental management of patients with autoimmune vesiculobullous disorders is complicated because of prominent involvement of oral mucosa, increased risk of oral disease, and difficulty in rendering dental care. Although these diseases are relatively uncommon, dental practitioners should be familiar with the oral sequelae of these conditions and their management. Pemphigus vulgaris, cicatricial pemphigoid, and epidermolysis bullosa represent the most common autoimmune oral vesiculobullous diseases. This case-illustrated review summarizes the pathogenesis, diagnostic features, and natural history of oral vesiculobullous disorders, placing an emphasis on the treatment and prevention of associated oral disease aimed at maintaining a healthy, functional dentition.

Paraneoplastic epidermolysis bullosa acquisita associated with multiple myeloma.

Epidermolysis bullosa acquisita is a rare acquired autoimmune subepidermal blistering disease that clinically resembles other vesiculobullous lesions such as pemphigus vulgaris and cicatricial pemphigoid. Multiple myeloma is the most common plasma cell malignant disorder characterized by a single clonal expansion and increased level of a single immunoglobulin. Epidermolysis bullosa acquisita has been reported with other systemic diseases such as lymphoma. In this case report, we present a patient with paraneoplastic epidermolysis bullosa acquisita associated with multiple myeloma.

Cytotoxicity of liposomal alpha-tocopheryl succinate towards hamster cheek pouch carcinoma (HCPC-1) cells in culture.

There is compelling evidence for the cancer chemopreventive effects of vitamin E and related compounds. Of all the vitamin E derivatives that have been investigated to date, vitamin E acid succinate is the most effective anti-cancer agent. This report describes the preparation and testing of liposomal formulation of mono alpha-tocopheryl ester of succinic acid (alpha-TOS) for cytotoxicity against hamster cheek pouch carcinoma cell line (HCPC-1). Small unilamellar vesicles (SUV) of phosphatidylcholine incorporating 70 microM alpha-TOS were superior to alpha-TOS alone or SUV without incorporated alpha-TOS, as inducers of apoptosis in HCPC-1 cells. Liposomal alpha-TOS perturbed the lipid structure in cells, promoted apoptosis, and decreased cell viability. The mechanism of action of alpha-TOS appears to involve membrane damage and induction of ceramide mediated apoptosis.

Sensory responses from loading of implants: a pilot study.

PURPOSE: Osseointegrated implants lack a periodontal ligament. Nevertheless, masticatory function in subjects with implant-supported restorations appears similar to function in those with natural dentition. It is not clear how the neurophysiologic mechanisms that modulate jaw movement are associated with osseointegrated implants. This study examined the output from the inferior alveolar nerve during implant loading. MATERIALS AND METHODS: In 3 dogs, 3 premolars were extracted in the mandible and 2 endosseous titanium implants were placed, allowed to osseointegrate for 3 months, and loaded with vibration force at the threshold response for tooth vibration, at 2x threshold, and at 3x threshold. Neurophysiologic recordings were made from the inferior alveolar nerve during loading of both implants and the adjacent molar and canine. The response magnitude in action potentials in the 50- ms poststimulus period and latency of inferior alveolar afferents in milliseconds were compared following implant loading. RESULTS: Detectable inferior alveolar nerve responses were recorded following loading from both the implants and the teeth at 2x and 3x threshold. However, the response magnitude of teeth (canine, 2.38 +/- 0.18 at 2x, 2.78 +/- 0.2 at 3x; molar, 2.2 +/- 0.16 at 2x, 2.5 +/- 0.21 at 3x) was twice that of the implants (anterior, 1.3 +/- 0.12 at 2x, 1.68 +/- 0.13 at 3x; posterior, 0.8 +/- 0.1 at 2x, 1.53 +/- 0.15 at 3x). The differences in response magnitude between the teeth and implants were significant (P < .05). The latency of response was similar. DISCUSSION: Management of the occlusion for implant-supported restorations has been empirically developed. An underlying assumption has been that implant-guided jaw function lacks significant proprioception to modulate mastication and related jaw movements. This animal study provides preliminary evidence that force application to implants does elicit a proprioceptive response. CONCLUSION: Loading of implants does elicit a sensory response that can be observed in the inferior alveolar nerve. The implications are that during occlusal function, information from regions associated with the implant can provide knowledge that could potentially modulate jaw activity in a manner similar to natural teeth.

Structural and functional injury in minipig salivary glands following fractionated exposure to 70 Gy of ionizing radiation: an animal model for human radiation-induced salivary gland injury.

This study explored the feasibility of developing an animal model for radiation-induced salivary gland injury with a radiation protocol identical to current clinical practice. Three male Hanford minipigs were subjected to fractionated daily irradiation with a total dose of 70 Gy; structural and functional measures were compared with those of a control group of minipigs. We found that irradiated submandibular and parotid glands were one-third to one-half the gross size of control glands. Whereas no pathologic changes were noted in control glands, irradiated glands consistently demonstrated significant parenchymal loss with extensive acinar atrophy and interstitial fibrosis, enlarged nuclei in remaining acinar cells, and ductal dilatation and proliferation. Stimulated salivary flow was reduced by 81% in irradiated animals compared with preirradiation flow (P <.001); salivary flow in the control group increased by 30% during the same period (P <.001). The observed radiation-induced structural and functional salivary gland changes are comparable in every respect to those observed following irradiation of human salivary glands.