Numb Chin with Mandibular Pain Or Masticatory

+ MODEL Journal of the Formosan Medical Association (2017) xx,1e10

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Original Article Numb chin with mandibular pain or masticatory weakness as indicator for systemic malignancy e A case series study Shin-Yu Lu a,*, Shu-Hua Huang b, Yen-Hao Chen c a Oral Pathology and Family Dentistry Section, Department of Dentistry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan b Department of Nuclear Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan c Department of HematoeOncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

Received 5 June 2017; received in revised form 2 July 2017; accepted 4 July 2017

KEYWORDS Background/Purpose: Numb chin syndrome (NCS) is a critical sign of systemic malignancy; Numb chin syndrome; however it remains largely unknown by clinicians and dentists. The aim of this study was to Mandibular pain; investigate NCS that is more often associated with metastatic cancers than with benign dis- Malignancy eases. Methods: Sixteen patients with NCS were diagnosed and treated. The oral and radiographic manifestations were assessed. Results: Four (25%) of 16 patients with NCS were affected by nonmalignant diseases (19% by medication-related osteonecrosis of the jaw and 6% by osteopetrosis); yet 12 (75%) patient conditions were caused by malignant metastasis, either in the mandible (62%) or intracranial invasion (13%). NCS was unilateral in 13 cases and bilateral in three cases. Mandibular pain and masticatory weakness often dominate the clinical features in NCS associated with cancer metastasis. In two patients, NCS preceded the discovery of unknown malignancy (breast cancer and leukemia). In nine others, NCS heralded malignancy relapse and progression. Metasta- tic breast cancer in four (36%) cases accounted for the most common malignancy. Other metastatic diseases included two multiple myelomas, and one each of leukemia, prostate cancer, colon cancer, lung cancer, maxillary sinus adenoid cystic carcinoma and adrenal gland neuroblastoma. Radiographic examinations showed obvious mandibular metastasis with compression of the inferior alveolar nerve or mental nerve in nine patients, and leptomeningeal seeding or intracranial metastasis to the trigeminal nerve root at the skull base in two patients.

* Corresponding author. Kaohsiung Chang Gung Memorial Hospital, 123 Dapi Road, Niaosong District, Kaohsiung, 833, Taiwan. Fax: þ886 7317123x2243. E-mail address: [email protected] (S.-Y. Lu). http://dx.doi.org/10.1016/j.jfma.2017.07.002 0929-6646/Copyright ª 2017, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Conclusion: NCS without obvious odontogenic causes or trauma often signals systemic malignancy. It may be the ﬁrst clue of occult malignancy. Copyright ª 2017, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/).

Introduction the multiple etiologies and significance of NCS are reviewed. Numb chin syndrome (NCS), also called mental nerve neuropathy (MNN), is characterized by hypoesthesia, pares- Methods thesia or prickling pain over the chin, lower lip and gingiva mucosa in the distribution of the mental nerve or inferior The study was approved by the necessary Institutional Re- alveolar nerve (IAN), and/or neuropathic weakness in the 1,2 view Board. A total of 157 patients including 53 cases with muscles of mastication. It is usually unilateral, but oral manifestations from metastatic cancers and 103 cases bilateral presentation may occur. The overall prevalence with medication-related osteonecrosis of the jaw (MRONJ) and incidence of NCS is not known. plus one case of osteopetrosis, were examined for NCS Various etiologies of NCS including traumatic, vascular, between October 1990 and June 2016. Sixteen consecutive inflammatory, demyelinating, infectious, and neoplastic 3e8 patients (12 females and 4 males) with numbness of lower disorders have been reported. However, mounting evi- face and a wide range of mandibular pain visiting the Oral dence suggests that NCS is most often a harbinger of cancer Medicine Clinic of Kaohsiung Chang Gung Memorial Hospital relapse and progression, or may precede the discovery of 9,10 and finally diagnosed with NCS, were included in this study. unknown cancer. The possibility of metastatic cancer, Those patients with numb chin caused by iatrogenic usually breast cancer or hematologic malignancy should be trauma, dental extraction, orthognathic surgery or oral first considered if dental diseases or trauma are 11e15 cancer operation were excluded from this survey. Data excluded. NCS, a seemingly benign presentation, is an were retrieved from chart notes made at each visit. A full important sign and dangerous symptom for primary care dental and medical history was recorded including oral clinicians. Nevertheless, NCS has been rarely mentioned in complaints, alteration in the oral mucosa and jaws, medi- either the undergraduate or postgraduate of dental and cations, previous care regarding internal cancers, and medical syllabuses. NCS is almost unknown or remains in 10,16 generalized symptoms and signs such as body weight loss, limited awareness by dentists and physicians. fatigue, tiredness, pallor, bone pain, headache or other The trigeminal nerve has three branches, the ophthalmic neuropathy. (V1), maxillary (V2) and mandibular (V3) nerves that pro- Patients underwent panoramic radiographs or special vide several sensory and motor functions to the face. The examinations including bone scintigraphy, multi-slice CT mandibular branch courses downward from the trigeminal scan of head, magnetic resonance imaging (MRI) of the ganglion and exits the middle cranial fossa inferiorly via the brain, and cone-beam computed tomography (CBCT) or a foramen ovale, then divides into an anterior motor division mandibular biopsy after informed consent. that supplies the masticatory muscles, and a posterior The incidence of NCS between metastatic cancer pa- sensory division that enters the mandibular canal as the tients and benign disease patients was analyzed by using inferior alveolar nerve (IAN). The V3 has five sensory nerves chi-square test. A value of p < 0.05 was considered statis- including meningeal, auriculotemporal, buccal, lingual and tically significant. the IAN, the latter that gives rise to the mental nerve via mental foramen. IAN provides pure sensory innervation to the cheek, lower teeth, gingiva, and floor of the mouth, Results lower lip and chin.2 Pathologic mechanism behind MNN in cancer patients is often induced by malignant infiltration of A total of 16 patients with a wide range of ages (9e83 IAN sheath or direct compression of IAN or mental nerve by years) and female predominance (12 of 16, 75%) com- mandibular metastasis or local tumor.3,9,10 However, lep- plaining about mostly oral symptoms led to the diagnosis of tomeningeal carcinomatosis and intracranial metastases to NCS associated with metastatic cancers in 12 (75%) pa- the base of skull have also been implicated in a small tients, MRONJ in three (19%) patients and osteopetrosis in percentage of patients who may represent NCS accompa- one (6%) patient (Table 1). The prevalence of NCS was 23% nying other neurological symptoms.17e19 (12 of 53) in those who had metastatic cancers and 4% (4 of Patients with NCS should be investigated aggressively 104) in those who had benign diseases with a significant without delay until proven otherwise. NCS is a rare but difference (p < 0.001, Table 2). well-documented neurological manifestation of metastatic NCS was unilateral in 13 (81%) cases and bilateral in malignancy. Clinical evaluation should include evaluation three (19%) cases. The histopathologic studies from for occult malignancy or relapse of any known previous mandibular biopsies confirmed clinical diagnosis of cancer cancer. Here we report 16 cases with NCS illustrating the metastasis in eight patients. In two (17%) of 12 patients, seriousness of this symptom and the literatures regarding NCS preceded the discovery of unknown malignancy (breast

Table 1 Patient characteristics of numb chin syndrome. Case Age/Gender Cancer type or others Chief symptoms Numb chin Mandible Jaw lesions/ Brain metastasis except numb chin lesions radiography 1 43/F Breast Teeth mobility, R Whole Osteolysis, No chewing weakness root resorption 2 55/F Breast Mandibular pain, B Whole Osteolysis, No chewing weakness loss of PDL, root resorption 3 35/F Breast Mandibular pain, L L Osteolysis of No local swelling IAN canal and ramus 4 59/F Breast Chewing weakness, RNN Yes standing weakness, diplopia 5 54/F Lung Chewing weakness, BNN Yes standing weakness 6 44/F Colon Mandibular pain L L Osteolysis No 7 60/M Prostate Mandibular pain L L Osteolysis No 8 32/F Right maxillary Chewing weakness, L L Osteolysis, No sinus adenoid saliva dropping from root resorption cystic carcinoma mouth angle 9 9/F Adrenal gland Mandibular pain, L L Osteolysis No Neuroblastoma local swelling 10 46/F Acute myeloid Mandibular pain; L L PDL widening No leukemia toothache, location of involved teeth unspecified 11 82/M Multiple myeloma Mandibular pain, L L Osteolysis, No local swelling pathologic fracture 12 68/F Multiple myeloma Bilateral numb chin B Whole Many punch-out No Osteolysis 13 73/F MRONJ, Osteoporosis Mandibular pain, L L Osteolytic lesion No extra-oral fistula with dead bone 14 80/M MRONJ, Colon cancer Mandibular pain, L L Osteolytic lesion No pus discharge with dead bone 15 68/M Spontaneous MRONJ, Mandibular pain, L L Osteolysis of No Prostate cancer chewing weakness, mandibular body, multiple fistula dead bone 16 43/F Osteopetrosis Mandibular pain R R Radiopaque/IAN No canal prominence Abbreviation: F, Female; M, Male; B, Bilateral; L, Left; R, Right; N, Normal; IAN, Inferior alveolar nerve; MRONJ, Medication-related osteonecrosis of the jaw; PDL, Periodontal ligament. cancer of case 1 in our previous report11 and leukemia of patients, eleven (69%) patients were accompanied by case 10). In the ten others, NCS heralded cancer relapse tingling mandibular pain and six (40%) patients complained and progression. Metastatic breast cancer in four of 12 about weakness or difficulty with chewing at the numb chin (33%) cases accounted for the most common malignancy. side. A chief presentation in a 32-year-old female (case 8) Other cancers included two multiple myelomas, and one with adenoid cystic carcinoma of right maxillary sinus was each of leukemia, prostate, colon, lung, right maxillary saliva dropping from left numb lip side uncontrollably. sinus adenoid cystic carcinoma and adrenal gland neuro- Some patients presented with focal swelling, loose teeth, blastoma. One leukemia patient without jaw abnormality and idiopathic or chewing-induced toothache. The pano- only showed widening of periodontal ligament space in the ramic jaw radiographs confirmed a clinical diagnosis of NCS (painful) left mandibular premolars. Nine patients showed associated with mandibular metastasis in nine patients who obvious mandibular metastasis with tumor invasion or revealed bony trabeculae alterations, osteolysis anywhere compression of IAN or mental nerve. Two patients revealed along the mandible in the region of the IAN or mental leptomeningeal carcinomatosis and intracranial metastasis nerve. In two patients with myeloma jaws, one showed to the trigeminal nerve root at the skull base. numerous punched-out osteolytic lesions in the bilateral No gross pathology in nine (75%) of 12 patients with mandibular body and endosteal scalloping along the cancer-related NCS could be seen clinically. Among 16 NCS mandibular border; another showed diffuse osteolysis

diplopia, loss of balance, and difficulty with standing or Table 2 Prevalence of numb chin syndrome (NCS) in walking. No gross pathology in the panoramic jaw radio- metastatic cancer patients and benign disease (medication graphs could be found (Fig. 3A). Examinations by CT scans related osteonecrosis of jaws plus osteopetrosis) patients.a and MRI of the brain revealed intracranial metastasis to Patient no. NCS (þ) NCS () the right cerebellopontine angle (CPA), meninges and Metastatic cancers 53 12 (23%) 41 (77%) para-cavernous sinus by tumor in the area of the root of Benign diseases 104 4 (4%) 100 (96%) the right trigeminal nerve (Fig. 3BeE) in a 59-year-old Total cases 157 16 141 female (case 4) with breast cancer, and diffuse lep- p <0.001 tomeningeal metastasis in the posterior fossa involving bilateral trigeminal nerves and the internal auditory canal Data are presented as n or n (%). in a 54-year-old female (case 5) with lung cancer. Lumber a The prevalence of NCS was significantly different between metastatic cancer patients and benign disease patients (chi- puncture and cytologic analysis of cerebrospinal fluid square test, <0.001). confirmed the diagnosis of leptomeningeal metastasis in the two cases. Cranial irradiation had led to the disap- pearance of diplopia and partial recovery of numb chin in resulting in a pathological fracture in the left mandibular the two patients with brain metastasis. Treatment of NCS body. Examination by CBCT of the jaws in four patients associated with metastatic disease was aimed at the un- provided a high-resolution and 3-D perspective image of the derlying diseases. Chemotherapy plus anti-resorptive destruction pattern and lesion progression in the involved medications to alleviate the symptoms was the mandible. preferred therapeutic modality. Local radiotherapy was A 55-year-old female (case 2) with a history of breast also utilized to solve mandibular pain in several patients. cancer treated by mastectomy, local irradiation, adjuvant However, prognosis of NCS in the patient with cancer chemotherapy and Tamoxifen showed negative finding of remained poor; survival was usually measured in months bony metastasis in whole bone scan within the first year. to 3 years. However, numbness of right chin and lip occurred after 14 Nonmalignant local diseases associated with NCS in the months delay from first diagnosis of breast cancer. No gross study included MRONJ in three patients and osteopetrosis in oral abnormality could be found, but mandibular metastasis one patient. In three MRONJ patients, the visibly intraoral was highly suspected because the lamina dura of several changes such as alveolar abscess, multiple intraoral fistulas teeth and the IAN canal in the right mandible became un- and necrotic bone exposure were obvious. Two MRONJ apparent (Fig. 1A and B). However, it was dismissed as cases also revealed non-healing sockets and extra-oral fis- osteomyelitis by the physicians of nuclear medicine and tula in the submandibular area. The radiographic findings oncology because the second bone scan and gallium-67 scan mimicked diffuse osteomyelitis with evident areas of only showed diffusely active bone lesion in the right mottled bone and sequestration or inflammatory changes in mandible crossing midline without other skeletal lesions the periodontal health of adjacent teeth such as widening (Fig. 2A). Five months later, she visited the dental periodontal ligament space and osteosclerotic lamina dura department again for severe mandibular pain, mobile or loose teeth. An 80-year-old male (case 14) who had colon teeth, chewing difficulty and bilateral chin numbness. The cancers and was undergoing monthly therapy with zoledr- second panoramic radiograph and the first CBCT survey onate for 14 months represented MNN and MRONJ of left revealed progressive osteolysis anywhere along the whole mandible after dental extraction. A mandibular biopsy was mandible and loss of lamina dura, root resorption, as well performed during debridement of necrotic bone to differ- as periodontal and periapical-like lesions with ill-defined entiate it from the neoplastic disease. A 68-year-old man borders in many teeth (Fig. 1C and E). A biopsy from the (case 15) with prostate cancer and skeletal metastasis un- mandibular symphysis showed complete destruction of the dergoing monthly therapy of denosumab over one year cortex (Fig. 1D) and confirmed metastatic breast cancer. suffered from MNN due to spontaneous MRONJ occurring in The third bone scan showed multiple active bone lesions in the left mandible. Cessation of bisphosphonates or deno- the whole mandible, skull at right temporal bone, thor- sumab and conservative debridement plus antibiotics had acolumbar spines, ribs, both sacroiliac joints and pelvic brought partial recovery of MNN in the two cases. However, bones, which represented general bony metastasis numb chin remained after successful resolution of MRONJ in (Fig. 2B). However, MRI of the brain showed no evidence of a 73-year-old female with osteoporosis (case 13) (Fig. 4). abnormality. All the clinical courses and images explained A 43-year-old female (case 16) without any systemic that the numb chin was the first and only manifestation of disease complained about progressive numbness of lower metastatic breast cancer. After monthly therapy with right face after serial extraction of three mandibular mo- denosumab for 1.5 years, spontaneous exfoliation of right lars due to recurrent pain and swelling of the right lower second molar and MRONJ with dead bone exposure in mandible within three years. No gross oral abnormality was right mandible developed (Fig. 1F and G). Accordingly, found clinically. Panoramic jaw radiograph showed a cessation of denosumab and the chemotherapy program diffuse increase in the radiopacity of the right mandible was changed, but her general condition had progressively including unusual dense and chalky white change, promi- worsened and died of brain metastasis and respiratory nence of IAN canal and undistinguishable border between failure thirty months after the diagnosis of NCS from met- cortical and cancellous bone (Fig. 5). Idiopathic adult-form astatic breast cancer. of osteopetrosis was diagnosed. However, no appropriate Two patients with treated malignancy showed MNN and treatment could reverse the damage that had already polyneuropathy including chewing weakness, headache, occurred.

Figure 1 An example (Case 2) demonstrated numb chin with mandibular pain and masticatory weakness as the first manifestation of breast cancer metastasis. (A and B) Initial panoramic radiograph showed unapparent IAN canal in right mandible highly suspicious f metastatic disease, and no gross oral abnormality in September 2014. (C and E) The second panoramic radiograph and the first CBCT survey revealed progressive osteolysis anywhere along whole mandible and many teeth with loss of lamina dura, root resorption, as well as periodontal and periapical-like lesions with ill-defined border in February 2015. (D) A biopsy from mandibular symphysis showed complete destruction of the cortex and confirmed metastasis from breast cancer. (F and G) Panoramic radiograph showed some bony resumption but medication-related osteonecrosis of right mandible with dead bone exposure following spontaneous exfoliation of right lower second molar developed after monthly therapy with denosumab for 1.5 years.

Figure 2 (A) Whole body bone scan in Case 2 showed diffusely active bone lesion in right mandible crossing midline without other skeletal lesions as the ﬁrst herald of bony metastasis from breast cancer in November 2014; however, it was initially dismissed as osteomyelitis. (B) Another bone scan revealed multiple active bone lesions in the whole mandible, skull at right temporal bone, thoracolumbar spines, ribs, both sacroiliac joints and pelvic bones, which represented general bony metastasis in March 2015.

Discussion astute clinician who realizes the potential of cancers to be involved in the pathophysiology of NCS can then exclude an In this retrospective case series of NCS, only four (25%) underlying cancer in the patient. patients were affected by nonmalignant diseases (MRONJ Many primary neoplasms commonly metastasize to and osteopetrosis), but 12 (75%) patient conditions were bones, but metastasis to jawbones is rare and frequently e 20e22 caused by cancer metastasis, either in the mandible (62%) occurs in patients aged 40 70 years. The amount of or via intracranial invasion (13%). Further, the incidence of red bone marrow and blood vessels in the jawbones tends NCS indicated a significant difference between metastatic to decrease with age due to the gradual replacement of red 22,23 cancer patients (23%, 12 of 53) and benign disease patients marrow with yellow or fatty marrow. This is why jaw (4%, 4 of 104). It is quite obvious that NCS is an important metastasis is less common than in other bones. Further- neurological manifestation of metastatic malignancy. Our more, metastases to oral soft tissue are even less frequent results showed a similar findings to many reports in that than in jawbones. Meyer and Shklar reviewed 2400 oral MNN or trigeminal neuropathy (TNO), in the absence of malignancies during a 12-year period and found only 25 odontogenic causes, are most often caused by metastatic metastatic tumors, which accounted for approximately 1% 20 tumor.10e25 In Lossos and Siegal’s study which was before of all oral malignancies. In 25% of the cases, oral metas- MRONJ reported, this etiology of metastatic cancer was tases were found to be the first sign of the metastatic found in 86% of the NCS affected cases, including metas- spread; and in 23% of the cases, it was the first indication of 20 tasis either in the mandible (50%), at the base of the skull an undiscovered malignancy at a distant site. A meta- (14%) or leptomeningeal seeding (22%).19 static tumor to the jaws more often occurs in the mandible Malignant MNN confers mortality over 78% within 2 than in the maxilla, and most often in the premolar-molar years.2,11 However, because of its rarity and the lack of region which is close to the IAN or mental nerve, so numb 22 gross abnormality, the clinical presentation of a metastatic chin or MNN may develop. lesion in the oral cavity can be deceiving, leading to Several distinct mechanisms behind MNN or TNO include misdiagnosis of a benign process. The quote by the French compression at intra- or extra-cranial portions of the nerve, 3,9,10 microbiologist Louis Pasteur (1822e1895), “Chance favors peri-neural spread, and metastasis. The most common only the prepared mind” can be fully applicable to NCS. An metastatic cancers in order of frequency are the breast

Figure 3 An example (Case 4) demonstrated numb chin with masticatory weakness as the initial manifestation of intracranial metastasis from breast cancer. (A) No gross pathology of the mandible in panoramic radiograph. Brain CT scan (B and C) and MRI (D and E) showed tumor metastasis to the right cerebellopontine angle, meninges and para-cavernous sinus in the area of the root of right trigeminal nerve.

(21.8%) followed by lung (12.6%), adrenal (8.7%), kidney (7.9%), colo-rectum (6.6%), and prostate (5.6%).20,21 Although any type of malignancy can metastasize to the mandible, in the evolution of neoplasia, adenocarcinoma is the most frequent histological subtype (70%).21e23 In women, breast cancer is the most common malignancy affecting the jawbones and soft tissues (41% and 24.3%, respectively).22 In this study, metastatic breast cancer (33%) accounted for the most common malignancy, followed by hematological malignancy (25%) and lung, colon, prostate or adrenal (8% respectively). Our ﬁndings corre- sponded to Laurencet’s study that found isolated MNN was frequently associated with breast cancer and lymphoproli- ferative diseases.23 When MNN was associated with metastatic cancer or infection, mandibular pain frequently dominated the clinical feature,24,25 which was discovered in eleven (69%) patients in the study. Painful MNN should not be confused with the myofascial pain or trigeminal neuralgia which is characterized by brief attacks of lancinating or shooting pain, and cutaneous or intraoral trigger for pain, but without sensory loss or motor weakness.2,26e28 As the disorder un- Figure 4 An example (Case 13) represented numb chin derlying it progresses and neurons are destroyed, neuro- caused by medication-related osteonecrosis of jaw after 4 pathic weakness in the masticatory muscles and numbness years of Fosamax therapy for osteoporosis. (A) Initial pano- usually occurs simultaneously.2 Six (40%) affected patients ramic radiograph showed a bony defect with mottled bone and complained about weakness or difﬁculty with chewing at dead bone formation in left mandibular body in August 2015 (B) the numb chin side, and one of them was also bothered Panoramic radiograph showed successful resolution of MRONJ with spontaneous saliva dropping from the numb lip side. with partial bone regeneration, but numb chin remained in Variable tooth mobility and swelling or edema change in the June 2016.

Figure 5 An example (Case 16) represented numb chin caused by osteopetrosis. (A and B) Panoramic and periapical radiograph showed unusual dense and chalky white change of right mandible, prominence of IAN canal and undistinguishable border between cortical and cancellous bone. (C) No gross oral abnormality except residual scar in the edentulous site of right mandible.

Please cite this article in press as: Lu S-Y, et al., Numb chin with mandibular pain or masticatory weakness as indicator for systemic malignancy e A case series study, Journal of the Formosan Medical Association (2017), http://dx.doi.org/10.1016/j.jfma.2017.07.002 + MODEL Numb chin as indicator for systemic malignancy 9 numb chin and gingiva mucosa became noticed when cell anemia, temporal arteritis, other vasculitis, Lyme dis- mandibular metastasis progressively worsened. Some pa- ease, syphilis, and human immunodeficiency virus infection tients showed limited ability to open the mouth fully when have been reported.3e8,34 In this study, NCS induced by metastatic cancer involved the masticatory space. benign lesions of MRONJ and idiopathic osteopetrosis was Any patient with lower facial numbness and pain should first reported. Stopping anti-resorptive therapies with be interviewed about symptoms of partial or complete bisphosphonate or denosumab can provide some help in anesthesia, hearing loss, diminished taste, and chewing resolution of MRONJ.35 However, successful resolution of weakness. The later complaint should be interpreted with MRONJ in two of three cases did not bring complete re- caution, as subjective difficulty with chewing may reflect covery of numb chin. We reinforce the importance of the pure sensory loss independently of any motor deficit.2 Vi- implementation of prophylactic dental assessment and sual inspection or manual palpation may reveal atrophy of enhanced dental intervention in the prevention of the temporalis and masseter muscles. Movement of the jaw MRONJ.34 Osteopetrosis may result in hypovascularized will deviate towards the side of a weakened pterygoid bone, which is predisposed to necrosis and inflamma- muscle. A history of conductive hearing loss and serous tion.35,36 Recurrent osteomyelitis-related osteopetrosis is otitis media may reflect Eustachian tube dysfunction from refractory to treatment by dental extraction, antibiotics, weakness of the tensor veli palatine muscle, which is steroids and debridement during acute mandibular pain innervated by the medial pterygoid nerve, a branch of attack. Dentists can play an important role in the early mandibular nerve (V3).2,26e29 diagnosis of osteopetrosis, but treatment of osteomyelitis- Furthermore, the possibility of a central neurological related osteopetrosis remains unfavorable. Preventive process such as intracranial metastasis or leptomeningeal management with reinforcing oral hygiene and avoiding carcinomatosis and cavernous sinus lesion may mimic a MNN further surgical trauma might be the best therapeutic or TNO.17e19 It is important to obtain a comprehensive approach.36,37 neurological evaluation, cerebrovascular examination and The study demonstrates that NCS accompanying neuroimaging by CT scans or MRI of the skull base and brain mandibular pain or masticatory weakness is more often for a patient who represents numb chin and other mani- associated with cancer metastasis than with benign diseases. festations of multiple cranial neuropathies such as head- In the absence of a benign cause, NCS is always indicative of ache, seizure, diplopia, pain on eye movement, often cancer progression or occult malignancy despite normal re- tongue biting and difficulty in standing or walking. When sults of bone scan and mandibular radiographs.11,38e40 systemic metastasis is present, generalized symptoms Medical and dental practitioners should be aware of the including weight loss, fatigue, anemia, or other skeletal condition and note that radiologic response does not yet pain might also accompany MNN. equate with pathologic response for metastatic disease; Diagnosis approaching NCS should be guided by the therefore, in any case with NCS and a known malignancy, a clinical history and various imaging examinations. The mandibular biopsy in osteolytic defects with ill-defined combination of CT scanning of the brain, base of the skull, borders is mandatory. A physical examination including and mandible, in conjunction with cytological analysis of mouth is essential for early perception of oral changes. cerebrospinal fluid (CSF), can yield a diagnosis in 89% of 19 patients with NCS and known malignancy. However, Conflict of interest panoramic jaw radiography is quite useful because most cases of NCS are caused by mandibular metastasis. The radiographic findings may reveal exquisite changes in bony The authors have no conflicts of interest relevant to this trabecula, osteolytic defects anywhere along the mandible, article. teeth, and in the region of the IAN canal or mental foramen. Myeloma jaw may exhibit numerous punched-out Acknowledgments osteolytic lesions with multilocular, honeycomb or soap bubble appearance in posterior mandible bilaterally, The study was self-funded by our institution after proper endosteal scalloping along the mandibular border, or Institutional Review Board approval (IRB 201700235B0 to diffuse osteolysis and a pathological fracture. 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