Trigeminal neuralgia secondary to multiple sclerosis: from the clinical picture to the treatment options

Pharmacological treatment of TN secondary to MS is challenging owing to the poor tolerability of drugs and the lack of evidence-based information in the literature. There are no placebo-controlled studies, and the studies that do exist are small, open-label trials based on carbamazepine (CBZ), lamotrigine, gabapentin, topiramate, misoprostol or combination therapies [32‐43]. These case series reported potential efficacy of lamotrigine as monotherapy or associated with gabapentin or carbamazepine, topiramate and gabapentin. Pregabalin was tested in a pilot study investigating the effect on painful paroxysmal symptoms in sixteen patients with MS, including two patients with TN [35]. Lamotrigine, with a mean dosage of 170 mg daily, significantly reduced pain related to TN in a group of 18 patients with MS [33]. In a recent, prospective, open-label, pilot study five patients with TN secondary to MS were successfully treated by a combination treatment of pregabalin plus lamotrigine [43]. The effect of topiramate was tested in six patients with MS and TN refractory to conventional medical therapy. Five out of six patients treated with topiramate (50–300 mg/day) reported complete pain relief [36]. Three studies reported efficacy of misoprostol (a prostaglandin-E1-analogue) in a total of 28 patients with TN secondary to MS [37, 44, 45]. Reder and Arnason reported that misoprostol (300–800 μg) relieved pain in six of seven patients who had failed to respond to conventional pharmacologic therapy, without serious side effects [37]. DMKG study group tested the effect of misoprostol (600 μg) in refractory TN associated with MS. Eighteen patients completed the study period and 14 of them showed a reduction of more than 50% in attack frequency and intensity beginning five days after treatment onset. There were only mild and transient drug-related side effects in three patients [45]. According to the international guidelines [18], there is insufficient evidence to support or refute the effectiveness of any medication in treating pain in TN secondary to MS. It is, however, generally agreed that the first line therapy is pharmacological and is based, as it is for classical and idiopathic TN, on the use of sodium-channel blockers, i.e. CBZ and oxcarbazepine (OXC) [46, 47]. These drugs block voltage-gated sodium-channels in a frequency-dependent manner and consequently reduce their action-potential firing frequency. Placebo-controlled trials in patients with classical and idiopathic TN demonstrated the efficacy of CBZ [48, 49], with a number needed to treat to obtain important pain relief of 1.7–1.8 [50]. However, this efficacy in classical and idiopathic TN is compromised by the tolerability, with a number needed to harm of 3.4 for minor adverse events and of 24 for severe adverse events [51, 52]. The most frequent adverse effects involve the central nervous system, and include somnolence, dizziness and postural imbalance. OXC has a comparable efficacy to that of CBZ but a greater tolerability [53] (except of the risk of hyponatremia) and a lower potential for drug interaction [54, 55]. In TN secondary to MS, many patients never advance to the regimen required for pain relief because of intolerable adverse effects. CBZ and OXC can result in adverse effects that mimic a disease exacerbation, and the sudden onset or sudden worsening of common MS symptoms may, consequently, be erroneously treated with intravenous steroids [32, 56]. As in classical and idiopathic TN, these drugs may be combined with lamotrigine, baclofen, pregabalin or gabapentin in patients that are unable to attain a full dosage of CBZ or OXC because of side effects [57].

Patients suffering from persistent pain between the paroxysms are more resistant to CBZ and OXC [57]. These drugs produce a frequency-dependent block of voltage-gated sodium channels and, thereby, by reducing the frequency of action potential firing, they effectively reduce paroxysmal pain; however, they have a far less positive effect on concomitant persistent pain. According to clinical experience, gabapentinoids and antidepressants might be more effective in persistent than in paroxysmal pain and are often tried as an add-on to OXC or CBZ in patients with the atypical form of TN with concomitant persistent pain [57]. No trial, however, has directly assessed the efficacy of this combination in patients with persistent pain and there is no evidence to support or refute its use in clinical practice [57].

A recent phase 2A study investigated the efficacy of a novel selective sodium-channel 1.7 blocker in patients with classical TN [58]. This novel drug, which targets nociceptive sodium-channel afferents and has no effect on the CNS, is likely to be tolerated better than CBZ and OXC.

Although the role of surgery in the management of TN secondary to MS remains uncertain [18], it is generally agreed that patients who do not respond to or cannot attain the therapeutic dosage required should be informed of the availability of surgery [22, 59, 60]. Reported outcomes on case series of TN patients with MS indicate that surgical procedures in such patients tend to be less effective than in patients with classical and idiopathic TN [61‐63]. The majority of available neurosurgical studies, however, are retrospective and without independent assessors of outcome.

A reduced long-term benefit in comparison with patients with classical and idiopathic TN and the occurrence of potentially serious adverse events suggest that surgical procedures should be reserved for medically refractory patients. Several authors have suggested that continuous pain in patients with TN is associated with poorer outcome after surgical intervention [47, 51] but this conclusion is still controversial. Surgical procedures include peripheral lesions distal to the ganglion, gasserian ganglion percutaneous techniques, stereotactic radiosurgery and microvascular decompression in the posterior fossa [64‐66]. The first group of surgical methods includes peripheral lesions of the trigeminal terminal nerves at their emergence from the facial bones: neurectomy, alcohol injections, radiofrequency lesions, or cryolesions. These procedures are usually well tolerated but none of these methods has ever been supported by adequate trials [67].

Percutaneous ganglion lesions include thermocoagulation by radiofrequency, chemical lesions by injection of high-concentration glycerol and mechanical compression by balloon inflation. Even though results vary in different case series, no convincing superiority of any surgical method has emerged in this patient category [68]. The major risks of all percutaneous ganglion lesion procedures are piercing of the maxillary artery and that of the dura mater covering the Meckel cave, with various possible consequences, from burning of an oculomotor nerve to infusion of glycerol into the CSF of the middle cranial fossa. Trigeminal sensory deficits are almost unavoidable; these are usually transient with balloon compression and glycerol injection and more severe and longer lasting after radiofrequency [68, 69].

Several studies with a follow-up exceeding one year have investigated the role of surgical procedures designed to lesion the Gasserian ganglion. Procedures were performed chemically by glycerol injections [61, 70‐72], mechanically by balloon compression [73‐76], or thermically by radiofrequency thermocoagulation [64, 77‐79]. Although most patients enrolled in these studies reported complete acute pain relief following the lesioning procedures, the recurrence rate during follow-up and the frequency of adverse events varied widely (Table 1). In the case series by Mohammad-Mohammadi and colleagues, a total of 96 patients underwent 277 procedures to treat TN secondary to MS, including percutaneous glycerol injection, balloon compressions, stereotactic radiosurgery, radiofrequency thermocoagulation and microvascular decompression. Symptoms recurred in 66% of patients and 181 procedures were performed for symptom recurrence. As an initial procedure, balloon compression had the highest initial pain-free response and median pain-free intervals, followed by glycerol injection [59]. There are no significant differences in the frequency of complications associated with the lesioning procedures. Each patient should thus be thoroughly informed of the advantages and limitations of each procedure, so that the most appropriate one can be chosen with the surgeon as an alternative option for the treatment of TN secondary to MS.

Other studies with a follow-up exceeding one year have investigated the role of stereotactic radiosurgery in patients with TN secondary to MS [65, 80‐83]. The probability of remaining pain-free without resorting to medication in five years and the frequency of adverse events are still unclear. In one case series of TN patients with MS who underwent stereotactic radiosurgery, only 38% of the patients were still pain-free without drugs after five years. The frequency of complications, which consist of trigeminal sensory disturbances was ranging widely from 5 to 57% [84]. A recent retrospective review of long-term outcomes involving 42 patients showed that the proportion of patients with pain relief after stereotactic radiosurgery was 62%, 29%, 22%, and 13% at 1, 3, 5, and 7 years [85]. Unlike the other types of intervention, the pain-relieving effect of stereotactic radiosurgery is not immediate and generally requires 6 to 8 weeks to develop. Another issue is the reliability and accuracy of the methods of finding the exact coordinates of the trigeminal root just before its entrance into the pons, where the radiation beams should collimate. On the other hand, stereotactic radiosurgery is associated with a lower rate of adverse events than Gasserian ganglion procedures. These two techniques may be therefore considered as valuable alternatives for treating TN secondary to MS, with the choice between them being based on the patient’s and surgeon’s preferences. Retrospective studies have compared the efficacy of stereotactic radiosurgery and Gasserian ganglion procedures [70, 86]. These studies have shown that patients treated with Gasserian ganglion procedures experience immediate pain relief and do not need to resort to TN drugs for longer periods than patients treated with stereotactic radiosurgery. In a recent study involving a small sample of patients radiofrequency thermocoagulation and stereotactic radiosurgery provide initial pain relief in 71% of patients. Over time, 60% of radiofrequency thermocoagulation and 29% of stereotactic radiosurgery patients required additional procedures to obtain satisfactory pain relief [87].

The conventional opinion that MS is an absolute contraindication to microvascular decompression, due to the supposed exclusive causative role of a demyelinating lesion affecting the trigeminal root entry zone, has been contrasted by some studies supporting the role of vascular compression in MS patients [22, 88, 89]. Neurovascular compression may act as a concurring mechanism that leads to the focal demyelination of primary afferents near the entry of the trigeminal root into the pons. This hypothesis is supported by the fact that severe neurovascular compression at the trigeminal root entry zone is found in most patients during surgery (from 50% to 100% of patients with TN secondary to MS) [20, 90, 91]. Microvascular decompression in patients with classical TN produces immediate pain relief in the majority of patients. However, when applied to patients with TN secondary to MS, this technique is generally reported to be less effective than in patients with classical TN. Indeed, after five years fewer than 50% of the patients in the case series described by Broggi and 15% in the case series described by Ariai were still pain-free (in comparison with approximately 80% of pain-free patients after surgery for classical TN). The adverse event rate of microvascular decompression is very low. In the two aforementioned case series, only one patient suffered long-term morbidity (facial nerve palsy). In larger case series by Barker et al. on microvascular decompression in patients with classical TN, the rate of adverse events was also low but included death (0.2%), brainstem infarction (0.1%), cerebellar hematoma and edema (0.5%) and severe or permanent cranial nerve damage (3%). This major surgical procedure requires general anesthesia, intubation and craniotomy. Given the serious nature of some of the reported adverse events, thorough presurgical patient information is important [92].

The reduced efficacy of microvascular decompression in TN secondary to MS points to the crucial role of the pontine demyelinating plaque in most patients with this form of TN; however, the observation that this surgical procedure is still effective in many patients lends support to the involvement of neurovascular compression in TN secondary to MS. On the other hand, we cannot exclude that, during microvascular decompression, manipulation of the trigeminal root may be a sufficiently traumatic procedure to disrupt the parossistic discharge behaviour of the axons. Before drawing definitive conclusions, we must await further high-quality evidence demonstrating that microvascular decompression is indeed an effective technique. Further studies using advanced neuroimaging techniques like diffusion tensor imaging (DTI) and 3.0 Tesla MRI are also warranted. Possibly, such studies have the potential to identify the trigeminal anatomical abnormalities that can predict the outcome of the different neurosurgical procedures and thereby guide future clinical decision-making and patient information.