Author(s): Chaitanya Konda, DO, Casey Salandra, DO, Mia Robb Stahler, DO
Originally published: July 17, 2013 Last updated: December 11, 2024
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Disease/Disorder

Definition

Trigeminal neuralgia (TN) or tic douloureux is a paroxysmal, usually unilateral disorder, characterized by brief painful episodes commonly described as intense, sharp, stabbing, shock-like pains within one or more divisions of the trigeminal nerve (ophthalmic V1, maxillary V2 and mandibular V3).1

According to the 2019 European Academy of Neurology guidelines, trigeminal neuralgia is classified into three forms: classical trigeminal neuralgia (typically caused by neurovascular compression), idiopathic trigeminal neuralgia (of unknown cause), and secondary trigeminal neuralgia (associated with structural lesions such as tumors or multiple sclerosis).22

The International Classification of Headache Disorders, Third Edition (ICHD-3) suggests the diagnostic criteria for TN as below:1

A) Recurrent paroxysms of unilateral facial pain in the distribution(s) of one or more divisions of the trigeminal nerve, with no radiation beyond, and fulfilling criteria B and C

B) Pain has all the following characteristics

  • Lasting from a fraction of a second to two minutes
  • Severe intensity
  • Electric shock-like, shooting, stabbing, or sharp in quality

C) Precipitated by innocuous stimuli within the affected trigeminal distribution

D) Not better accounted for by another ICHD-3 diagnosis

Etiology

TN caused by focal compression of the trigeminal root by tortuous or aberrant vessels in the posterior fossa.1,2,3,4 Other causes are slowly growing tumors, saccular aneurysms or arteriovenous malformations compressing the trigeminal nerve root near the dorsal root entry zone.1,2,3,4 TN may also be idiopathic.

Epidemiology including risk factors and primary prevention

TN is a rare disease. Epidemiological studies showed that approximately 4 to 28.9/100,000 persons worldwide experience TN.1,4,5,6In the United States, there are approximately 15,000 new cases each year.5,6 Classic TN accounts for about 80% of cases, secondary TN 15% and idiopathic TN 5%.22, 23

Females are 1.5 times more likely to have trigeminal neuralgia.2,5,6

The disease can appear at any age however it is rare in children, and it occurs after age 40 in more than 90% of cases. Peak age of disease onset is between 52-58 years old for classical type TN and 30-35 years for the secondary form of TN.2,3

Familial cases, though rare, have also been reported.20,21

Hypertension and migraines may be risk factors for developing TN.24,25,26

No methods for primary prevention have been proposed.

Patho-anatomy/physiology

To elaborate on the three variants of TN

  • Classical trigeminal neuralgia is typically caused by neurovascular compression near the brainstem, which leads to focal demyelination and ephaptic crosstalk between adjacent nerve fibers. Recent research also highlights the role of microvascular ischemic changes that further lower the excitatory threshold of affected fibers, contributing to the high-frequency discharges characteristic of TN.3 Additionally, Schwann cell activation has been identified as a key process in nerve repair, with two signaling pathways—NGF-trkA and BDNF-trkB—potentially playing a role in promoting myelin repair following nerve injury.11
  • Secondary trigeminal neuralgia (STN) is caused by a structural lesion other than vascular compression such as from tumors (either benign or malignant), multiple sclerosis, or arteriovenous malformations.1,3,4
  • Idiopathic trigeminal neuralgia is when no pathology is identified

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time):

There is no evidence showing increase in frequency of the paroxysmal attacks of TN or duration of the attacks with the disease duration. Unlike other forms of neuropathic pain, TN can enter periods of complete remission in up to 63% of patients, with the remission periods lasting from weeks to years.4 Early prediction of outcomes is difficult due to significant variability in recurrence. While known predictors of recurrence include female sex, symptoms lasting more than eight years, venous compression of the trigeminal-root entry zone, recent insights suggest that Schwann cell activation may also influence the long-term progression of TN. These cells play a crucial role in nerve repair, and their activation could help explain variations in disease recurrence and remission periods.2,11,12

Specific secondary or associated conditions and complications

TN pain often provokes muscle spasm on the affected side, known as tic douloureux.1,2,3,4 Lacrimation and rhinorrhea are rare. 2.4% of MS patients develop TN; however, patients with other demyelinating disorders such as Charcot-Marie-Tooth develop TN rarely.1,2,3

Essentials of Assessment

History

The diagnosis of TN can be made usually by history alone. It should be distinguished from other causes of facial pain.1

TN is typically unilateral but a few patients develop bilateral symptoms which occur most commonly in individuals diagnosed with multiple sclerosis.

The pain strictly follows the distribution of the trigeminal nerve branches and does not extend to the posterior third of the scalp, posterior portion of the external ear, or the angle of the mandible.

Stimulus-evoked pain is a striking feature of TN. Triggers and trigger zones are non-noxious mechanical stimuli within the trigeminal territory over the face, lips, gums, including the oral cavity. Such stimuli include light touch, a whiff of air, shaving, application of makeup, brushing, eating, drinking, usual movements such as smiling, talking. This pain paroxysm resembles allodynia in other conditions of neuropathic pain but unlike allodynia, TN has limited trigger zones and characteristic brisk facial muscle contractions (tics).

Physical examination

The physical examination is typically normal in TN which is a more useful finding to exclude other diagnoses. A thorough neurological examination as well as head and neck examination should be performed, given the association of MS and tumors with TN. The ears, mouth, teeth, and temporomandibular joint should be evaluated for other causes of facial pain.9 Atypical features of the disease such as abnormal neurologic examination, ataxia, sensory abnormalities in the trigeminal area, abnormal trigeminal reflexes (corneal reflex, blink reflex, masseter inhibitory periods, jaw-jerk), focal weakness, abnormal oral, dental or ear examination, hearing abnormality or visual changes suggest secondary trigeminal neuralgia or an alternative diagnosis.5,9,14 The finding of typical trigger areas, which are most frequently perioral, is pathognomonic for TN.9

Functional assessment

Using a multidisciplinary approach, the patient should be evaluated to determine how debilitated or limited he/she is by TN pain. Different therapeutic approaches may be used to establish baseline function and to educate the patient about pain management, such as Graded Exposure Therapy. The functional assessment may be determined using the Functional Independence Measure or other functional scales, depending on the rehabilitation team’s preference.

Imaging

Advanced imaging techniques, particularly contrast-enhanced Constructive Interference in Steady State (CISS) MRI, have significantly improved the detection of neurovascular compression in classical TN. This imaging method not only correlates better with symptoms but also offers enhanced predictive capabilities for surgical outcomes, especially in patients undergoing microvascular decompression.5

MRI readily identifies major neurologic diseases such as cerebellopontine angle tumors or multiple sclerosis plaques that may be the culprit for secondary TN.

A meta-analysis from 2014 further delineated imaging features on MRI that could diagnose symptomatic TN. Contact with the trigeminal root alone had a sensitivity of 66% and specificity of 90% for diagnosis of TN. Whereas when nerve atrophy co-existed, sensitivity was 52%, but specificity was increased to 100%.6

Supplemental assessment tools

Other exams such as neurophysiologic recording of trigeminal reflexes and trigeminal evoked potentials are options for patients who cannot undergo MRI.

Neurophysiological recording of trigeminal reflexes can differentiate classical TN from secondary TN. The trigeminal reflexes consist of the R1 and R2 components of the blink reflex after electrical stimulation of the ophthalmic division, SP1 and SP2 components of the masseter inhibitory reflex after electrical stimulation of the maxillary or mandibular division, and the jaw jerk to chin taps.8,10 These reflexes assess function of the trigeminal afferents from all trigeminal territories as well as the trigeminal central circuits in the brainstem.7 Typically, all reflexes are normal in classical TN but the short-latency oligosynaptic reflexes may be abnormal in secondary TN.7,8,9,10 Sensory changes in TN are usually not clinically significant and may be detected only with quantitative somatosensory testing comparisons with the unaffected side.11

Early predictions of outcomes

Early prediction of outcomes is difficult, because there is significant variability in recurrence. Significant predictors of recurrence include female sex, symptoms lasting more than eight years, venous compression of the trigeminal-root entry zone, and the lack of immediate postoperative cessation of tic.12

Environmental

Environmental factors that could incite TN symptoms should be assessed.

Social role and social support system

Patients should be questioned as to how they are coping with chronic pain. Inquiries should be made into whether they would be receptive to support groups or psychological services. Patients can be directed to resources, such as the TNA Facial Pain Association website.

Professional issues

Changes in location, severity, or quality of pain should alert the physician to the possibility of an alternative diagnosis.9

Rehabilitation Management and Treatments

Available or current treatment guidelines

Treatment of TN is based on the use of antiepileptic drugs. First line therapy should be carbamazepine (200-1200mg/day) or oxcarbazepine (600-1800mg/day). There have been multiple Class I and II studies that established carbamazepine as effective, less so for oxcarbazepine but patients may tolerate the latter better.2,3 An additional consideration exists for patients with Asian ancestry who carry the HLA-B*15:02 gene which indicates a genetic susceptibility to developing Steven-Johnson syndrome and/or toxic epidermal necrolysis with use of carbamazepine, thus should be avoided in these patients.27

Second-line treatment for refractory cases is based on little evidence. Other seizure medications such as valproate, lamotrigine, gabapentin, pimozide, anti-spasticity agents such as tizanidine, baclofen, botulinum toxin A and topical capsaicin have been tried. Typically, lamotrigine can be added on (400mg/day) or patient may be transitioned to lamotrigine or baclofen (80mg/day max).2,3,17

For analgesia while oral medications are titrated, intravenous infusion of lidocaine (5 mg/kg administered over one hour), phenytoin (15 mg/kg administered over 30-120 minutes), fosphenytoin or subcutaneous sumatriptan (3mg injection subcutaneous followed by one week of 50mg daily oral for one week) may be used, though the evidence for this is low-grade.28,29,30

Botulinum toxin A has shown increasing efficacy as an alternative treatment for trigeminal neuralgia, especially in patients who are refractory to standard oral medications. A 2016 meta-analysis demonstrated significant pain reduction and improved outcomes with botulinum toxin therapy, making it a promising non-invasive treatment option.17

Topical ophthalmic anesthesia has been found to be ineffective for controlling pain in patients with classic TN, hence should not be prescribed.3

In terms of managing secondary TN, not enough evidence has been found to support or to refute the effectiveness of any medication to treat it. There have been no placebo-controlled studies for this type of TN and existing ones are small, open label trials of MS-associated TN using lamotrigine, gabapentin, topiramate or misoprostol.2

At different disease stages

There are no distinct disease stages in TN. Occasionally episodes of TN may present without the typical characteristics but will respond well to carbamazepine. This is known as pre-TN, a dull, continuous, aching pain most often in the jaw which later develops the hallmark signs.16

Coordination of care

An interdisciplinary team approach is strongly recommended, with initial pharmacologic management by physiatrist or pain specialist. Connecting patients to resources is important. Consultations with a neuropsychologist and an occupational therapist may prove helpful.

Complementary and alternative medicine (CAM), such as acupuncture, relaxation techniques and meditation, can be considered as adjunct or alternative to pharmacotherapy. Consultation with nutritionist is indicated if poor oral intake stems from severe pain.13,16 Referral to neurosurgery is indicated for cases refractory to medical management.2,4

Patient & family education

Referral to support group services should be offered. They should be educated about uncertainty of prognosis.

Measurement of Treatment Outcomes including those that are impairment-based, activity participation-based and environmentally based

A multidisciplinary team approach that includes physical and occupational therapy and neuropsychology is indicated. This approach should incorporate consistent use of Cognitive Behavioral Therapy, Graded Exposure Therapy, desensitization techniques. Patient functional changes can be measured with Quality Improvement scores or other functional grading measures.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Some experts recommend expedited referral for surgery or an interventional procedure. This should be done in a timely manner so as not to result in marked deterioration in activities of daily living.

Such interventions include

  • Peripheral techniques like cryotherapy, neurotomies, alcohol injection, phenol injection, peripheral acupuncture, radiofrequency ablation, thermocoagulation: these target portions of the trigeminal nerve distal to the Gasserian ganglion.1,2,3,4
  • Percutaneous Gasserian ganglion techniques: these are destructive interventions targeting the Gasserian ganglion itself through radiofrequency thermocoagulation or percutaneous glycerol rhizolysis, or balloon compression.1,2,3,4
  • Gamma knife radiosurgery uses a beam of radiation to target the trigeminal root. It remains an option for patients who cannot undergo open surgery or who have blood coagulation problems (e.g., patients who are taking warfarin).1,2,3,4
  • Posterior fossa microvascular decompression of the neurovascular contact remains the gold standard for sustained pain relief in classical TN. The use of contrast-enhanced CISS MRI has improved diagnostic accuracy, helping predict which patients will benefit the most from this surgical intervention.5

Peripheral nerve stimulation has recently been gaining ground and growing evidence as a treatment option for chronic pain syndromes unresponsive to other interventions. It entails a subcutaneous insertion of one or several electrodes in the painful area and subsequent electrical stimulation.14,15

Cutting Edge/Emerging and Unique Concepts and Practice

Voltage gated potassium channel openers are being examined as potential therapeutic agents for TN pain.18 Preliminary data also suggests that selective sodium channel blockers targeting the Nav1.7 sodium receptor may offer improved efficacy compared to traditional treatments like carbamazepine or oxcarbazepine.22Additionally, Schwann cell activation has emerged as a promising therapeutic target in TN. Research has identified two key signaling pathways, NGF-trkA and BDNF-trkB, which are crucial in promoting myelin repair following trigeminal nerve injury. These findings suggest that future therapies aimed at enhancing nerve regeneration through Schwann cell pathways could improve long-term outcomes for patients with TN.12

There are reports of deep brain stimulation, electric stimulation of structures deep in the brain by an implanted pacemaker, successfully treating post-herpetic TN.19 Additionally, use of peripheral nerve stimulation is gaining favor in some pain and neurosurgical circles.

Gaps in the Evidence-Based Knowledge

While the clinical presentation of TN is well characterized, more research can be done to establish a link between other comorbid pathologies such as hypertension and migraines24,25,26

Novel approaches to treatment including development of sodium channel blockers of the Nav 1.7 sodium receptor, botulinum toxin and research into signaling pathways of the trigeminal nerve should also be explored to develop more targeted therapies for TN.

In summary, TN is a clinical diagnosis that, as the name states, has symptoms confined within the trigeminal area. Neurologic exam is typically normal and if not, secondary causes of TN or other causes of a patient’s signs and symptom should be considered.

  • Classical TN is unusual under the age of 40 years.
  • Carbamazepine is the drug of choice for initial treatment.
  • Microvascular decompression is the gold-standard surgical technique for classical TN.
  • The finding of typical trigger areas, which are most frequently perioral, is pathognomonic for TN.
  • A multidisciplinary approach, which includes the patient, physiatrist, PT, OT, neuropsychologist, and other specialties such as neurology, nutrition, pain medicine or neurosurgery would be the most appropriate for patients with TN.

References

  1. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition.” Cephalalgia : an international journal of headache vol. 38,1 (2018): 1-211.
  2. Bendtsen L, et al. European Academy of Neurology guideline on trigeminal neuralgia. European Journal of Neurology. 2019; 26(6):831-849.
  3. Bendtsen L, et al. Advances in diagnosis, classification, pathophysiology, and management of trigeminal neuralgia. The Lancet Neurology. 2020; 19(9):784-796
  4. Brainstem Function and Dysfunction. Amsterdam, the Netherlands: Elsevier; 2006:171-186.
  5. Blitz AM, et al. Contrast-enhanced CISS imaging for evaluation of neurovascular compression in trigeminal neuralgia: Improved correlation with symptoms and prediction of surgical outcomes. AJNR American Journal of Neuroradiology. 2018; 39(9):1724-1732.
  6. Antonini G, et al. Magnetic resonance imaging contribution for diagnosing symptomatic neurovascular contact in classical trigeminal neuralgia: A blinded case-control study and meta-analysis. Pain. 2014; 155(8):1464-1471.
  7. Jensen TS, Rasmussen P, Reske-Nielsen E. Association of trigeminal neuralgia with multiple sclerosis: clinical and pathological features. Acta Neurologica Scandinavica. 1982;65:182–189.
  8. Chmielewska B, Keszek KM. Progression of preexisting trigeminalgia to Tolose-Hunt-like syndrome. The importance of neuroimaging for early diagnosis. Neurological Sciences. 2003;24:281–285.
  9. Gupta, et al. Familial trigeminal neuralgia. Neurology India. 2001;50(1):87-89.
  10. Katusic S, Beard CM, Bergstralh E, Kurland LT. Incidence and clinical features of trigeminal neuralgia, Rochester, Minnesota, 1945–1984. Annals of Neurology. 1990;27(1):89–95.
  11. Liao JY, et al. Schwann cells and trigeminal neuralgia. Molecular Pain. 2020; 16:1744806920963809.
  12. Burchiel KJ. Abnormal impulse generation in focally demyelinated trigeminal roots. Journal of Neurosurgery. 1980;53:674–683.
  13. Dubner R, Sharav Y, Gracely RH, Price DD. Idiopathic trigeminal neuralgia: sensory features and pain mechanisms. Pain. 1987;31:23–33.
  14. Tanaka, et al. Trigeminal neuralgia associated with tentorial agenesis and temporal lobe herniation: a case report. Neurol Med Chir. 2000;40(2):124-127.
  15. Gronseth, 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. 2008;71(15):1183-1190.
  16. Bennetto, et al. Trigeminal neuralgia and its management. BMJ. 2007;334:201-205.
  17. Morra ME, et al. Therapeutic efficacy and safety of botulinum toxin A therapy in trigeminal neuralgia: A systematic review and meta-analysis of randomized controlled trials. The Journal of Headache and Pain. 2016; 17(1):63.
  18. Takeda, at al. Potassium channels as a potential therapeutic target for trigeminal neuropathic and inflammatory pain. Molecular Pain. 2011;7.
  19. Green D, et al. Post-herpetic trigeminal neuralgia treated with deep brain stimulation. Journal of Clinical Neuroscience. 2003;10:512-514.
  20. Fleetwood, I G et al. “Familial trigeminal neuralgia. Case report and review of the literature.” Journal of neurosurgery vol. 95,3 (2001): 513-7. doi:10.3171/jns.2001.95.3.0513
  21. Panchagnula, Shreyas et al. “Familial Trigeminal Neuralgia Cases Implicate Genetic Factors in Disease Pathogenesis.” JAMA neurology vol. 76,1 (2019): 9-10. doi:10.1001/jamaneurol.2018.3322
  22. Cruccu, Giorgio. “Trigeminal Neuralgia.” Continuum (Minneapolis, Minn.) vol. 23,2, Selected Topics in Outpatient Neurology (2017): 396-420. doi:10.1212/CON.0000000000000451
  23. Lee, Albert et al. “Trigeminal neuralgia occurs and recurs in the absence of neurovascular compression.” Journal of neurosurgery vol. 120,5 (2014): 1048-54. doi:10.3171/2014.1.JNS131410
  24. Teruel, Antonia et al. “Prevalence of hypertension in patients with trigeminal neuralgia.” The journal of headache and pain vol. 10,3 (2009): 199-201. doi:10.1007/s10194-009-0107-5
  25. Pan, S-L et al. “Increased risk of trigeminal neuralgia after hypertension: a population-based study.” Neurology vol. 77,17 (2011): 1605-10. doi:10.1212/WNL.0b013e3182343354
  26. Lin, Kuan-Hsiang et al. “Increased risk of trigeminal neuralgia in patients with migraine: A nationwide population-based study.” Cephalalgia : an international journal of headache vol. 36,13 (2016): 1218-1227. doi:10.1177/0333102415623069
  27. Ferrell, P Brent Jr, and Howard L McLeod. “Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations.” Pharmacogenomics vol. 9,10 (2008): 1543-6. doi:10.2217/14622416.9.10.1543
  28. Stavropoulou, Evmorfia et al. “The Effect of Intravenous Lidocaine on Trigeminal Neuralgia: A Randomized Double Blind Placebo Controlled Trial.” ISRN Pain vol. 2014 853826. 10 Mar. 2014, doi:10.1155/2014/853826
  29. Tate, Rebekah et al. “Treatment of refractory trigeminal neuralgia with intravenous phenytoin.” American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists vol. 68,21 (2011): 2059-61. doi:10.2146/ajhp100636
  30. Kanai, Akifumi et al. “Subcutaneous sumatriptan for refractory trigeminal neuralgia.” Headache vol. 46,4 (2006): 577-82; discussion 583-4. doi:10.1111/j.1526-4610.2006.00405.x

Original Version of the Topic 

Marykatharine Nutini, DO, Dennis Nutini, MD. Trigeminal Neuralgia. 7/17/2013.

Previous Revision(s) of the Topic 

Ada Lyn Yao, MD, Ashot Kotcharian, MD. Trigeminal Neuralgia. 3/27/2017.

Kirk Lercher, MD, Prathusha Maduri, DO. Trigeminal Neuralgia. 11/17/2021

Author Disclosure

Chaitanya Konda, DO
Nothing to Disclose

Casey Salandra, DO
Nothing to Disclose

Mia Robb Stahler, DO
Nothing to Disclose