SpringerLink
Log in

Trigeminal neuralgia

  • Primer
  • Published:

From Nature Reviews Disease Primers

View current issue Sign up to alerts

Abstract

Trigeminal neuralgia (TN) is a facial pain disorder characterized by intense and paroxysmal pain that profoundly affects quality of life and presents complex challenges in diagnosis and treatment. TN can be categorized as classical, secondary and idiopathic. Epidemiological studies show variable incidence rates and an increased prevalence in women and in the elderly, with familial cases suggesting genetic factors. The pathophysiology of TN is multifactorial and involves genetic predisposition, anatomical changes, and neurophysiological factors, leading to hyperexcitable neuronal states, central sensitization and widespread neural plasticity changes. Neurovascular compression of the trigeminal root, which undergoes major morphological changes, and focal demyelination of primary trigeminal afferents are key aetiological factors in TN. Structural and functional brain imaging studies in patients with TN demonstrated abnormalities in brain regions responsible for pain modulation and emotional processing of pain. Treatment of TN involves a multifaceted approach that considers patient-specific factors, including the type of TN, with initial pharmacotherapy followed by surgical options if necessary. First-line pharmacological treatments include carbamazepine and oxcarbazepine. Surgical interventions, including microvascular decompression and percutaneous neuroablative procedures, can be considered at an early stage if pharmacotherapy is not sufficient for pain control or has intolerable adverse effects or contraindications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: Proposed mechanisms of TN.
Fig. 2: Pathophysiology of TN.
Fig. 3: Proposed molecular mechanisms of TN.
Fig. 4: Anatomical localization of pain in TN.
Fig. 5: Neuroimaging in TN.
Fig. 6: Treatment of TN.

Similar content being viewed by others

References

  1. Cruccu, G., Di Stefano, G. & Truini, A. Trigeminal neuralgia. N. Engl. J. Med. 383, 754–762 (2020).

    Article  PubMed  Google Scholar 

  2. Headache classification committee of the International Headache Society (IHS) the International Classification of Headache Disorders, 3rd edition. Cephalalgia 38, 1–211 (2018).

  3. Cruccu, G. et al. Trigeminal neuralgia: new classification and diagnostic grading for practice and research. Neurology 87, 220–228 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  4. International Classification of Orofacial Pain, 1st edition (ICOP). Cephalalgia 40, 129–221 (2020).

  5. Bendtsen, L. et al. Advances in diagnosis, classification, pathophysiology, and management of trigeminal neuralgia. Lancet Neurol. 19, 784–796 (2020).

    Article  CAS  PubMed  Google Scholar 

  6. Brewis, M., Poskanzer, D. C., Rolland, C. & Miller, H. Neurological disease in an English city. Acta Neurol. Scand. 42, 21–89 (1966).

    Google Scholar 

  7. Katusic, S., Beard, C. M., Bergstralh, E. & Kurland, L. T. Incidence and clinical features of trigeminal neuralgia, Rochester, Minnesota, 1945-1984. Ann. Neurol. 27, 89–95 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. Hall, G. C., Carroll, D., Parry, D. & McQuay, H. J. Epidemiology and treatment of neuropathic pain: the UK primary care perspective. Pain 122, 156–162 (2006).

    Article  PubMed  Google Scholar 

  9. Koopman, J. S. et al. Incidence of facial pain in the general population. Pain 147, 122–127 (2009).

    Article  PubMed  Google Scholar 

  10. Svedung Wettervik, T., Snel, D., Kristiansson, P., Ericson, H. & Abu Hamdeh, S. Incidence of trigeminal neuralgia: a population-based study in Central Sweden. Eur. J. Pain 27, 580–587 (2023).

    Article  PubMed  Google Scholar 

  11. Katusic, S., Williams, D. B., Beard, C. M., Bergstralh, E. J. & Kurland, L. T. Epidemiology and clinical features of idiopathic trigeminal neuralgia and glossopharyngeal neuralgia: similarities and differences, Rochester, Minnesota, 1945-1984. Neuroepidemiology 10, 276–281 (1991).

    Article  CAS  PubMed  Google Scholar 

  12. Lee, C. H., Jang, H. Y., Won, H. S., Kim, J. S. & Kim, Y. D. Epidemiology of trigeminal neuralgia: an electronic population health data study in Korea. Korean J. Pain 34, 332–338 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Di Stefano, G. et al. Familial trigeminal neuralgia — a systematic clinical study with a genomic screen of the neuronal electrogenisome. Cephalalgia 40, 767–777 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Eide, P. K. Familial occurrence of classical and idiopathic trigeminal neuralgia. J. Neurol. Sci. 434, 120101 (2022).

    Article  PubMed  Google Scholar 

  15. Sjaastad, O. & Bakketeig, L. S. The rare, unilateral headaches. Vaga study of headache epidemiology. J. Headache Pain 8, 19–27 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Mueller, D. et al. Prevalence of trigeminal neuralgia and persistent idiopathic facial pain: a population-based study. Cephalalgia 31, 1542–1548 (2011).

    Article  PubMed  Google Scholar 

  17. De Toledo, I. P. et al. Prevalence of trigeminal neuralgia: a systematic review. J. Am. Dent. Assoc. 147, 570–576.e2 (2016).

    Article  PubMed  Google Scholar 

  18. Bölük, C., Türk Börü, Ü. & Taşdemir, M. The prevalence of trigeminal neuralgia in Turkey: a population-based study. Neurol. Res. 42, 968–972 (2020).

    Article  PubMed  Google Scholar 

  19. Bang, S. et al. Prevalence of common causes of neuropathic pain in Korea: population-based observational study. J. Int. Med. Res. 48, 300060519888102 (2020).

    Article  PubMed  Google Scholar 

  20. Katheriya, G., Chaurasia, A., Khan, N. & Iqbal, J. Prevalence of trigeminal neuralgia in Indian population visiting a higher dental care center in North India. Natl J. Maxillofac. Surg. 10, 195–199 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hardaway, F. A. et al. Sex-dependent posterior fossa anatomical differences in trigeminal neuralgia patients with and without neurovascular compression: a volumetric MRI age- and sex-matched case-control study. J. Neurosurg. 132, 631–638 (2019).

    Article  PubMed  Google Scholar 

  22. Mazzucchi, E., Brinzeu, A. & Sindou, M. Arachnoiditis as an outcome factor for microvascular decompression in classical trigeminal neuralgia. Acta Neurochir. 161, 1589–1598 (2019).

    Article  PubMed  Google Scholar 

  23. Ericson, H. et al. Cerebrospinal fluid biomarkers of inflammation in trigeminal neuralgia patients operated with microvascular decompression. Pain 160, 2603–2611 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Joshi, I., Mattoo, B., Mohan, V. K. & Bhatia, R. Aberrant pain modulation in trigeminal neuralgia patients.J. Basic Clin. Physiol. Pharmacol. https://doi.org/10.1515/jbcpp-2019-0274 (2020).

    Article  PubMed  Google Scholar 

  25. Tolle, T., Dukes, E. & Sadosky, A. Patient burden of trigeminal neuralgia: results from a cross-sectional survey of health state impairment and treatment patterns in six European countries. Pain Pract. 6, 153–160 (2006).

    Article  PubMed  Google Scholar 

  26. Zakrzewska, J. M., Wu, J., Mon-Williams, M., Phillips, N. & Pavitt, S. H. Evaluating the impact of trigeminal neuralgia. Pain 158, 1166–1174 (2017).

    Article  PubMed  Google Scholar 

  27. Cruccu, G. Trigeminal neuralgia. Continuum 23, 396–420 (2017).

    PubMed  Google Scholar 

  28. Sandell, T., Holmen, J. & Eide, P. K. Hypertension in patients with cranial nerve vascular compression syndromes and comparison with a population-based cohort. J. Neurosurg. 119, 1302–1308 (2013).

    Article  PubMed  Google Scholar 

  29. Xu, Z. et al. Diabetes mellitus in classical trigeminal neuralgia: a predisposing factor for its development. Clin. Neurol. Neurosurg. 151, 70–72 (2016).

    Article  PubMed  Google Scholar 

  30. Gronseth, G. et al. Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology 71, 1183–1190 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Lin, K. H., Chen, Y. T., Fuh, J. L. & Wang, S. J. Increased risk of trigeminal neuralgia in patients with migraine: a nationwide population-based study. Cephalalgia 36, 1218–1227 (2016).

    Article  CAS  PubMed  Google Scholar 

  32. Cheng, J., Long, J., Hui, X., Lei, D. & Zhang, H. Effects of microvascular decompression on depression and anxiety in trigeminal neuralgia: a prospective cohort study focused on risk factors and prognosis. Clin. Neurol. Neurosurg. 161, 59–64 (2017).

    Article  PubMed  Google Scholar 

  33. Macianskyte, D., Januzis, G., Kubilius, R., Adomaitiene, V. & Sciupokas, A. Associations between chronic pain and depressive symptoms in patients with trigeminal neuralgia. Medicina 47, 386–392 (2011).

    Article  PubMed  Google Scholar 

  34. Cheng, Y. H., Wu, C. H., Wang, W. T., Lu, Y. Y. & Wu, M. K. Trigeminal neuralgia is a dementia risk factor: a retrospective cohort study. Int. J. Environ. Res. Public Health 19, 106073 (2022).

    Google Scholar 

  35. Wu, T. H. et al. Risk of psychiatric disorders following trigeminal neuralgia: a nationwide population-based retrospective cohort study. J. Headache Pain 16, 64 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Maarbjerg, S., Gozalov, A., Olesen, J. & Bendtsen, L. Trigeminal neuralgia — a prospective systematic study of clinical characteristics in 158 patients. Headache 54, 1574–1582 (2014).

    Article  PubMed  Google Scholar 

  37. Cruccu, G. et al. Trigeminal neuralgia and pain related to multiple sclerosis. Pain 143, 186–191 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Solaro, C. et al. The prevalence of pain in multiple sclerosis: a multicenter cross-sectional study. Neurology 63, 919–921 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. O’Connor, A. B., Schwid, S. R., Herrmann, D. N., Markman, J. D. & Dworkin, R. H. Pain associated with multiple sclerosis: systematic review and proposed classification. Pain 137, 96–111 (2008).

    Article  PubMed  Google Scholar 

  40. Pan, S. L., Yen, M. F., Chiu, Y. H., Chen, L. S. & Chen, H. H. Increased risk of trigeminal neuralgia after hypertension: a population-based study. Neurology 77, 1605–1610 (2011).

    Article  PubMed  Google Scholar 

  41. Keller, J. J., Sheu, J. J. & Lin, H. C. Chronic periodontitis and the subsequent risk of trigeminal neuralgia: a 5-year follow-up study. J. Clin. Periodontol. 39, 1017–1023 (2012).

    Article  PubMed  Google Scholar 

  42. Su, Y. F., Wu, C. H., Wang, W. T. & Lieu, A. S. The risk of trigeminal neuralgia following osteoporosis. Medicina 58, 447 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Lange, V. et al. The association between bone quality and atherosclerosis: results from two large population-based studies. Int. J. Endocrinol. 2017, 3946569 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cappuccio, F. P., Meilahn, E., Zmuda, J. M. & Cauley, J. A. High blood pressure and bone-mineral loss in elderly white women: a prospective study. Study of Osteoporotic Fractures Research Group. Lancet 354, 971–975 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Miller, J. P., Acar, F., Hamilton, B. E. & Burchiel, K. J. Radiographic evaluation of trigeminal neurovascular compression in patients with and without trigeminal neuralgia. J. Neurosurg. 110, 627–632 (2009).

    Article  PubMed  Google Scholar 

  46. Maarbjerg, S., Wolfram, F., Gozalov, A., Olesen, J. & Bendtsen, L. Significance of neurovascular contact in classical trigeminal neuralgia. Brain 138, 311–319 (2015).

    Article  PubMed  Google Scholar 

  47. Bowsher, D. Dynamic mechanical allodynia in neuropathic pain. Pain 116, 164–165 (2005).

    Article  PubMed  Google Scholar 

  48. Maarbjerg, S., Gozalov, A., Olesen, J. & Bendtsen, L. Concomitant persistent pain in classical trigeminal neuralgia — evidence for different subtypes. Headache 54, 1173–1183 (2014).

    Article  PubMed  Google Scholar 

  49. Mannerak, M. A., Lashkarivand, A. & Eide, P. K. Trigeminal neuralgia and genetics: a systematic review. Mol. Pain 17, 17448069211016139 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mousavi, S. H., Lindsey, J. W., Westlund, K. N. & Alles, S. R. A. Trigeminal neuralgia as a primary demyelinating disease: potential multimodal evidence and remaining controversies. J. Pain 25, 302–311 (2024).

    Article  CAS  PubMed  Google Scholar 

  51. Devor, M., Amir, R. & Rappaport, Z. H. Pathophysiology of trigeminal neuralgia: the ignition hypothesis. Clin. J. Pain 18, 4–13 (2002).

    Article  PubMed  Google Scholar 

  52. Zhang, Y. et al. Dysregulation of pain- and emotion-related networks in trigeminal neuralgia. Front. Hum. Neurosci. 12, 107 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Liu, H. et al. Structural and functional brain changes in patients with classic trigeminal neuralgia: a combination of voxel-based morphometry and resting-state functional MRI study. Front. Neurosci. 16, 930765 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Desouza, D. D., Moayedi, M., Chen, D. Q., Davis, K. D. & Hodaie, M. Sensorimotor and pain modulation brain abnormalities in trigeminal neuralgia: a paroxysmal, sensory-triggered neuropathic pain. PLoS ONE 8, e66340 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Huff, T., Weisbrod, L. J. & Daly, D. T. Neuroanatomy, Cranial Nerve 5 (Trigeminal). StatPearls [Internet] https://www.ncbi.nlm.nih.gov/books/NBK482283/ (updated 20 April 2024).

  56. Brazis, P., Madeu, J. C. & Biller, J. In: Localization in Clinical Neurology 9 (eds Brazis, P. W., Masdeu, J. C. & Biller, J.) 353-368 (Wolters Kluwer, 2021).

  57. Bathla, G. & Hegde, A. N. The trigeminal nerve: an illustrated review of its imaging anatomy and pathology. Clin. Radiol. 68, 203–213 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Messlinger, K., Dostrovsky, J. O. & Strassman, A. M. in The Headaches (eds Olesen, J. et al.) 95–119 (Lippincott, Williams & Wilkins, 2005).

  59. Gobel, S., Hockfield, S. & Ruda, M. in Oral-Facial Sensory and Motor Functions (eds Kawamura, Y. & Dubner, R.) 211–223 (Quintessence, 1988).

  60. Panchagnula, S., Sularz, A. K. & Kahle, K. T. Familial trigeminal neuralgia cases implicate genetic factors in disease pathogenesis. JAMA Neurol. 76, 9–10 (2019).

    Article  PubMed  Google Scholar 

  61. Cervera-Martinez, C., Martinez-Manrique, J. J. & Revuelta-Gutierrez, R. Surgical management of familial trigeminal neuralgia with different inheritance patterns: a case report. Front. Neurol. 9, 316 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Mustafá, E. R. et al. Electrophysiological and computational analysis of Cav3.2 channel variants associated with familial trigeminal neuralgia. Mol. Brain 15, 91 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Alsaloum, M. et al. A novel gain-of-function sodium channel β2 subunit mutation in idiopathic small fiber neuropathy. J. Neurophysiol. 126, 827–839 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mereaux, J. L., Lefaucheur, R., Hebant, B., Guegan-Massardier, E. & Grangeon, L. Trigeminal neuralgia and Charcot-Marie-Tooth disease: an intriguing association. lessons from a large family case report and review of literature. Headache 59, 1074–1079 (2019).

    Article  PubMed  Google Scholar 

  65. Pineda-Farias, J. B., Loeza-Alcocer, E., Nagarajan, V., Gold, M. S. & Sekula, R. F. Jr. Mechanisms underlying the selective therapeutic efficacy of carbamazepine for attenuation of trigeminal nerve injury pain. J. Neurosci. 41, 8991–9007 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Luiz, A. P., Kopach, O., Santana-Varela, S. & Wood, J. N. The role of Nav1.9 channel in the development of neuropathic orofacial pain associated with trigeminal neuralgia. Mol. Pain 11, 72 (2015).

    PubMed  PubMed Central  Google Scholar 

  67. Xu, W., Zhang, J., Wang, Y., Wang, L. & Wang, X. Changes in the expression of voltage-gated sodium channels Nav1.3, Nav1.7, Nav1.8, and Nav1.9 in rat trigeminal ganglia following chronic constriction injury. Neuroreport 27, 929–934 (2016).

    Article  CAS  PubMed  Google Scholar 

  68. Siqueira, S. R., Alves, B., Malpartida, H. M., Teixeira, M. J. & Siqueira, J. T. Abnormal expression of voltage-gated sodium channels Nav1.7, Nav1.3 and Nav1.8 in trigeminal neuralgia. Neuroscience 164, 573–577 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Tanaka, B. S. et al. A gain-of-function mutation in Nav1.6 in a case of trigeminal neuralgia. Mol. Med. 22, 338–348 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gualdani, R. et al. Trigeminal neuralgia TRPM8 mutation: enhanced activation, basal [Ca2+]i and menthol response. Neurol. Genet. 7, e550 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Gualdani, R. et al. A TRPM7 mutation linked to familial trigeminal neuralgia: Omega current and hyperexcitability of trigeminal ganglion neurons. Proc. Natl Acad. Sci. USA 119, e2119630119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Romero, J. et al. Polymorphisms of Nav1.6 sodium channel, brain-derived neurotrophic factor, catechol-O-methyltransferase and guanosine triphosphate cyclohydrolase 1 genes in trigeminal neuralgia. Clin. Neurol. Neurosurg. 208, 106880 (2021).

    Article  PubMed  Google Scholar 

  73. Sekula, R. F., Deeley, K., Denwood, H. & Vieira, A. R. Gain-of-function mutation Met136Val in SCN8A may not be a common cause of trigeminal neuralgia. Mol. Genet. Genom. Med. 9, e1587 (2021).

    Article  CAS  Google Scholar 

  74. Moon, H. C. et al. 7 Tesla magnetic resonance imaging of caudal anterior cingulate and posterior cingulate cortex atrophy in patients with trigeminal neuralgia. Magn. Reson. Imaging 51, 144–150 (2018).

    Article  PubMed  Google Scholar 

  75. Obermann, M. et al. Gray matter volume reduction reflects chronic pain in trigeminal neuralgia. Neuroimage 74, 352–358 (2013).

    Article  PubMed  Google Scholar 

  76. DeSouza, D. D., Hodaie, M. & Davis, K. D. Structural magnetic resonance imaging can identify trigeminal system abnormalities in classical trigeminal neuralgia. Front. Neuroanat. 10, 95 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  77. DeSouza, D. D., Davis, K. D. & Hodaie, M. Reversal of insular and microstructural nerve abnormalities following effective surgical treatment for trigeminal neuralgia. Pain 156, 1112–1123 (2015).

    Article  PubMed  Google Scholar 

  78. Noorani, A. et al. Pain relief reverses hippocampal abnormalities in trigeminal neuralgia. J. Pain 23, 141–155 (2022).

    Article  PubMed  Google Scholar 

  79. Richards, P., Shawdon, H. & Illingworth, R. Operative findings on microsurgical exploration of the cerebello-pontine angle in trigeminal neuralgia. J. Neurol. Neurosurg. Psychiatry 46, 1098–1101 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Rappaport, Z. H., Govrin-Lippmann, R. & Devor, M. An electron-microscopic analysis of biopsy samples of the trigeminal root taken during microvascular decompressive surgery. Stereotact. Funct. Neurosurg. 68, 182–186 (1997).

    Article  CAS  PubMed  Google Scholar 

  81. Peker, S., Kurtkaya, O., Uzun, I. & Pamir, M. N. Microanatomy of the central myelin-peripheral myelin transition zone of the trigeminal nerve. Neurosurgery 59, 354–359 (2006).

    Article  PubMed  Google Scholar 

  82. Burchiel, K. J. Abnormal impulse generation in focally demyelinated trigeminal roots. J. Neurosurg. 53, 674–683 (1980).

    Article  CAS  PubMed  Google Scholar 

  83. Leandri, M., Eldridge, P. & Miles, J. Recovery of nerve conduction following microvascular decompression for trigeminal neuralgia. Neurology 51, 1641–1646 (1998).

    Article  CAS  PubMed  Google Scholar 

  84. Bethamcharla, R., Reddy, H., Teich, A. F. & Sekula, R. F. Jr. Histopathology of the trigeminal ganglion and nerve: a historical review. J. Neurosci. Res. 101, 1203–1204 (2023).

    Article  CAS  PubMed  Google Scholar 

  85. Obermann, M. et al. Impaired trigeminal nociceptive processing in patients with trigeminal neuralgia. Neurology 69, 835–841 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Di Stefano, G. et al. Concomitant continuous pain in patients with trigeminal neuralgia is associated with trigeminal nerve root atrophy. Cephalalgia 40, 1502–1510 (2020).

    Article  PubMed  Google Scholar 

  87. Jani, R. H. et al. Trigeminal nerve compression without trigeminal neuralgia: intraoperative vs imaging evidence. Neurosurgery 84, 60–65 (2019).

    Article  PubMed  Google Scholar 

  88. Bjerring, B. et al. Comparison of the blink reflex in classical and idiopathic trigeminal neuralgia. Cephalalgia 43, 3331024231191136 (2023).

    Article  PubMed  Google Scholar 

  89. Ha, S. M. et al. Patients with idiopathic trigeminal neuralgia have a sharper-than-normal trigeminal-pontine angle and trigeminal nerve atrophy. Acta Neurochir. 154, 1627–1633 (2012).

    Article  PubMed  Google Scholar 

  90. Moon, H. C. et al. 7.0 Tesla MRI tractography in patients with trigeminal neuralgia. Magn. Reson. Imaging 54, 265–270 (2018).

    Article  PubMed  Google Scholar 

  91. Lee, Y. J., Moon, H. C., Tak, S., Cheong, C. & Park, Y. S. Atrophic changes and diffusion abnormalities of affected trigeminal nerves in trigeminal neuralgia using 7-T MRI. Stereotact. Funct. Neurosurg. 97, 169–175 (2019).

    Article  PubMed  Google Scholar 

  92. Lutz, J. et al. Microstructural alterations in trigeminal neuralgia determined by diffusion tensor imaging are independent of symptom duration, severity, and type of neurovascular conflict. J. Neurosurg. 124, 823–830 (2016).

    Article  PubMed  Google Scholar 

  93. Andersen, A. S. S. et al. Microvascular decompression in trigeminal neuralgia — a prospective study of 115 patients. J. Headache Pain 23, 145 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Branstetter, B. F., Reddy, N., Patel, K. & Sekula, R. Sagittal angle of the trigeminal nerve at the porus trigeminus: a novel measurement to distinguish different causes of classic trigeminal neuralgia. AJNR Am. J. Neuroradiol. 43, 1460–1463 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Brinzeu, A., Dumot, C. & Sindou, M. Role of the petrous ridge and angulation of the trigeminal nerve in the pathogenesis of trigeminal neuralgia, with implications for microvascular decompression. Acta Neurochir. 160, 971–976 (2018).

    Article  PubMed  Google Scholar 

  96. Pang, H., Sun, H. & Fan, G. Correlations between the trigeminal nerve microstructural changes and the trigeminal-pontine angle features. Acta Neurochir. 161, 2505–2511 (2019).

    Article  PubMed  Google Scholar 

  97. Grunwald, I., Papanagiotou, P., Nabhan, A., Politi, M. & Reith, W. Anatomy of the cerebellopontine angle [German]. Radiologe 46, 192–196 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Chaynes, P. et al. Endoscopic anatomy of the cerebellopontine angle: a study in cadaver brains. Neurosurg. Focus 5, e8 (1998).

    Article  CAS  PubMed  Google Scholar 

  99. Lak, A. M. & Khan, Y. S. Cerebellopontine Angle Cancer. StatPearls [Internet] https://www.ncbi.nlm.nih.gov/books/NBK559116/ (updated 26 June 2023).

  100. Samii, M. & Gerganov, V. M. Tumors of the cerebellopontine angle. Handb. Clin. Neurol. 105, 633–639 (2012).

    Article  PubMed  Google Scholar 

  101. Noory, N. et al. Neurovascular contact plays no role in trigeminal neuralgia secondary to multiple sclerosis. Cephalalgia 41, 593–603 (2021).

    Article  PubMed  Google Scholar 

  102. Fatehi, F., Nafissi, S., Basiri, K., Amiri, M. & Soltanzadeh, A. Chronic inflammatory demyelinating polyneuropathy associated with diabetes mellitus. J. Res. Med. Sci. 18, 438–441 (2013).

    PubMed  PubMed Central  Google Scholar 

  103. Staff, N. P. & Windebank, A. J. Peripheral neuropathy due to vitamin deficiency, toxins, and medications. Continuum 20, 1293–1306 (2014).

    PubMed  PubMed Central  Google Scholar 

  104. Aggarwal, A. & Wood, I. Low vitamin B12 syndrome in trigeminal neuralgia.J. Pain Relief 1, 109 (2012).

    Article  Google Scholar 

  105. Dhole, P. et al. Evaluation of serum vitamin B12 levels and its correlation with clinical presentation in patients with trigeminal neuralgia. J. Oral Biol. Craniofac. Res. 12, 843–846 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Cruccu, G. et al. Mandibular nerve involvement in diabetic polyneuropathy and chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 21, 1673–1679 (1998).

    Article  CAS  PubMed  Google Scholar 

  107. Urban, P. P. et al. Incidence of subclinical trigeminal and facial nerve involvement in diabetes mellitus. Electromyogr. Clin. Neurophysiol. 39, 267–272 (1999).

    CAS  PubMed  Google Scholar 

  108. Woolf, C. J. Central sensitization: implications for the diagnosis and treatment of pain. Pain 152, S2–S15 (2011).

    Article  PubMed  Google Scholar 

  109. Hagenacker, T. et al. Patient-conducted anodal transcranial direct current stimulation of the motor cortex alleviates pain in trigeminal neuralgia. J. Headache Pain 15, 78 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  110. De Stefano, G. et al. Unravelling the role of unmyelinated nerve fibres in trigeminal neuralgia with concomitant continuous pain. Clin. Neurophysiol. 142, 52–58 (2022).

    Article  PubMed  Google Scholar 

  111. Truini, A., Garcia-Larrea, L. & Cruccu, G. Reappraising neuropathic pain in humans — how symptoms help disclose mechanisms. Nat. Rev. Neurol. 9, 572–582 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. Moisset, X. et al. Functional brain imaging of trigeminal neuralgia. Eur. J. Pain 15, 124–131 (2011).

    Article  PubMed  Google Scholar 

  113. Yuan, J. et al. Altered spontaneous brain activity in patients with idiopathic trigeminal neuralgia: a resting-state functional MRI study. Clin. J. Pain 34, 600–609 (2018).

    Article  PubMed  Google Scholar 

  114. Xu, H. et al. Altered structural and functional connectivity of salience network in patients with classic trigeminal neuralgia. J. Pain 23, 1389–1399 (2022).

    Article  PubMed  Google Scholar 

  115. Borsook, D., Edwards, R., Elman, I., Becerra, L. & Levine, J. Pain and analgesia: the value of salience circuits. Prog. Neurobiol. 104, 93–105 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Raichle, M. E. The brain’s default mode network. Annu. Rev. Neurosci. 38, 433–447 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Zhang, P. et al. Altered brain functional network dynamics in classic trigeminal neuralgia: a resting-state functional magnetic resonance imaging study. J. Headache Pain 22, 147 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Sabalys, G., Juodzbalys, G. & Wang, H. L. Aetiology and pathogenesis of trigeminal neuralgia: a comprehensive review. J. Oral Maxillofac. Res. 3, e2 (2013).

    PubMed  PubMed Central  Google Scholar 

  119. Maikap, D. & Padhan, P. Trigeminal neuralgia as an initial presentation of systemic autoimmune diseases: a case series. Mediterr. J. Rheumatol. 33, 333–338 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Kumar, V., Kaur, J., Pothuri, P. & Bandagi, S. Atypical trigeminal neuralgia: a rare neurological manifestation of systemic lupus erythematosus. Am. J. Case Rep. 18, 42–45 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Nascimento, I. S. et al. Clues for previously undiagnosed connective tissue disease in patients with trigeminal neuralgia. J. Clin. Rheumatol. 16, 205–208 (2010).

    Article  PubMed  Google Scholar 

  122. Yuan, J. et al. Case report of primary Sjögren syndrome with simple trigeminal lesion as initial symptom. J. Neuroimmunol. 324, 126–128 (2018).

    Article  CAS  PubMed  Google Scholar 

  123. Kalluri, A. L. et al. Preoperative characteristics and postoperative pain outcomes in trigeminal neuralgia with concomitant autoimmune disease. Neurosurgery 93, 1075–1081 (2023).

    Article  PubMed  Google Scholar 

  124. Svedung Wettervik, T. et al. Cerebrospinal fluid in classical trigeminal neuralgia: an exploratory study on candidate biomarkers. Biomedicines 10, 998 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ostertag, C., Friedman, T. N., Keough, M. B., Kerr, B. J. & Sankar, T. Heightened presence of inflammatory mediators in the cerebrospinal fluid of patients with trigeminal neuralgia. Pain Rep. 8, e1117 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Shi, S. et al. PD-L1 and PD-1 expressed in trigeminal ganglia may inhibit pain in an acute migraine model. Cephalalgia 40, 288–298 (2020).

    Article  PubMed  Google Scholar 

  127. Liu, M. X., Zhong, J., **a, L., Dou, N. N. & Li, S. T. A correlative analysis between inflammatory cytokines and trigeminal neuralgia or hemifacial spasm. Neurol. Res. 41, 335–340 (2019).

    Article  PubMed  Google Scholar 

  128. Zhang, Y., Lian, Y., Zhang, H., **e, N. & Chen, Y. CGRP plasma levels decrease in classical trigeminal neuralgia patients treated with botulinum toxin type A: a pilot study. Pain Med. 21, 1611–1615 (2020).

    Article  PubMed  Google Scholar 

  129. Burstein, R., Blumenfeld, A. M., Silberstein, S. D., Manack Adams, A. & Brin, M. F. Mechanism of action of onabotulinumtoxinA in chronic migraine: a narrative review. Headache 60, 1259–1272 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Qin, Z. L. et al. Clinical study of cerebrospinal fluid neuropeptides in patients with primary trigeminal neuralgia. Clin. Neurol. Neurosurg. 143, 111–115 (2016).

    Article  PubMed  Google Scholar 

  131. Schou, W. S., Ashina, S., Amin, F. M., Goadsby, P. J. & Ashina, M. Calcitonin gene-related peptide and pain: a systematic review. J. Headache Pain 18, 34 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Retsky, R., Ashina, S., Oved, D. & Sharon, R. Calcitonin gene-related peptide and trigeminal neuralgia. SN Compr. Clin. Med. 5, 75 (2023).

    Article  Google Scholar 

  133. Gambeta, E., Gandini, M. A., Souza, I. A. & Zamponi, G. W. CaV3.2 calcium channels contribute to trigeminal neuralgia. Pain 163, 2315–2325 (2022).

    Article  CAS  PubMed  Google Scholar 

  134. Mohammed, H., Rimondini, L. & Rocchetti, V. Molecular basis of trigeminal nerve disorders and healing. Eur. Rev. Med. Pharmacol. Sci. 22, 5755–5764 (2018).

    CAS  PubMed  Google Scholar 

  135. Liu, M., Zhong, J., **a, L., Dou, N. & Li, S. The expression of voltage-gated sodium channels in trigeminal nerve following chronic constriction injury in rats. Int. J. Neurosci. 129, 955–962 (2019).

    Article  CAS  PubMed  Google Scholar 

  136. Liu, M. X., Zhong, J., **a, L., Dou, N. N. & Li, S. T. IL-6 contributes to Nav1.3 up-regulation in trigeminal nerve following chronic constriction injury. Neurol. Res. 42, 504–514 (2020).

    Article  CAS  PubMed  Google Scholar 

  137. Alaklabi, A. M., Gambeta, E. & Zamponi, G. W. Electrophysiological characterization of a CaV3.1 calcium channel mutation linked to trigeminal neuralgia. Pflug. Arch. 475, 711–718 (2023).

    Article  CAS  Google Scholar 

  138. Dong, W. et al. Exome sequencing implicates impaired GABA signaling and neuronal ion transport in trigeminal neuralgia. iScience 23, 101552 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Chen, Q. et al. The molecular basis and pathophysiology of trigeminal neuralgia. Int. J. Mol. Sci. 23, 3604 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Latremoliere, A. & Woolf, C. J. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J. Pain 10, 895–926 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Song, R. S. et al. ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion. Proc. Natl Acad. Sci. USA 110, 15437–15442 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Schrader, L. A. et al. ERK/MAPK regulates the Kv4.2 potassium channel by direct phosphorylation of the pore-forming subunit. Am. J. Physiol. Cell Physiol. 290, C852–C861 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Di Stefano, G., Maarbjerg, S., Nurmikko, T., Truini, A. & Cruccu, G. Triggering trigeminal neuralgia. Cephalalgia 38, 1049–1056 (2018).

    Article  PubMed  Google Scholar 

  144. Lambru, G., Zakrzewska, J. & Matharu, M. Trigeminal neuralgia: a practical guide. Pract. Neurol. 21, 392–402 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  145. De Stefano, G. et al. Sex differences in trigeminal neuralgia: a focus on radiological and clinical characteristics. Neurol. Sci. 44, 4465–4472 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Maarbjerg, S., Wolfram, F., Gozalov, A., Olesen, J. & Bendtsen, L. Association between neurovascular contact and clinical characteristics in classical trigeminal neuralgia: a prospective clinical study using 3.0 Tesla MRI. Cephalalgia 35, 1077–1084 (2015).

    Article  PubMed  Google Scholar 

  147. Maarbjerg, S. & Benoliel, R. The changing face of trigeminal neuralgia-a narrative review. Headache 61, 817–837 (2021).

    Article  PubMed  Google Scholar 

  148. Bennetto, L., Patel, N. K. & Fuller, G. Trigeminal neuralgia and its management. BMJ 334, 201–205 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Bendtsen, L. et al. European Academy of Neurology guideline on trigeminal neuralgia. Eur. J. Neurol. 26, 831–849 (2019).

    Article  CAS  PubMed  Google Scholar 

  150. Venda Nova, C., Zakrzewska, J. M., S, R. B. & Ni Riordain, R. Patient reported outcome measures in trigeminal neuralgia — a systematic review of psychometric performance. Eur. J. Pain 25, 1449–1461 (2021).

    Article  PubMed  Google Scholar 

  151. Benoliel, R. et al. Trigeminal neuralgia (part II): factors affecting early pharmacotherapeutic outcome. Cephalalgia 36, 747–759 (2016).

    Article  CAS  PubMed  Google Scholar 

  152. Heinskou, T. B. et al. Favourable prognosis of trigeminal neuralgia when enrolled in a multidisciplinary management program — a two-year prospective real-life study. J. Headache Pain 20, 23 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Di Stefano, G., Maarbjerg, S. & Truini, A. Trigeminal neuralgia secondary to multiple sclerosis: from the clinical picture to the treatment options. J. Headache Pain 20, 20 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Tohyama, S. et al. Should trigeminal neuralgia be considered a clinically isolated syndrome? Mult. Scler. 29, 637–641 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Truini, A. et al. Joint European Academy of Neurology–European Pain Federation–Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment. Eur. J. Neurol. 30, 2177–2196 (2023).

    Article  PubMed  Google Scholar 

  156. Lambru, G. et al. Trigeminal neurovascular contact in SUNCT and SUNA: a cross-sectional magnetic resonance study. Brain 143, 3619–3628 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Onan, D. et al. Debate: differences and similarities between tension-type headache and migraine. J. Headache Pain 24, 92 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Burstein, R., Cutrer, M. F. & Yarnitsky, D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 123, 1703–1709 (2000).

    Article  PubMed  Google Scholar 

  159. von Eckardstein, K. L., Keil, M. & Rohde, V. Unnecessary dental procedures as a consequence of trigeminal neuralgia. Neurosurg. Rev. 38, 355–360 (2015).

    Article  Google Scholar 

  160. Romero-Reyes, M. et al. Pharmacological management of orofacial pain. Drugs 83, 1269–1292 (2023).

    Article  PubMed  Google Scholar 

  161. Slettebo, H. Is this really trigeminal neuralgia? Diagnostic re-evaluation of patients referred for neurosurgery. Scand. J. Pain 21, 788–793 (2021).

    Article  PubMed  Google Scholar 

  162. Teshima, T., Zakrzewska, J. M. & Potter, R. A systematic review of screening diagnostic tools for trigeminal neuralgia. Br. J. Pain 17, 255–266 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Corcoran, T. B., Haigh, F., Seabrook, A. & Schug, S. A. The quality of internet-sourced information for patients with chronic pain is poor. Clin. J. Pain 25, 617–623 (2009).

    Article  PubMed  Google Scholar 

  164. Joseph, P., Silva, N. A., Nanda, A. & Gupta, G. Evaluating the readability of online patient education materials for trigeminal neuralgia. World Neurosurg. 144, e934–e938 (2020).

    Article  PubMed  Google Scholar 

  165. Wassef, D. W., Barinsky, G. L., Peddireddy, S. & Paskhover, B. Evaluating youtube as a resource for trigeminal neuralgia patient education. J. Oral Maxillofac. Surg. 79, 1457.e1–1457.e4 (2021).

    Article  PubMed  Google Scholar 

  166. Robertson, C. Cranial neuralgias.Continuum 27, 665–685 (2021).

    PubMed  Google Scholar 

  167. Granger, P. et al. Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin. Mol. Pharmacol. 47, 1189–1196 (1995).

    CAS  PubMed  Google Scholar 

  168. Al-Quliti, K. W. Update on neuropathic pain treatment for trigeminal neuralgia. The pharmacological and surgical options. Neurosciences 20, 107–114 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Liu, L. et al. The mechanism of carbamazepine aggravation of absence seizures. J. Pharmacol. Exp. Ther. 319, 790–798 (2006).

    Article  CAS  PubMed  Google Scholar 

  170. Shi, Y. W. et al. HLA-A*24:02 as a common risk factor for antiepileptic drug-induced cutaneous adverse reactions. Neurology 88, 2183–2191 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Zakrzewska, J. M. Medical management of trigeminal neuropathic pains. Expert Opin. Pharmacother. 11, 1239–1254 (2010).

    Article  CAS  PubMed  Google Scholar 

  172. Taylor, J. C., Brauer, S. & Espir, M. L. Long-term treatment of trigeminal neuralgia with carbamazepine. Postgrad. Med. J. 57, 16–18 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Di Stefano, G., La Cesa, S., Truini, A. & Cruccu, G. Natural history and outcome of 200 outpatients with classical trigeminal neuralgia treated with carbamazepine or oxcarbazepine in a tertiary centre for neuropathic pain. J. Headache Pain 15, 34 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Santos-Lasaosa, S. et al. Evidence of and experience with the use of onabotulinumtoxinA in trigeminal neuralgia and primary headaches other than chronic migraine. Neurologia 35, 568–578 (2020).

    Article  CAS  PubMed  Google Scholar 

  175. Parascandolo, E., Levinson, K., Rizzoli, P. & Sharon, R. Efficacy of erenumab in the treatment of trigeminal neuralgia: a retrospective case series. Neurol. Clin. Pract. 11, 227–231 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Schott Andersen, A. S. et al. Safety and efficacy of erenumab in patients with trigeminal neuralgia in Denmark: a double-blind, randomised, placebo-controlled, proof-of-concept study. Lancet Neurol. 21, 994–1003 (2022).

    Article  CAS  PubMed  Google Scholar 

  177. Yang, A. I. et al. Patterns of opioid use in patients with trigeminal neuralgia undergoing neurosurgery. J. Neurosurg. 131, 1805–1811 (2019).

    Article  CAS  PubMed  Google Scholar 

  178. Green, M. W. & Selman, J. E. Review article: the medical management of trigeminal neuralgia. Headache 31, 588–592 (1991).

    Article  CAS  PubMed  Google Scholar 

  179. Adamo, D., Coppola, N., Pecoraro, G., Nicolo, M. & Mignogna, M. D. Lacosamide in trigeminal neuralgia: report of a case refractory to first- and second-generation anticonvulsants. Cranio 41, 126–130 (2023).

    Article  PubMed  Google Scholar 

  180. Munoz-Vendrell, A. et al. Oral lacosamide for the treatment of refractory trigeminal neuralgia: a retrospective analysis of 86 cases. Headache 63, 559–564 (2023).

    Article  PubMed  Google Scholar 

  181. Munoz-Vendrell, A., Teixidor, S., Sala-Padro, J., Campoy, S. & Huerta-Villanueva, M. Intravenous lacosamide and phenytoin for the treatment of acute exacerbations of trigeminal neuralgia: a retrospective analysis of 144 cases. Cephalalgia 42, 1031–1038 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Peiris, J. B., Perera, G. L., Devendra, S. V. & Lionel, N. D. Sodium valproate in trigeminal neuralgia. Med. J. Aust. 2, 278 (1980).

    Article  CAS  PubMed  Google Scholar 

  183. Gilron, I., Booher, S. L., Rowan, J. S. & Max, M. B. Topiramate in trigeminal neuralgia: a randomized, placebo-controlled multiple crossover pilot study. Clin. Neuropharmacol. 24, 109–112 (2001).

    Article  CAS  PubMed  Google Scholar 

  184. Domingues, R. B., Kuster, G. W. & Aquino, C. C. Treatment of trigeminal neuralgia with low doses of topiramate. Arq. Neuropsiquiatr. 65, 792–794 (2007).

    Article  PubMed  Google Scholar 

  185. Lechin, F. et al. Pimozide therapy for trigeminal neuralgia. Arch. Neurol. 46, 960–963 (1989).

    Article  CAS  PubMed  Google Scholar 

  186. Sindou, M., Leston, J., Howeidy, T., Decullier, E. & Chapuis, F. Micro-vascular decompression for primary Trigeminal Neuralgia (typical or atypical). Long-term effectiveness on pain; prospective study with survival analysis in a consecutive series of 362 patients. Acta Neurochir. 148, 1235–1245 (2006).

    Article  CAS  PubMed  Google Scholar 

  187. Menna, G. et al. Surgical and clinical outcomes of microvascular decompression: a comparative study between young and elderly patients. Brain Sci. 12, 1216 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Sun, J., Wang, M., Zhang, L. & Yu, Y. A meta-analysis of the effectiveness and safety of microvascular decompression in elderly patients with trigeminal neuralgia. J. Clin. Neurosci. 99, 22–34 (2022).

    Article  CAS  PubMed  Google Scholar 

  189. Hardaway, F. A., Gustafsson, H. C., Holste, K., Burchiel, K. J. & Raslan, A. M. A novel scoring system as a preoperative predictor for pain-free survival after microsurgery for trigeminal neuralgia. J. Neurosurg. https://doi.org/10.3171/2018.9.JNS181208 (2019).

    Article  PubMed  Google Scholar 

  190. Rapisarda, A. et al. Outcome comparison of drug-resistant trigeminal neuralgia surgical treatments-an umbrella review of meta-analyses and systematic reviews. Brain Sci. 13, 530 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Liu, J. et al. Long-term retrospective analysis of microvascular decompression in patients with recurrent trigeminal neuralgia. Front. Neurol. 11, 584224 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Capelle, H.-H., Brandis, A., Tschan, C. A. & Krauss, J. K. Treatment of recurrent trigeminal neuralgia due to Teflon granuloma. J. Headache Pain 11, 339–344 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Sun, T. et al. Teflon granuloma: a common cause of recurrent trigeminal neuralgia. World Neurosurg. 158, e612–e617 (2022).

    Article  PubMed  Google Scholar 

  194. Wu, Z., Zhao, Y., Liu, J., Fan, Y. & Yang, Y. Comparison of the safety and efficacy of radiofrequency thermocoagulation with percutaneous balloon compression for treating trigeminal neuralgia: a systematic review and meta-analysis. Front. Neurol. 14, 1178335 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Bethamcharla, R. et al. Percutaneous glycerol rhizolysis of the trigeminal ganglion for the treatment of idiopathic and classic trigeminal neuralgia: outcomes and complications. Eur. J. Neurol. 30, 3307–3313 (2023).

    Article  PubMed  Google Scholar 

  196. Howard, S. D. & Soti, V. How far has radiofrequency thermocoagulation come along as a treatment procedure in treating trigeminal neuralgia patients? Cureus 15, e40311 (2023).

    PubMed  PubMed Central  Google Scholar 

  197. Zheng, S. et al. Long-term recurrence-free survival and complications of percutaneous balloon compression and radiofrequency thermocoagulation of Gasserian ganglion for trigeminal neuralgia: a retrospective study of 1313 cases. Pain Pract. 22, 532–540 (2022).

    Article  PubMed  Google Scholar 

  198. Kourilsky, A. et al. Multivariate models to predict pain recurrence and sensitive complications after percutaneous balloon compression in trigeminal neuralgia. J. Neurosurg. https://doi.org/10.3171/2022.2.JNS212644 (2022).

    Article  PubMed  Google Scholar 

  199. Lovo, E. E. et al. Gamma ray radiosurgery for trigeminal neuralgia: targeting proximal or distal to the dorsal root entry zone. Cureus 13, e15194 (2021).

    PubMed  PubMed Central  Google Scholar 

  200. Park, S. H. & Chang, J. W. Gamma knife radiosurgery on the trigeminal root entry zone for idiopathic trigeminal neuralgia: results and a review of the literature. Yonsei Med. J. 61, 111–119 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Somaza, S., Montilla, E. M. & Mora, M. C. Gamma knife radiosurgery on the trigeminal ganglion for idiopathic trigeminal neuralgia: results and review of the literature. Surg. Neurol. Int. 10, 89 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Régis, J. et al. Long-term safety and efficacy of Gamma Knife surgery in classical trigeminal neuralgia: a 497-patient historical cohort study. J. Neurosurg. 124, 1079–1087 (2016).

    Article  PubMed  Google Scholar 

  203. Tuleasca, C. et al. Stereotactic radiosurgery for trigeminal neuralgia: a systematic review. J. Neurosurg. 130, 733–757 (2018).

    Article  PubMed  Google Scholar 

  204. Warnick, R. E. et al. The relevance of biologically effective dose for pain relief and sensory dysfunction after Gamma Knife radiosurgery for trigeminal neuralgia: an 871-patient multicenter study.J. Neurosurg. https://doi.org/10.3171/2023.12.JNS231569 (2024).

    Article  PubMed  Google Scholar 

  205. Pollock, B. E., Phuong, L. K., Foote, R. L., Stafford, S. L. & Gorman, D. A. High-dose trigeminal neuralgia radiosurgery associated with increased risk of trigeminal nerve dysfunction. Neurosurgery 49, 58–62 (2001).

    CAS  PubMed  Google Scholar 

  206. Moore, D., Chong, M. S., Shetty, A. & Zakrzewska, J. M. A systematic review of rescue analgesic strategies in acute exacerbations of primary trigeminal neuralgia. Br. J. Anaesth. 123, e385–e396 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Andersen, A. S. S. et al. Intravenous fosphenytoin as treatment for acute exacerbation of trigeminal neuralgia: a prospective systematic study of 15 patients. Cephalalgia 42, 1138–1147 (2022).

    Article  PubMed  Google Scholar 

  208. Swain, B. P., Vidhya, S., Jadon, A., Chandra, K. N. & Kumar, S. Trigeminal neuralgia in pregnancy: a management challenge. Pain Pract. 18, 368–373 (2018).

    Article  PubMed  Google Scholar 

  209. Motwani, M., Fadnavis, A. & Dhole, A. Efficacy of transcutaneous electrical nerve stimulation (TENS) in the management of trigeminal neuralgia: a systematic review and meta-analysis. J. Clin. Exp. Dent. 15, e505–e510 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Ang, L. et al. Acupuncture for the treatment of trigeminal neuralgia: a systematic review and meta-analysis. Complement. Ther. Clin. Pract. 52, 101763 (2023).

    Article  PubMed  Google Scholar 

  211. Worm, J. et al. Efficacy of surgical treatment in patients with trigeminal neuralgia secondary to multiple sclerosis: a prospective study of 18 cases with evaluation of outcome and complications by independent evaluators. Cephalalgia 43, 3331024231167130 (2023).

    Article  PubMed  Google Scholar 

  212. Hung, P. S. et al. Regional brain morphology predicts pain relief in trigeminal neuralgia. NeuroImage Clin. 31, 102706 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Yan, J. et al. Alterations of dynamic regional homogeneity in trigeminal neuralgia: a resting-state fMRI study. Front. Neurol. 10, 1083 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Ziegeler, C., Brauns, G. & May, A. Characteristics and natural disease history of persistent idiopathic facial pain, trigeminal neuralgia, and neuropathic facial pain. Headache 61, 1441–1451 (2021).

    Article  PubMed  Google Scholar 

  215. Debta, P. et al. Natural history of trigeminal neuralgia — a hospital-based retrospective study. Oral Dis. 26, 647–655 (2020).

    Article  PubMed  Google Scholar 

  216. Melek, L. N., Smith, J. G., Karamat, A. & Renton, T. Comparison of the neuropathic pain symptoms and psychosocial impacts of trigeminal neuralgia and painful posttraumatic trigeminal neuropathy. J. Oral Facial Pain Headache 33, 77–88 (2019).

    Article  PubMed  Google Scholar 

  217. Jacques, N., Karoutsos, S., Marais, L. & Nathan-Denizot, N. Quality of life after trigeminal nerve block in refractory trigeminal neuralgia: a retrospective cohort study and literature review. J. Int. Med. Res. 50, 3000605221132027 (2022).

    Article  PubMed  Google Scholar 

  218. Hilgenberg-Sydney, P. B., Calles, B. M. & Conti, P. C. R. Quality of life in chronic trigeminal neuralgia patients.Rev. Dor. 16, 195–197 (2015).

    Article  Google Scholar 

  219. Kotecha, R. et al. Stereotactic radiosurgery for trigeminal neuralgia improves patient-reported quality of life and reduces depression. Int. J. Radiat. Oncol. Biol. Phys. 98, 1078–1086 (2017).

    Article  PubMed  Google Scholar 

  220. Shibahashi, K., Morita, A. & Kimura, T. Surgical results of microvascular decompression procedures and patient’s postoperative quality of life: review of 139 cases. Neurol. Med. Chir. 53, 360–364 (2013).

    Article  Google Scholar 

  221. Young, B., Shivazad, A., Kryscio, R. J., St Clair, W. & Bush, H. M. Long-term outcome of high-dose gamma knife surgery in treatment of trigeminal neuralgia. J. Neurosurg. 119, 1166–1175 (2013).

    Article  PubMed  Google Scholar 

  222. Tan, C. Y., Shahrizaila, N. & Goh, K. J. Clinical characteristics, pain, and quality of life experiences of trigeminal neuralgia in a multi-ethnic Asian cohort. J. Oral Facial Pain Headache 31, e15–e20 (2017).

    Article  PubMed  Google Scholar 

  223. Yoshizaki, W. et al. Effects of microvascular decompression on quality-of-life in trigeminal neuralgia patients aged 70 years and older. Surg. Neurol. Int. 14, 41 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Gao, J., Zhao, C., Jiang, W., Zheng, B. & He, Y. Effect of acupuncture on cognitive function and quality of life in patients with idiopathic trigeminal neuralgia. J. Nerv. Ment. Dis. 207, 171–174 (2019).

    Article  PubMed  Google Scholar 

  225. Pan, H. C. et al. Quality-of-life outcomes after gamma knife surgery for trigeminal neuralgia. J. Neurosurg. 113, 191–198 (2010).

    Article  PubMed  Google Scholar 

  226. Haviv, Y. et al. The impact of chronic orofacial pain on daily life: the vulnerable patient and disruptive pain. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 123, 58–66 (2017).

    Article  PubMed  Google Scholar 

  227. Antonaci, F. et al. Pitfals in recognition and management of trigeminal neuralgia. J. Headache Pain 21, 82 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Hung, P. S.-P. et al. Sex differences in patient journeys to diagnosis, referral, and surgical treatment of trigeminal neuralgia: implications for equitable care. J. Neurosurg. https://doi.org/10.3171/2022.11.JNS221191 (2022).

    Article  PubMed  Google Scholar 

  229. Reinard, K. et al. Racial disparities in the diagnosis and management of trigeminal neuralgia. J. Neurosurg. 126, 368–374 (2017).

    Article  PubMed  Google Scholar 

  230. Dong, B., Xu, R. & Lim, M. The pathophysiology of trigeminal neuralgia: a molecular review. J. Neurosurg. 139, 1471–1479 (2023).

    Article  CAS  PubMed  Google Scholar 

  231. Smith, C. A., Paskhover, B. & Mammis, A. Molecular mechanisms of trigeminal neuralgia: a systematic review. Clin. Neurol. Neurosurg. 200, 106397 (2021).

    Article  PubMed  Google Scholar 

  232. Fried, K. & Hansson, P. T. Animal models of trigeminal neuralgia: a commentary. Mol. Pain 16, 1744806920980538 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  233. Kernisant, M., Gear, R. W., Jasmin, L., Vit, J. P. & Ohara, P. T. Chronic constriction injury of the infraorbital nerve in the rat using modified syringe needle. J. Neurosci. Methods 172, 43–47 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  234. Tohyama, S., Walker, M. R., Zhang, J. Y., Cheng, J. C. & Hodaie, M. Brainstem trigeminal fiber microstructural abnormalities are associated with treatment response across subtypes of trigeminal neuralgia. Pain 162, 1790–1799 (2021).

    Article  CAS  PubMed  Google Scholar 

  235. Zakrzewska, J. M. et al. Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial. Lancet Neurol. 16, 291–300 (2017).

    Article  CAS  PubMed  Google Scholar 

  236. Witkin, J. M., Pandey, K. P. & Smith, J. L. Clinical investigations of compounds targeting metabotropic glutamate receptors. Pharmacol. Biochem. Behav. 219, 173446 (2022).

    Article  CAS  PubMed  Google Scholar 

  237. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05217628 (2024).

  238. Gallay, M. N., Moser, D. & Jeanmonod, D. MR-guided focused ultrasound central lateral thalamotomy for trigeminal neuralgia. single center experience. Front. Neurol. 11, 271 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  239. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04579692 (2024).

  240. Ma, Y., Hsu, G. & Zhang, F. The applicability and efficacy of magnetic resonance-guided high intensity focused ultrasound system in the treatment of primary trigeminal neuralgia. Med. Hypotheses 139, 109688 (2020).

    Article  PubMed  Google Scholar 

  241. Pollock, B. E. & Ecker, R. D. A prospective cost-effectiveness study of trigeminal neuralgia surgery. Clin. J. Pain 21, 317–322 (2005).

    Article  PubMed  Google Scholar 

  242. Sivakanthan, S. et al. Surgical management of trigeminal neuralgia: use and cost-effectiveness from an analysis of the Medicare Claims Database. Neurosurgery 75, 220–226 (2014).

    Article  PubMed  Google Scholar 

  243. Lemos, L. et al. Pharmacological versus microvascular decompression approaches for the treatment of trigeminal neuralgia: clinical outcomes and direct costs. J. Pain Res. 4, 233–244 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Grunberg, V. A., Reichman, M., Lovette, B. C., Vranceanu, A. M. & Greenberg, J. “No one truly understands what we go through and how to treat it”: lived experiences with medical providers among patients with orofacial pain. Int. J. Environ. Res. Public Health 19, 10396 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  245. Perugino, F., De Angelis, V., Pompili, M. & Martelletti, P. Stigma and chronic pain. Pain Ther. 11, 1085–1094 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  246. Costa, G. M. F., Rocha, L. P. C., Siqueira, S., Moreira, P. R. & Almeida-Leite, C. M. No association of polymorphisms in nav1.7 or nerve growth factor receptor genes with trigeminal neuralgia. Pain Med. 20, 1362–1369 (2019).

    Article  PubMed  Google Scholar 

  247. Gambeta, E., Gandini, M. A., Souza, I. A., Ferron, L. & Zamponi, G. W. A CACNA1A variant associated with trigeminal neuralgia alters the gating of Cav2.1 channels. Mol. Brain 14, 4 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Cui, W., Yu, X. & Zhang, H. The serotonin transporter gene polymorphism is associated with the susceptibility and the pain severity in idiopathic trigeminal neuralgia patients. J. Headache Pain 15, 42 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  249. Di Lorenzo, C. et al. The upstream variable number tandem repeat polymorphism of the monoamine oxidase type A gene influences trigeminal pain-related evoked responses. Eur. J. Neurosci. 39, 501–507 (2014).

    Article  PubMed  Google Scholar 

  250. Wang, A. et al. MARS1 mutations linked to familial trigeminal neuralgia via the integrated stress response. J. Headache Pain 24, 4 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  251. Koizumi, M. et al. P2X(3) receptor upregulation in trigeminal ganglion neurons through TNFα production in macrophages contributes to trigeminal neuropathic pain in rats. J. Headache Pain 22, 31 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Ma, X., Zhu, T. & Ke, J. Progress in animal models of trigeminal neuralgia. Arch. Oral Biol. 154, 105765 (2023).

    Article  PubMed  Google Scholar 

  253. Ding, W. et al. An improved rodent model of trigeminal neuropathic pain by unilateral chronic constriction injury of distal infraorbital nerve. J. Pain 18, 899–907 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. BIDMC Comprehensive Headache Center, Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Sait Ashina

  2. BIDMC Comprehensive Headache Center, Department of Anaesthesia, Critical Care and Pain Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Sait Ashina

  3. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Sait Ashina

  4. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Carrie E. Robertson & Lars Bendtsen

  5. Faculty of Medicine, King Mongkut’s Institute of Technology Ladkrabang, Bangkok, Thailand

    Anan Srikiatkhachorn

  6. Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy

    Giulia Di Stefano & Giorgio Cruccu

  7. Department of Evaluation and Treatment of Pain, FHU INOVPAIN, Centre Hospitalier Universitaire de Marseille, Hopital de la Timone, Assistance Publique-Hopitaux de Marseille, Marseille, France

    Anne Donnet

  8. Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto, Ontairo, Canada

    Mojgan Hodaie

  9. Department of Neurology, Hospital Weser-Egge, Hoexter, Germany

    Mark Obermann

  10. Department of Neurology, University Hospital Essen, Essen, Germany

    Mark Obermann

  11. Department of Pain and Neural Sciences, Brotman Facial Pain Clinic, University of Maryland, School of Dentistry, Baltimore, MD, USA

    Marcela Romero-Reyes

  12. Department of Medical Neuroscience, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea

    Young Seok Park

  13. Department of Neurosurgery, Gamma Knife Icon Center, Chungbuk National University Hospital, Cheongju, Republic of Korea

    Young Seok Park

  14. Department of Neurology, University of Copenhagen, Danish Headache Center, Copenhagen University Hospital – Rigshospitalet, Glostrup, Copenhagen, Denmark

    Lars Bendtsen

Authors
  1. Sait Ashina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carrie E. Robertson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anan Srikiatkhachorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giulia Di Stefano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne Donnet
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mojgan Hodaie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mark Obermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marcela Romero-Reyes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Young Seok Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Giorgio Cruccu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lars Bendtsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Introduction (S.A. and L.B.); Epidemiology (S.A., G.D.-S. and G.C.); Mechanisms/pathophysiology (S.A., G.D.-S., M.O., A.D., Y.S.P., C.E.R., L.B., M.R.-R. and A.S.); Diagnosis, screening and prevention (S.A., G.D.-S., M.H., M.O., A.D., C.E.R., L.B. and M.R.-R.); Management (S.A., M.H., M.O., G.C., Y.S.P., C.E.R., L.B. and M.R.-R.); Quality of life (S.A., G.D.-S., M.H. and A.D.); Outlook (S.A., M.H., M.O., L.B. and A.S.); overview of the Primer (S.A.).

Corresponding author

Correspondence to Sait Ashina.

Ethics declarations

Competing interests

S.A. received honoraria for consulting or teaching from Allergan/AbbVie, Eli Lilly, Impel NeuroPharma, Linpharma, Lundbeck, Pfizer, Satsuma, Teva, and Theranica. C.E.R. has served on advisory boards for Lundbeck, Biohaven, Impel, Linpharma, and Satsuma, and has received research support from Teva, Pfizer, Lundbeck, with funds paid to her institution, and she also receives royalties as author and section editor for UpToDate. M.O. has received scientific support, travel support and/or honoraria from Biogen, Novartis, Sanofi, Pfizer, and Teva, Lilly, and Heel, and he received research grants from Allergan, Electrocore, Heel, and the German Ministry for Education and Research (BMBF). M.R.-R. received grant support from Amgen and honoraria for consulting from Pfizer. L.B. has given lectures and served on the scientific advisory board for Abbvie, Eli Lilly, Lundbeck, Novartis, Pfizer and Teva. All other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Disease Primers thanks R. Sekula, D. Lunsford and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ashina, S., Robertson, C.E., Srikiatkhachorn, A. et al. Trigeminal neuralgia. Nat Rev Dis Primers 10, 39 (2024). https://doi.org/10.1038/s41572-024-00523-z

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41572-024-00523-z

  • Springer Nature Limited

Search

Navigation