25 Natural History and Management Options of Trigeminal Neuralgia

Adrian Praeger, Peter Teddy, Sarah Cain, Andranik Kahramanian, and Bhadrakant Kavar

Abstract

Trigeminal neuralgia is a challenging clinical problem for patient and clinician. An early multidisciplinary approach is vital. When medical therapies fail to obtain pain control, surgical options are available. When possible, the nerve preservation option of microvascular decompression should be considered in non-MS patient group. Alternatively, the ablative options of radiofrequency thermocoagulation, glycerol injection, ballon compression, or radiosurgery have a high but varing success rate.

Trigeminal neuralgia (TN), also known as tic douloureux, is a chronic debilitating neuropathic pain that affects the trigeminal nerve. Classically, it has been described as sudden, sharp, and lancinating unilateral facial pain that lasts from a few seconds to minutes per episode, followed by a refractory period. The pain may be triggered by light mechanical contact from a restricted site (trigger point or trigger zone). The attacks are paroxysmal and may occur at intervals, many times a day, or, in rare instances, follow one another almost continuously. Periodicity is characteristic, with episodes occurring for a few weeks to a month or two, followed by a pain-free interval of months or years and then recurrence of another bout of pain.1

TN incidence is estimated around 4.7/100,000 with a female preponderance (female-to-male ratio of 3:2). The maxillary (V2) and/or mandibular divisions (V3) are typically the most affected.² The peak age of incidence is between the sixth and eighth decades of life.³ The most common cause of TN is a compressing loop of an artery (classically the superior cerebellar artery [SCA] but can be the anterior inferior cerebellar artery [AICA], a dolichoectatic vertebrobasilar complex, or a persistent fetal trigeminal artery).^{4,​ 5,​ 6,​ 7,​ 8} Other causes include compression due to cerebellopontine angle (CPA) tumors or cysts, perineural tumor spread, multiple sclerosis, and demyelinating disease.^{9,​ 10}

Several classifications of facial pain have been proposed (Table 25.1). The Burchiel classification¹¹ is comprehensive, widely used, and incorporates pathophysiology. Cruccu et al¹² provided a simpler classification that is also widely used. Typical TN, due to neurovascular conflict, is described as either TN type 1 (Burchiel) or classic TN (Cruccu, International Classification of Headache Disorders, 3rd edition [ICDH-3]). The diagnosis of TN is based on a patient’s clinical history, and an imaging study is usually indicated to exclude posterior fossa pathologies (e.g., mass lesion in the CPA, demyelination). Vascular contact deforming the trigeminal nerve is seen in about 15% of cases.

Table 25.1 Classifications of trigeminal neuralgia/facial pain

25.2 Selected Papers on the Natural History of Trigeminal Neuralgia

●Burchiel KJ, Slavin KV. On the natural history of trigeminal neuralgia. Neurosurgery 2000;46(1):152–154, discussion 154–155

●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 2014;15(1):34

●Taylor JC, Brauer S, Espir ML. Long-term treatment of trigeminal neuralgia with carbamazepine. Postgrad Med J 1981;57(663):16–18

25.3 Natural History of Trigeminal Neuralgia

The natural history of TN is not well defined. The initial presentation is often misdiagnosed, and the correct diagnosis is delayed for weeks to years. Attacks of pain present for weeks to months with periods of remission lasting for months to years. Almost invariably, the pain recurs with increasing duration, frequency, and severity—mandating reevaluation of the initial diagnosis (if that of TN was not made), to the point where TN-specific treatment will be required.^{13,​ 14} Our systematic review of the literature identified no adequate study on the natural history of “untreated” TN or one that captures the patient population in which pain may resolve without treatment.

The initial response to treatment with carbamazepine is generally excellent. Even patients who have an unsatisfactory response to carbamazepine typically have an initial partial response, often within the first 48 hours.15^{,​ 16,​ 17} This can be used to differentiate between typical TN and other causes of facial pain.¹⁸ When the patient does not respond to carbamazepine, the diagnosis should be revisited.¹⁹

To assess the response to carbamazepine, we examined the literature and identified 744 patients in 10 studies (Table 25.2).^{15,​ 17,​ 18,​ 20,​ 21,​ 22,​ 23,​ 24,​ 25,​ 26} Initial positive response rate is around 79.5% (range: 68–98%) with a declining control rate to 66.3% (range: 54–100%) over time. Studies with stricter inclusion criteria, that is, only type 1 TN (classic TN) without previous treatment generally reported better success rates. Di Stefano et al²⁰ reported 98% of 95 patients had an initial positive response. However, 27% of patients ceased taking carbamazepine because they had either a relapse of their pain or side effects, requiring a reduction of carbamazepine until it was no longer adequately controlling their pain.

Table 25.2 Characteristics of carbamazepine response and sides effects in 744 patients across 10 studies

The risk of side effects is low, particularly if carbamazepine is commenced at a low dose and increased slowly. Side effects can include cognitive side effects (drowsiness, confusion, and changes in mood), dizziness, ataxia, electrolyte, hematological, and liver function test (LFT) derangement. Rash is also common, with a significant potential for Stevens–Johnson syndrome in people with the allele HLA-B*1502, which is common in those of Han Chinese, Hong Kong Chinese, or Thai origin. Thus, these patients should be screened before the use of carbamazepine.²⁷

25.4 Selected Papers on the Treatment of Trigeminal Neuralgia

●Bendtsen L, Zakrzewska JM, Abbott J, et al. European Academy of Neurology guideline on trigeminal neuralgia. Eur J Neurol 2019;26(6):831–849

●Gronseth G, Cruccu G, Alksne J, 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

●Holste K, Chan AY, Rolston JD, Englot DJ. Pain outcomes following microvascular decompression for drug-resistant trigeminal neuralgia: a systematic review and meta-analysis. Neurosurgery 2020;86(2):182–190

●Barker FG II, Jannetta PJ, Bissonette DJ, Larkins MV, Jho HD. The long-term outcome of microvascular decompression for trigeminal neuralgia. N Engl J Med 1996;334(17):1077–1083

25.5 Treatment Options of Trigeminal Neuralgia

Optimal management for TN should include a multidisciplinary approach involving the neurologist, neurosurgeon, and pain management physician. Conservative management with medical therapy should be initially attempted in all patients. If this fails, the main treatment options are microvascular decompression (MVD), percutaneous ablative procedures (balloon microcompression, radiofrequency thermocoagulation, and glycerol injection), and stereotactic radiosurgery (SRS). Treatment recommendation should be based on the underlying etiology, radiological findings, patient symptoms and comorbidities, as well as the experience of the treating team.

25.5.1 Medical Therapy

Medical therapy is the mainstay of initial treatment, with literature evidence to support the use of either carbamazepine or oxcarbazepine as first-line therapy.^{20,​ 28,​ 31} Di Stefano et al²⁰ reported 98% of patients had an initial response to carbamazepine, but 27% had to stop taking the drug due to side effects. In contrast, 94% of patients had initial control with oxcarbazepine, whereas 18% had to stop it due to side effects.

Other medical options to consider include baclofen, lamotrigine, gabapentin, botulinum toxin type A, pregabalin, and phenytoin. These can be prescribed in combination with or instead of carbamazepine or oxcarbazepine. Data to support the routine use of any of the second-line medical therapies is low (Table 25.3).^{16,​ 18,​ 19,​ 20,​ 21,​ 24,​ 28,​ 29,​ 32,​ 33,​ 34,​ 35,​ 36,​ 37,​ 38,​ 39,​ 40,​ 41,​ 42,​ 43,​ 44}

Table 25.3 Literature summary for medical management of trigeminal neuralgia

If a patient develops medically refractory pain or intolerable side effects to medication, they should progress to one of the more definitive treatments, either MVD or the percutaneous ablative techniques or SRS.⁴⁵

25.5.2 Microvascular Decompression

MVD of the trigeminal nerve is generally the treatment of choice. MVD is generally recommended for patients with inadequate medical control, in whom a greater than 5-year survival is expected and who are medically fit.⁴⁶ In our analysis of the literature on the outcomes of MVDs, a total of 36 papers were included encompassing a total of 6,315 patients with an average age range of 41.6 to 79.4 years (Table 25.4).^{32,​ 33,​ 34,​ 35,​ 36,​ 45,​ 47,​ 48,​ 49,​ 50,​ 51,​ 52,​ 53,​ 54,​ 55,​ 56,​ 57,​ 58,​ 59,​ 60,​ 61,​ 62,​ 63,​ 64,​ 65,​ 66,​ 67,​ 68,​ 69,​ 70,​ 71,​ 72,​ 73,​ 74,​ 75,​ 76} It should be noted, however, that there is wide variation in the literature, with heterogeneity in patient population (pure typical TN vs. studies that mix typical TN and atypical TN), previous treatments, selection criteria for treatment, definition and documentation of retreatments, definition of treatment success, as well as wide variability in the documentation and nonuniform definition of complications. This makes it difficult to compare studies and explains some of the wide variability in the reported outcomes.

Table 25.4 Systematic review on outcomes following MVD surgery

Initially, 87% (range: 67.3–100%) of patients were reported as being pain free and off medication. When patients reported as being pain free but still taking medication were included, this improved to 95% (range: 70.3–100%). Long term, with an average, follow-up of 6.9 years, 83% of patients were pain free. The reported recurrence rate varied between 6.1 and 29%, with some of the higher recurrence rates being reported in the earlier papers.

The above findings are supported by Barker et al3 in their large study of 1,185 patients over 20 years with a mean follow-up of 6.2 years. Short-term outcome analysis revealed that 80% of patients had excellent results 1 year following MVD with an additional 8% achieving partial relief. Long-term data at 10 years after surgery demonstrated 70% with excellent results and 4% with partial relief. In total, 11% of patients required a second MVD, whereas 10% had a subsequent ablative procedure.

The postoperative complications following MVDs are summarized in Table 25.4. Mortality ranged from 0 to 2% but was 0.2 and 0.24% in the two largest series (Table 25.4).^{50,​ 71} In the same two large series, hearing loss was 1.4 and 0.94%, whereas facial paralysis was 1.7%. Cerebrospinal fluid (CSF) leak was 1.6 and 0.47%. A permanent ocular palsy was recorded in 4.6% of patients. Anesthesia dolorosa was not recorded in any paper included in this systematic review; however, it is accepted that there is a low risk of it occurring post-MVD.⁷⁷

Positive predictors of success of an MVD included disease duration less than 5 years, arterial compression, SCA involvement, and type 1 facial pain.³⁰ In addition, Barker et al’s³ retrospective study of 1,336 MVDs identified immediate postoperative relief, male sex, absence of venous compression, and less than 8 years of preoperative symptoms as positive predictors of success. These findings were reinforced by Panczykowski et al’s⁷⁸ preoperative TN scoring system, which used classic TN, positive response to carbamazepine and/or oxcarbazepine, and the presence and nature of the neurovascular compression as the positive predictors. The nature and severity of the neurovascular conflict in a preoperative magnetic resonance imaging (MRI) appears to be related with outcome for MVD⁷⁹ and is included in another preoperative TN score, aimed at predicting the success of an MVD.⁸⁰ Negative predictors of success include previous ablative procedures and patients with MS.⁸¹

25.5.3 Percutaneous Ablative Procedures

The three percutaneous ablative procedures (radiofrequency thermocoagulation, balloon compression [BC], and glycerol/alcohol injection) are used for patients who are a poor anesthetic risk, the elderly, patients with MS, and patients who decline an MVD.⁷⁹

The most frequently used percutaneous technique is radiofrequency thermocoagulation (PRfT) for which the patient needs to be sedated/awake/sedated to ensure accurate placement of the electrode.⁸² Glycerol/alcohol injection into the Meckel s cave is performed under general anesthesia (GA) and thus avoids the awake phase of PRfT.^{46,​ 83} BC is also performed under GA with favorable results in most patients.^{84,​ 85,​ 86} Literature review outcomes of the three percutaneous procedures are presented in detail in Table 25.5.

Table 25.5 Literature summary of outcomes following ablative procedures or SRS for trigeminal neuralgia

25.5.4 Percutaneous Radiofrequency Thermocoagulation

A total of 8,454 patients across 12 studies underwent PRfT.36^{,​ 82,​ 87,​ 88,​ 89,​ 90,​ 91,​ 92,​ 93,​ 94,​ 95,​ 96} The initial success rate ranged between 91 and 100%, with an early failure rate of 3.2 and 6.0% (often due to inability to cannulate the foramen ovale). The initial positive response typically declined over time, with the reported pain-free rate, with or without medication, diminishing to 52% at last follow-up (mean follow-up range: 22.6–111.6 months). Some patients may periodically require repeat procedures to maintain a good therapeutic response. The mean recurrence rate was noted at 19.8% (range: 9.6–25.1%), with rates typically higher in patients who reported less hypoesthesia after the initial procedure. The overall initial facial numbness rate ranged from 11.3 to 98.0% of patients, whereas the range of prolonged/permanent facial numbness was between 9 and 15.2%.

While this procedure is generally well tolerated, complications can occur (Table 25.4). These include a diminished or absent corneal reflex (3–19.7%), keratitis (0–6.4%), and anesthesia dolorosa (< 2%; range: 0.2–8.9%). Mortality was low ranging from 0 to 0.3%.

25.5.5 Glycerol/Alcohol Injection

Glycerol/alcohol injection has several advantages including the ease and speed of the procedure, and the lack of requirement for GA with no awake phase and no stimulation. Sensory loss is variable and, if performed appropriately, should not result in corneal numbness secondary to V1 involvement. Meticulous positioning of the patient will minimize that risk, which was 2 to 9.3% in our literature review.

Excluding studies with less than 50 patients, 15 studies reported on outcomes for 6,168 patients.97^{,​ 98,​ 99,​ 100,​ 101,​ 102,​ 103,​ 104,​ 105,​ 106,​ 107,​ 108,​ 109,​ 110,​ 111} The mean follow-up time varied between 12 and 72 months with a range of 0 to 300 months. Pain relief may be immediate or take 1 to 2 days to develop and rarely occurs after 2 weeks.¹¹² A repeat procedure can be considered if no relief is reported in 7 days following the index procedure.¹¹³ The initial pain-free outcomes were noted in 73.0 to 97.1% of patients, with early failure rate noted in 5 to 20%. There was significant variability in the pain-free rates at last follow-up, with the range varying from 8.1 to 90%. The 8.1% appeared to be an outlier, with all other long-term rates being above 43%, and came from a study with significant loss to follow-up. The mean recurrence rate was 17.7% (range: 8–80%) with a mean time to recurrence of 5 to 25 months. Retreatments were documented by five studies and ranged between 15.7 and 45.9% of patients in those studies.

25.5.6 Balloon Compression

In total, 3,941 patients across 23 papers were included in the systematic review on BC, and the results are summarized in Table 25.5.^{85,​ 87,​ 96,​ 105,​ 114,​ 115,​ 116,​ 117,​ 118,​ 119,​ 120,​ 121,​ 122,​ 123,​ 124,​ 125,​ 126,​ 127,​ 128,​ 129,​ 130,​ 131,​ 132} Initial control of pain varied from 61.6 to 98.6%. The recurrence rate varied between 5.2 and 77.4%. Patients pain free at last treatment varied widely from 31 to 100%. In terms of complications, prolonged facial numbness was seen in up to 44% of patients and diplopia in up to 8% of patients. Mortality ranged between 0 and 1.5%.

25.5.7 Stereotactic Radiosurgery

The mechanism of action is presumed to be axonal degeneration secondary to radiation as shown by Kondziolka et al on a primate model¹³³ and later confirmed histologically in a patient who had subsequent recurrent TN and underwent partial sectioning of the nerve.¹³⁴

Although this was usually reserved for refractory TN and failure of other treatment options,¹³⁵ this practice is changing. It is the least invasive and ideal for patients with high morbidity or on antiplatelet or anticoagulants. In some series, the results are comparable to those of MVD.^{136,​ 137,​ 138,​ 139} In total, 4,409 patients were included in 15 studies in the systematic review (Table 25.5).^{64,​ 123,​ 140,​ 141,​ 142,​ 143,​ 144,​ 145,​ 146,​ 147,​ 148,​ 149,​ 150,​ 151,​ 152} Initially, up to 90.7% of patients were pain free, with the number of patients being pain free at last follow-up ranging from 32 to 91.8%. After SRS, there is a delay to treatment effect of weeks to months, and some patients may need to wait 12 months to be pain free.¹⁴⁵ The recurrence rate ranged from 19 to 43.7%.

Favorable prognostic factors for SRS include higher radiation dose (i.e., > 70 Gy),¹⁵³ previously unoperated patient, typical TN, and normal sensation pretreatment. The major complication is hyperesthesia in 20% after initial SRS and 32% after repeat treatment¹⁵⁴ and higher with higher radiation dose.¹³⁷ Patients with MS are less responsive than those without MS. SRS can be repeated with similar results as the initial SRS, but only 48 to 65% have good pain control.¹⁵⁵

Maesawa et al found a higher rate of recurrence if patients had previously undergone an unsuccessful MVD with complete pain relief of 60% at 1 year, 53% at 2 years, and 33% at 5 years.¹⁵⁶

25.6 Trigeminal Neuralgia in Multiple Sclerosis

TN is the most common pain syndrome in MS and MS-related TN (MS-TN) and represents 2 to 8% of all cases of TN.^{157,​ 158,​ 159,​ 160} Although the initial treatment should be medical, it is not unusual for patients to have medication-related side effects earlier, and/or exacerbation of their MS-related symptoms as a result of the medication. This often precipitates the need for consideration of surgical treatment; however, outcomes are less satisfactory in MS patients.

The mainstays of surgical management of MS-TN are the ablative procedures of PRfT, glycerol rhizolysis (GR), and BC. As the most likely cause for the pain is demyelination and not vascular compromise, there is generally no role for MVD in MS-TN.^{161,​ 162} However, MVD can be considered if there is evidence of vascular compromise and no evidence of demyelination in the pons or in the region of the trigeminal nerve.

All ablative procedures are reasonable treatment options for MS-TN. However, a recent retrospective analysis and review in the MS group of patients revealed 53.1% achieved excellent pain relief at 3 months, better for PRfT (55.2%) and BC (56.3%) than for GR (47.4%). Of note, the percentage of patients with ongoing severe pain was much higher after GR (21.1%) compared with PRfT (3.4%) or BC (6.3%).¹⁵⁷ Overall, several recent analyses confirm that the results of the ablative procedures are worse in the MS group of patients when compared to non-MS patients.^{163,​ 164}

SRS/Gamma Knife surgery (GKS) is rarely used due to delay in achieving short-term pain control. However, SRS/GKS should be considered if other modalities fail. In a recent retrospective commentary, Vulpe and Wang suggest that MS-TN patients are poorer responders to SRS, both after the primary treatment and repeat SRS.¹⁶⁵

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