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Trigeminal neuralgia is characterized by recurrent paroxysms of severe facial pain, radiating along the distribution of one or more of the trigeminal nerve branches. In 90% of cases it is caused by vascular compression of the trigeminal nerve (primary TN), whereas in the remaining minority it is a result of an underlying disease state, e.g. multiple sclerosis (secondary TN). Axonal demyelination, common in both types of TN, sets off an ephaptic cross-talk between light-touch and pain fibres of the trigeminal nerve. Consequently, light tactile stimuli are often sufficient to provoke the paroxysms of facial pain. A history of recurrent episodes of unilateral lancinating pain with asymptomatic intervals is a diagnosis of primary TN; whereas evidence of bilateral pain with loss of corneal reflex may suggest secondary TN. The management of TN is aimed at improving quality of life. Pharmacological therapy with anticonvulsants is often adequate, but surgery is considered if this proves ineffective. Carbamazepine is used as a first-line treatment but uncertainty remains as to which drug to use if carbamazepine cannot be tolerated. Studies suggest oxcarbazepine or gabapentin as second-line treatments. Other drugs to consider are lamotrigine, baclofen and phenytoin. Surgical procedures include microvascular decompression, percutaneous ablative procedures, and gamma-knife radiosurgery.
Lack of high quality evidence makes it difficult to evaluate the effectiveness of the majority of these therapeutic options, thus the ideal approach to treatment remains obscure. This report aims to highlight such shortcomings in our current knowledge. It will present the underlying health problem (TN) and provide a comparative analysis of the evidence available for its management, with an attempt to propose an algorithm of treatment.
Trigeminal neuralgia (TN) is a chronic neuropathic pain syndrome that occurs in the sensory distribution of the fifth (trigeminal) cranial nerve (Kumar and Clark, 2005). Sensory fibres of this nerve supply the skin of the face, the oronasal mucous membranes and the teeth, the dura mater and major intracranial blood vessels (FitzGerald et al., 2007). They form 3 divisions, the ophthalmic (V1), maxillary (V2) and mandibular (V3), which pass to the Gasserian ganglion at the apex of the petrous temporal bone (figure 1). From here central fibres enter the brainstem and divide into ascending and descending fibres. The former transmit light touch sensation to the pons, while the latter transmit pain and temperature sensation to the medulla oblongata. The trigeminal nerve also sends motor fibres to the muscles of mastication. These arise in the upper pons and join the mandibular branch of the sensory division (Kumar and Clark, 2005).
TN most typically affects the maxillary and mandibular branches either alone or in combination, with infrequent involvement of the ophthalmic branch (Bennetto et al., 2007) (figure 1). Facial pain is nearly always unilateral and radiates within the territory of distribution of one or more of the affected sensory branches. Paroxysms last seconds to minutes. They may be infrequent, occurring over many years or frequent, occurring several times a day, with spontaneous episodes of remission (Cruccu et al., 2006). TN most commonly presents after the age of 40, and has a slight female predominance (5.9 females compared to 3.4 males per 100,000). It is usually sporadic, even though there have been some reports of genetic predisposition (Hall et al., 2006). The condition is often unrelated to an underlying disease state, but can also occur in 1-2% of patients with multiple sclerosis (MS). Although TN appears to be relatively uncommon, with an annual incidence of 4.7 per 100,000 in the UK (Hall et al., 2006), it causes unbearable pain that responds poorly to analgesics.
Research has thus been devoted to study the causes, pathophysiology, diagnosis and management of TN. Despite the wide range of medical and surgical treatments that have been introduced, these have been largely based on non-randomized controlled trials, which ultimately pose an uncertainty as to how best to use available interventions.
(B)The first aim of this report is to provide a thorough description of TN to facilitate our understanding on the treatment propositions. The second aim is to present a comparative analysis of available evidence on the management of TN and finally suggest an algorithm of treatment.
(A) C:\Users\user\AppData\Local\Microsoft\Windows\Temporary Internet Files\Content.Word\diagram0001.jpg
Figure 1: The Distribution of the Trigeminal Nerve and Trigeminal Neuralgia: (A) Sensory input of trigeminal nerve (red); Motor input of facial nerve (blue). SOF: superior orbital fissure; FO: foramen ovale; FR: foramen rotundum; GG: Gasserian ganglion; SF: stylomastoid foramen (B) The maxillary division (V2) is affected in 35% of cases, followed by the mandibular division (V3) in 30% of cases and the ophthalmic division (V1) being the least affected in only 4%. Simultaneous V2 and V3 pathology is more common (20%) than combined V1 and V2 (10%), while pathology in all three trigeminal divisions is rare (1%).
Adapted from Kumar and Clark 2005; (B) adapted from Bennetto et al., 2007
Description of Trigeminal Neuralgia
Aetiology and Pathophysiology
The precise aetiology of TN remains obscure, but evidence suggests that focal demyelination of the trigeminal nerve root is involved in its pathogenesis (Love and Coakham, 2001). Primary TN occurs when there is no visible organic cause other than vascular compression; whereas secondary TN is a complication of an underlying disease state (Zakrzewska, 2002).
Jannetta (1967) was the first to recognize that primary TN is caused by compression of the trigeminal nerve root by an aberrant loop of artery or vein, at the point of entry into the pons. This is the point where fibres subserving light touch and those involved in pain lie in closest proximity. It is now well known that vascular compression accounts for 90% of cases of TN. It causes demyelination of the trigeminal nerve and close apposition of demyelinated axons (Hilton et al., 1994). This makes axons prone to ectopic impulses, which transfer from light touch fibres to nearby pain fibres by ephaptic conduction. Love and Coakham (2001) have proposed the superior cerebellar artery as the most likely offending vessel due to its close proximity to the trigeminal nerve root.
Secondary TN is far less common than primary (10%) and can be caused by a variety of non-vascular compressive lesions e.g. meningiomas, epidermoid cysts, schwannomas or osteomas (Mohanty et al., 1997; Kato et al., 1995). In such cases, compression of the trigeminal nerve at the root entry zone can be mediated by the tumour itself and in some cases cause neuralgia on the contralateral side of the mass lesion (Matsuura and Kondo, 1996). Nonetheless, all available research presents secondary TN as a well-recognized complication of MS. Pathological analysis of trigeminal rhizotomy specimens from MS patients have identified demyelinated axons comparable to those seen in non-MS specimens with primary TN. Additionally, in MS specimens there has been evidence of lipid-laden macrophages revealing disease activity (Love et al., 2001). Secondary TN can also be a consequence of myelin sheath infiltration of the nerve, the nerve root or the Gasserian ganglion by a tumour or amyloid (Bornemann et al., 1993). Once all above possible causes of TN have been excluded, there remains a small proportion of cases which are idiopathic (Nurmikko and Eldridge, 2001).
Despite differences in the aetiology between primary and secondary TN, focal demyelination and ephaptic cross-talk between light touch and pain pathways is also a feature of secondary TN (Love et al., 2001). This cross-talk may explain why light tactile stimulation is often sufficient to provoke paroxysms of trigeminal neuralgia. Brushing of the teeth, talking, smiling, chewing, shaving and even thermal stimulation i.e. wind or cool temperature on the face are examples of trivial stimuli that provoke pain (Bennetto et al., 2007). Paroxysms may be so profound that patients may avoid grooming or washing on the affected side of the face, or avoid even the slightest stimulation of trigger zones, which are pathognomonic for TN (Nurmikko and Eldridge, 2001).
Prompt diagnosis and management of TN is critical to avoid development of the 'atypical' state, which is refractory to treatment. Atypical TN is defined as primary TN, which has been left untreated over time and has resulted in a change in pain character from the (typical) paroxysms of shooting pain to the (atypical) persistent dull pain, associated with mild sensory impairment (Burchiel and Slavin, 2000) .
Patients with TN present with a description of recurrent episodes of severe unilateral facial pain, characterized as "sharp", "shock-like" and "stabbing", which occurs in the distribution of one or more divisions of the trigeminal nerve (International Headache Society , 2004)). It is initially localized to one division, usually V2, but with time it tends to spread to other divisions and increase in severity. Rarely does the first paroxysm of pain occur in V1, but it may spread to the forehead from the cheek and later appear to start from behind the eye (Jennett and Lindsay, 1994). The right side of the face is more commonly affected than the left due to narrower foramina (Neto et al., 2005). Pain may be preceded by symptoms of tingling or numbness and precipitated from trigger zones or by triggers of light tactile sensation. The fact that it is elicited by minimal tactile stimuli may render patients almost frightened to move, walk or eat during the period of attacks. This can furthermore lead to consequent complications of weight loss and depression (Nurmikko and Eldridge, 2001). Episodes last several seconds but rarely occur during the night. Moreover, spontaneous remissions may last months or years before recurrence, the latter of which is almost inevitable (Kumar and Clark, 2005). Patients are usually asymptomatic between paroxysms of pain, unless they suffer from atypical TN. In rare cases (3-5%) pain may become bilateral, either soon after the onset or after years of unilateral pain. Studies have shown that there is a greater incidence of bilateral pain in secondary TN (18%) than in primary TN (5%), making MS the predisposing factor (Brisman, 1987).
An accurate history may reveal the stereotyped paroxysms of unilateral pain with asymptomatic intervals typical of primary TN, or prove useful for differential diagnoses. For example, a patient presenting with bilateral pain and additional neurologic symptoms such as dizziness, ataxia, unilateral vision changes and focal weakness will prompt the practitioner to consider TN secondary to MS (Zakrzewska, 2002). Furthermore, an evaluation of differential diagnoses is often indicated in younger patients since TN is unusual below the age of 40 (Cruccu et al., 2006), and because other causes of facial pain are much more common than TN (Table 1). Rarer alternatives to TN also exist, many of which are manifested as forehead pain that is relatively uncommon in TN e.g. cluster headache (Bennetto et al., 2007).
Features that help distinguish from TN
Dental infection or cracked tooth
Pain well localized to tooth
Local swelling and erythema
Confirmed by dental examination
Temporomandibular joint pain
May radiate behind ear, to neck and temples
Limited jaw opening than can produce an audible "click"
Pain often preceded by aura
Severe unilateral headache
Nausea, neck stiffness, photophobia and phonophobia
Atypical facial pain
Bilateral and may extend out of trigeminal territory
Often continuous, mild to moderate severity
Throbbing in character
Temporal pain; constant
Often associated with jaw claudication, fever, weight loss
Temporal arteries may be firm and non-pulsatile
Common in the elderly
Table 1: Common Differential Diagnoses that can be easily distinguished from TN
Own table produced in Microsoft Word. Data obtained from Bennetto et al., 2007.
Differentiating between primary and secondary TN (and an alternative cause of facial pain) is important to direct appropriate treatment. In the latter, treatment should focus on the underlying condition. Overall, persistent pain that occurs in episodes lasting more than 2 minutes should highlight the possibility of differential diagnoses (International Headache Society, 2004).
Useful diagnostic clues can also be obtained by close observation. The patient may present with a scarf around the head and talk very little or out of the corner of the mouth. In addition, there may be evident signs of weight loss and dehydration from not eating, and a dirty face from not washing or shaving (Jennett and Lindsay, 1994).
Neurologic examination is normal in patients with primary TN and the finding of trigger zones verifies the diagnosis. If the examination shows absence of corneal reflex, sensory abnormalities in the trigeminal territory, or weakness in facial muscles, it should alert the physician to consider secondary TN or other causes of facial pain (Krafft, 2008). Following this, additional investigations should be performed to (1) verify the differential diagnosis e.g. dental X-rays if there is dental pain, and (2) to identify a plausible cause, especially when there is a view to surgical cure e.g. brain MRI (Patel et al., 2003).
Management of Trigeminal Neuralgia
The goal is to achieve optimal control of the condition by eliminating the pain or at least reducing it to an acceptable level to improve quality of life (Lim and Ayiku, 2004). Pharmacological therapy is usually adequate; however, if pain control cannot be achieved or side-effects of drugs are unacceptable, then surgical options should be considered.
Anticonvulsants are the most effective drugs for managing TN and have become the mainstay treatment despite limited randomized-controlled trials (RCTs).
The first-line treatment for TN is almost always carbamazepine (Tegretol) (100-1600mg/day). It reduces the severity of attacks for approximately 75% of patients (Wiffen et al., 2005). Due to its effectiveness, it has replaced the original drug of TN (phenytoin), and response to carbamazepine is diagnostic for the condition (Sindrup and Jensen, 2002). RCTs have shown that compared to placebo, carbamazepine has been more effective in providing pain relief in the short-term (5-14 days), but less effective in long-term pain control (5-16 years) (Rockliff and Davis, 1966). Nevertheless, carbamazepine has shown to lower both the intensity and frequency of pain paroxysms and the number needed to treat (NNT) is less than 2 (Campbell et al., 1966). One of the major limitations with carbamazepine is that its efficacy is largely compromised by its dose-related adverse effects. These include drowsiness, ataxia, decreased mental acuity, nausea and constipation (Canavero and Bonicalzi, 2006). For this reason it is important to build up the dose slowly with increments of 100 mg every 3 days, starting with 300 mg a day, and using the lowest dose possible for maintenance (NHS Clinical Knowledge Summaries, 2009). Evidence has further described leucopenia, rashes and abnormal liver function tests as common side-effects of carbamazepine. In addition, bone suppression can rarely occur and drug interactions, e.g. with warfarin, may further limit carbamazepine's use (Wiffen et al., 2005). Observational data has shown that 6-10% of patients cannot tolerate carbamazepine (Taylor et al., 1981). If this is the case, or if carbamazepine proves ineffective for pain relief, alternative anticonvulsants should be considered and these may substitute or replace carbamazepine as required.
Oxcarbazepine (Trileptal) is a pro-drug of carbamazepine, with equivalent efficacy in pain relief (600-1800 mg/day). This is evident by a double-blind cross-over trial that showed that both drugs reduced the frequency of pain attacks by 50% from the baseline after 4-6 weeks of treatment (Zakrzewska and Patsalos, 2002). Although the data was not significant, a comparable analgesic effect has been confirmed by subsequent double-blind RCTs (Beydoun et al., 2002). The major advantage of oxcarbazepine over carbamazepine is that it is better tolerated owing to fewer adverse effects. Studies have reported incidences of dizziness, ataxia, and fatigue; however cases were fewer than those reported with carbamazepine (Carrazana and Mikoshiba, 2003). Contradictory data has shown that the efficacy of oxcarbazepine decreases over time (Zakrzewska and Patsalos, 2002); however it could be argued that this is largely due to increase in disease severity rather than in drug tolerance per se. Although oxcarbazepine is not licensed for use in the treatment of neuralgias in the UK, it can be used in clinical practice when there is evidence of benefit (NHS Clinical Knowledge Summaries, 2009).
Lamotrigine (Lamictal) and Baclofen (Lioresal) can be used in combination with the first-line treatment in patients who are refractory to carbamazepine or oxcarbazepine, and particularly in those who have refused or cannot undergo surgery (Zakrzewska et al., 2005). Due to lack of good quality evidence to support their use, they are not recommended for primary care of TN. One small double-blind RCT found that in 14 people already using either carbamazepine or phenytoin, addition of 400 mg of lamotrigine increased the number of those who improved after 4 weeks of treatment (77%), compared to those who received an add-on of placebo (57%) (Zakrzewska et al., 1997). It should be noted however that the short duration of treatment as well as the simultaneous use of other drugs limits the interpretation of these results. Importantly, lamotrigine is most effective when used for long-term control of moderate pain. It requires a slow escalation of dosage to avoid allergic reactions e.g. skin rash (Canavero and Bonicalzi, 2006), and this subsequently renders it inappropriate for the acute management of TN.
Carbamazepine, phenytoin, oxcarbazepine and lamotrigine act by binding to voltage-gated sodium channels in the inactivated state, preventing them from returning to the resting sate (Rang et al., 2007). This reduces the number of functional channels available to generate action potentials, thus effectively reducing ectopic discharges in the trigeminal ganglion. Baclofen on the other hand is a selective agonist of GABAB receptors. Its antispastic action is attributed to its ability to inhibit both monosynaptic and polysynaptic activation of motor neurons (Rang et al., 2007) and therefore proves useful in the treatment of spasticity associated with MS. Three RCTs have been conducted to investigate the effect of baclofen in TN, but these have provided insufficient evidence of benefit (Fromm et al., 1984; Fromm and Terrace, 1987; Parekh et al., 1989). Despite this, it may be useful for pain control in MS patients with secondary TN, who are already taking baclofen and may not require additional carbamazepine therapy.
Several open-label trials have proposed therapeutic benefit from a number of other anticonvulsant drugs i.e. gabapentin (Neurontin), clonazepam (Klonopin) and sodium valproate (Epilim). Although, 64% of patients taking clonazepam showed improved pain relief, intolerable sedation and dizziness was reported in over 60% (Court and Kase, 1976). Moreover, sodium valproate is at least as effective as carbamazepine, but nausea and disturbance in hepatic function restrict its effective use (Diamond and Coniam, 1997).
Gabapentin is licensed for neuropathic pain; however evidence for its use in TN is insufficient. Studies have shown that fewer patients improve with gabapentin than with carbamazepine, and over 50% of patients experience no pain relief (Cheshire, 2002). In contrast to this, two RCTs have shown that gabapentin is effective in the treatment of diabetic neuropathy (Backonja et al., 1998) and post-herpetic neuralgia (Rowbotham et al., 1998). Moreover, MS patients have reported substantial pain relief with gabapentin in three open label studies (Khan, 1998; Solaro et al., 1998; Solaro et al., 2000). In addition, the effectiveness of gabapentin has shown to be significantly increased when used in combination with lamotrigine or carbamazepine in idiopathic TN (Solaro et al., 2000). The mechanism of action of gabapentin greatly differs from other anticonvulsants. It interacts with Î±2Î´ subunit of T-type voltage-gated calcium channels, increasing the concentration and the rate of synthesis of GABA within the brain, consequently suppressing pain at the level of the central nervous system (Rang et al., 2007). The use of gabapentin in the management of TN appears rather promising. It is associated with mild dose-related adverse effects (mainly sedation and ataxia); it is neither metabolized nor bound to serum protein; and interactions with other drugs are rare (Cheshire, 2002). Due to this favourable safety profile, one could argue that gabapentin is more advantageous than commonly used drugs in TN, particularly for the elderly who have a narrower window of tolerability. This may explain why it is commonly recommended as a substitute of carbamazepine by the NHS, in doses starting at 300 mg/day and titrated in increments of 300mg/day every 2-3 days, up to a maximum of 3600 mg/day (NHS Clinical Knowledge Summaries, 2009). Nevertheless, high-quality evidence is required to compare the effectiveness of gabapentin to alternative treatments and subsequently justify its use in TN.
Having analyzed the available research, there are evidently numerous shortcomings in our current knowledge regarding the management of TN. There is insufficient data to support the efficacy of alternative drugs used in cases of allergy or intolerance to carbamazepine. In addition, there are no studies investigating the probability of a patient responding to a second or third drug if the initial medication fails. Although most trials are add-on designs, there are no published studies that directly compare the efficacy of polytherapy with monotherapy (Jorns and Zakrzewska, 2007). Furthermore, despite the availability of open labelled studies demonstrating the use of baclofen and gabapentin in MS patients with TN, there are no RCTs assessing the effectiveness of these or other drugs in secondary TN. Finally, gabapentin, as well as tricyclic antidepressants have been shown to be effective in managing other neuropathic pains but their use in TN remains unconfirmed (Bennetto et al., 2007).
Surgical procedures can be divided into three types, namely microvascular decompression, percutaneous ablative techniques, and gamma knife radiosurgery (Bennetto et al., 2007). Deciding on which procedure to use depends on patient and disease characteristics, expert skills, equipment availability, as well as patient choice. Subsequently, patients need to be well informed about the options available, as well as the related risks and likely outcomes associated with each procedure.
This is the most radical option since it involves open-skull surgery to directly expose the trigeminal rootlets in the cerebellopontine angle. Nevertheless, its attractive point is that it removes the cause of pain and avoids unpleasant sensory side-effects. It involves interposing a small piece of sponge between the artery and nerve at the dorsal root entry zone, which provides pain relief to 80% of patients (Jennett and Lindsay, 1994). The most common side effects are hearing loss, aseptic meningitis, haematomoas, infarcts and CSF leaks. Although it offers the best cure rates, it is associated with a mortality risk of 1% and threat of serious morbidity. For this reason, it is reserved for patients under the age of 70 years in good general health (Barker et al., 1996).
Percutaneous ablative procedures
These include radiofrequency thermoregulation rhizotomy, retrogasserian glycerol rhizolysis ad trigeminal ganglion balloon compression (Krafft, 2008).
Radiofrequency thermoregulation rhizotomy involves insertion of an electrode through the foramen ovale that produces sensations (paraesthesias), identified by the patient at the site of original pain. Once the patient is sedated, the electrode is heated to produce a radiofrequency lesion at the previously located pain site and subsequent analgesia in the target facial area (Jennett and Lindsay, 1994). Although studies report a success rate of over 70%, this procedure tends to produce larger areas of altered sensation that are more troublesome than the original pain (Lopez et al., 2004). Barker et al., (1996) have shown that 75% of 179 patients have reported facial pain and numbness after thermal rhizotomy, as compared to 22% after microvascular decompression.
Glycerol rhizolysis involves insertion of a needle through the foramen ovale into the trigeminal (Meckel's) cave and injection of glycerol, which damages the trigeminal nerve and blocks pain signals (Jennett and Lindsay, 1994). Pain relief is achieved in 70-80% of people, although some have reported recurrence of pain and the majority experience facial numbness (Fujimaki et al., 1990).
Balloon compression involves insertion of a hollow needle in the Meckel's cave, followed by passage of a catheter through the needle. A balloon at the end of the catheter is inflated with a non-ionic radiocontrast solution to produce enough pressure as to damage the nerve and subsequently block pain signals (Jennett and Lindsay, 1994). Although the success rate is 70%, spontaneous remission of pain has been reported in the majority of patients accompanied by temporary or permanent weakness of the muscles of mastication (Lopez et al., 2004)
Percutaneous techniques have an advantage over microvascular decompression in that they are relatively non-invasive, require a short hospital stay, and have lower rates of mortality (Bennetto et al., 2007). Nevertheless, they are associated with higher rates of TN recurrence and sensory impairment.
This is the latest technological development, approved by NICE in 2004. It provides effective pain relief within 48 hours for 72-96% of patients with a complication rate of only 4-6% (Lim and Ayiku, 2004). These include, facial numbness, paraesthesias and worsened trigeminal nerve dysfunction. Despite this, it demands a very accurate stereotactic system with expert skill and given the limited number of gamma knife machines in the UK, access to this treatment is limited (Lim and Ayiku, 2004). It involves delivering a high-dose focused radiation to the trigeminal root that damages the trigeminal nerve to reduce or eliminate pain (Kondziolka et al., 1996). Pain recurrence is lower compared to percutaneous ablative procedures but higher than microvascular decompression. In addition, owing to the novelty of this procedure and the limited amount of research available, technical failures are high (Lim and Ayiku, 2004).
Overall, it appears that all surgical techniques are effective in providing initial pain relief but none of the techniques provide long-term cure. Moreover, studies have postulated that patients with secondary or atypical TN have less favourable pain relief than those with primary TN (Lim and Ayiku, 2004). As with the pharmacological management of TN, research is largely based on case series reports, which are difficult to compare due to differences in sample size, diagnostic criteria and outcome measures. Subsequently, direct comparison between surgical treatments could be achieved more reliably with RCTs and future research should also examine patient
Trigeminal neuralgia is a relatively uncommon pain syndrome usually caused by vascular compression of the trigeminal nerve or, in the minority of cases, as a result of an underlying condition. The pain is intolerable and neuropathic in nature, and responds poorly to analgesics. As a consequence of this, it has drawn the attention of research studies that attempt to explore plausible options of management. Carbamazepine remains the most effective drug, but should be used with caution in elderly patients in whom benefits are outweighed by side-effects. For those who are intolerant to carbamazepine, oxcarbazepine or gabapentin are the drugs of choice owing to their favourable safety profile. Although gabapentin is licensed for use in neuropathic pain, there is insufficient evidence to justify its effectiveness in TN. Alternative drugs to consider are lamotrigine, baclofen, clonazepam and sodium valproate. Lamotrigine is not recommended for the acute management of TN and the long-term efficacy of baclofen remains to be evaluated. It appears that there are no set rules as to which treatment regimen offers the best results. Rather, patients are encouraged to keep pain diaries that will help them, and practitioners, adjust the therapy to the fluctuating paroxysms of TN. Owing to the clinical presentation of the condition, researchers should consider assessing patients before and after trials to investigate the possibility of pain remission. If medical therapy fails, this should prompt a review of the diagnosis and surgical options should then be considered. Microvascular compression remains the gold standard method for treatment of TN in young, healthy patients. Percutaneous ablative procedures on the other hand are particularly attractive for elderly patients who cannot tolerate a craniotomy, and in cases where TN involves multiple trigeminal nerve divisions (V2 and V3). Gamma knife radiosurgery is probably a good choice when TN is restricted to a single division (V1).
Most of our knowledge about the management of TN appears to be based on case series and open-labelled trials that vary in the number of patients studied, lack standardized outcome measures, and have ill-defined diagnostic criteria. In addition, there is insufficient evidence for the management of patients who are contraindicated for surgery, as to which drug should be used if the initial medication fails. Moreover, given that the aim of treatment is to improve quality of life, measuring this factor in research studies would seem a rational choice yet it has rarely been considered. Due to the severity of TN it may be unethical to carry out placebo-controlled trials, nevertheless high-quality RCTs are evidently required to shed light to the unexplored issues of management.