Radiosurgery for Functional Disorders and Epilepsy

Introduction

Trigeminal neuralgia (TN) is currently the most common among functional indications (approximately 90%) in the radiosurgical field, as stated by the Leksell Gamma Knife Society statistics. It has been named “tic douloureux” by Nicholas André, a French neurosurgeon. The prevalence is rare, 12.6 per 100,000 persons, and remains a serious health problem.

The most accepted pathophysiological theory for TN appearance is the one of a neurovascular conflict at the root entry zone (REZ), close to or at the point of the entry of the nerve in the pons, either by arterial (very frequent) or venous (rare) loop. In close relation to this, Love et al. supported the principle of a demyelination process of trigeminal sensory fibers within either the nerve root or, less common, the brainstem. Although intimate pathophysiological mechanisms remain largely undiscovered, remyelination is considered responsible by some authors for the spontaneous remissions or relief after surgical treatments.

Diagnosis remains clinical and should be performed before any procedure is considered. The clinical semiology for classical trigeminal neuralgia (CTN) is typical, while people usually present a severe and unexpected pain in the face, described as an electric shock. CTN, including all cases without established etiology (the so-called idiopathic), must be separated from symptomatic TN. Classical TN is usually associated with more than 50% episodic pain, while the former with more than 50% constant pain, as stated in the classification by Burchiel et al. An MRI is mandatory to exclude any secondary cases related to tumor, multiple sclerosis (MS), arteriovenous malformations, etc.

TN is a fascinating disease and its surgical treatment is one of the most ancient neurosurgical indications, which actually started far before the medical therapies of this disease. As a brief historical vignette, the first intervention for TN targeted the Meckel cave and has been named “gasserectomy” and proposed by Wears in 1885 and performed by Roos in 1890, followed by Hartley, Horsley, and Cushing. In 1920, Dandy developed a neurotomy at the level of the entrance in the pons. The decompression of the gasserian ganglion by the opening of the roof of the Meckel cave proposed by Taarnhoj in 1952 was also rapidly abandoned due to its poor efficacy. Subsequently, first through a direct approach (Shelden 1955) and then through percutaneous approach, physical treatments of the gasserian ganglion have been investigated. Thermocoagulation (Kirshner 1933; Sweet 1969), compression (Mullan 1979), and glycerol alcoolization (Hâkanson 1981) were developed and extensively practiced. Microvascular decompression (MVD, the reference technique) of the cisternal trigeminal nerve first, attempting to treat the main cause of the Tic, performed by Gardner in 1959 and then popularized by Janetta in 1966, became the reference technique. In 1951, the first historical cases of stereotactic radiosurgery (SRS) for TN in human were performed by Lars Leksell, at the level of the gasserian ganglion, based only upon X-rays films. Furthermore, SRS and particularly Gamma Knife radiosurgery (GKR) have created what we called a “revolution in functional neurosurgery,” with a constant increase of numbers in minimally invasive procedures and especially for TN (but not only), and a demonstrated safety and efficacy. The first therapeutic line is pharmacological with carbamazepine. Initial effectiveness has been reported in nearly 90% of patients and is the only antiepileptic drug demonstrated in randomized controlled trails to reduce both the intensity and frequency of the attacks.

Stereotactic Radiosurgery for Trigeminal Neuralgia: Historical Insight

The initial target used by Leksell was the gasserian ganglion, successfully applied to 40 patients, described initially by Leksell himself and further by Lindquist. In the early 1980s, Hâkanson noticed that glycerol injection, used for a better visualization of the Meckel cave, was very efficient in relieving TN. The former, in combination with poor imaging techniques at that time, limited the use of SRS for TN until the early 1990s. However, the appearance and further development of MR techniques allowed better visualization of the trigeminal nerve and more accurate targeting. The former, in conjunction with the clear limitations of both medical and surgical techniques, produced a real renaissance in the use of SRS for TN, in what was called “a revolution in functional neurosurgery.” Moreover, other targets have been proposed. Rand et al. suggested using the trigeminal cisternal part and reported a series of 12 patients with almost 70% initial pain relief. In 1993, Lindquist came with the elegant suggestion to target the REZ (improperly called dorsal root entry zone [DREZ] in the literature) with a 4-mm shot and a dose of 70 Gy at the 100% isodose, “including the nerve root and adjacent brainstem within the 50% isodose surface (35 Gy).” After the seminal paper of Kondziolka et al., the use of SRS in TN on large scale went toward a rise in functional neurosurgery, with most of the published data being the Gamma Knife (GK) series. In Marseille and in Lausanne, it has been used since the very beginning a very anterior (retrogasserian) target, located 7 to 8 mm from the entrance of the nerve into the pons. ^, The only randomized controlled trial was published in 2006 by Régis et al. The long-term results using this technical strategy were published in 2016. Kondziolka et al. and, respectively, Régis et al. reported the results for the REZ and the anterior cisternal target for long-term follow-up periods, reporting patients without medication at 10 years. These two studies are the only ones in the current literature reporting long-term follow-up.

In 2018, the International Stereotactic Radiosurgery Society (ISRS) published a systematic review in an attempt to establish guidelines and evaluate the level of evidence of SRS for CTN.

Outcome Measures

A vast majority of studies reported outcomes using Barrow Neurological Institute (BNI) Pain Intensity Scale or variations from the former: I, complete pain relief without medication; II, some pain, but still requiring medication; III, some pain, but adequately controlled with medications; IV, some pain, but inadequately controlled with medication; V, continued severe pain or no pain relief. However, there are additional heterogenic scales to report outcomes, which makes it somehow difficult to compare all the published series under the same umbrella.

Stereotactic Radiosurgery Procedure for Trigeminal Neuralgia

GK uses a stereotactic head-frame immobilization. The Leksell stereotactic G frame (Elekta Instruments, AB, Sweden) is fixed on the patient’s head under local anesthesia in such a way to make it parallel to the intracisternal part of the fifth cranial nerve, which can be accomplished by correspondence of the plane of the frame base to the orbitomeatal plane. The projection of the trigeminal incisura of the petrous bone can be localized 1.5 cm anterior and 1.5 cm superior to the external auditory meatus. This former point was positioned close to the center of the Y-axis with appropriate adjustment in the Z-axis. Linac-based systems are based on stereotactic head-frame immobilization or facial mask with image guidance. In the vast majority of studies, a spherical dose distribution is delivered by 5 to 7 noncoplanar arcs through a circular collimator (4 to 5 mm). The CyberKnife treatment necessitates facial mask immobilization, and the radiation dose is delivered by an X-band Linac, mounted on a robotic arm, and guided by real-time imaging-assisted target tracking. The CyberKnife dose plan is prepared using a CT image that is further fused with MR image for delineation of the nerve and brainstem. A 5- or 7.5-mm cone and trigeminal node set, which has shorter source-to-axis distance, are used.

Technical Nuances

Target Placement

Four types of targets or targeting manners have been reported to date: (1) Gasserian ganglion (Leksell); (2) REZ (Lindquist); (3) retrogasserian, cisternal, or far anterior (Marseille, Lausanne) ( Fig. 97.1 ); and (4) irradiating a longer nerve length (several CyberKnife studies, reproduced in the GK randomized controlled trial by Flickinger). The classical cisternal target is defined at 7 to 8 mm from the entrance of the nerve in the brainstem, using a unique 4-mm shot and a high dose of radiation, 90 Gy at the 100% isodose. The REZ target (improperly called DREZ target) is the one at the level or very close to the edge of the pons. This zone is characterized by the passage from the peripheral (Schwann cells) to central (oligodendrocytic cells) myelin and might be very variable in terms of location, as demonstrated by De Ridder. As it is impossible to evaluate this in vivo, the term DREZ target should be used cautiously as it remains somehow inappropriate.

There are three comparative studies of the anterior versus posterior target: Matsuda et al. (anterior target, which was very close to the plexus triangularis, as initially described by Leksell, so much more anterior than the one described by Régis et al.), Park et al. (similar range of doses, the anterior target had better outcomes, with a similar rate of pain relief and fewer bothersome complications), and Xu et al. (facial numbness [BNI score II and III] was more frequent in the proximal REZ group compared to the distal one [53% compared to 25%, P = .015]). They concluded a similar efficacy rate for both, with higher toxicity for the REZ one.

The clinical impact, especially in terms of complications, and depending on the target, is not the same. Gorgulho et al. at UCLA published a series of 126 patients, treated with a 4-mm shot at the entrance of the nerve in the pons, with 90 Gy at the center. The hypoesthesia rate was 58.3% (30.5% subjective dry eye; 30.5% decreased corneal reflex). John Adler reported a CyberKnife series (DREZ target), while treating a considerable volume of the TN. He used single fraction SRS, a median marginal dose of 62 Gy, and a mean length of the treated nerve of 6.75 mm (range 3 to 12). Pain relief was not higher than other published data, but there was a dramatic increase in toxicity, with 74% numbness rate (39% severe numbness). Unlike the series of Adler et al., Fariselli et al., who used also a CyberKnife after limiting the brainstem radiation dose to 14 Gy, reported no bothersome facial numbness.

Currently, based upon level 2 evidence, as given by comparative studies, ISRS guidelines favor an anterior target. Furthermore, from studies analyzing the dose-volume histograms (DVH), there is evidence that increasing the dose to the REZ and/or the brainstem (VB20, VB50, etc.) will increase the probability of numbness appearance, which further might have an important impact on patient’s quality of life.

Predictors for Initial Pain Relief (During the First 6 Months After Stereotactic Radiosurgery)

Pretherapeutic positive predictors for initial pain relief (during the first 6 months) are age more than 70 years ^, and typical pain, while negative predictors are atypical pain component, ^, prior surgery, ^{, ,} previous MVD, distance between the isocenter and the emergence of the nerve greater than 8 mm, and MS. ^,

The particular aspect of a neurovascular conflict and its incidence on efficacy and toxicity has been analyzed in several studies. As an example, Massager et al. found no statistically significant relationship. Moreover, Sheehan et al. retrospectively analyzed 106 cases, treated with GKR as a first intention treatment, using the REZ as a target and a mean maximal dose of 78.7 Gy (range 70 to 90), with a median follow-up period of 31 months. Sixty-three cases (59%) had a neurovascular conflict. The authors established that there was no significant relationship in pain relief between those with and without vascular impingement.

Another relevant question is related to the incidence on the safety/efficacy of the presence or absence of a contrast enhancement on the targeted nerve. Massager et al. studied a group of 78 patients treated with GKR for TN. Target accuracy was assessed from deviation of the stereotactic coordinates of the intended target compared with the center of enhancement on postoperative MRI. The authors concluded that the median deviation found in clinical assessment of GKR for TN was low and compatible with its high rate of efficiency. Furthermore, in their experience, focal enhancement of the trigeminal nerve after radiosurgery (RS) occurred in 83% of the cases and was not associated with clinical outcome.

Our Group’s Perspective

Our recommendation is to place a unique 4-mm shot on the cisternal portion of the trigeminal nerve, at a median distance of 7.6 mm (range 4.5 to 14) from the entrance of the nerve into the brainstem. The median maximal dose (100%) was 85 Gy (range 70 to 90). We usually start by prescribing 90 Gy at the 100% isodose line. We further evaluate the dose received by the brainstem on the first 10 cubic millimeters. If this dose is more than 15 Gy, we decrease the dose and even use plugging if necessary, avoiding the so-called Flickinger effect.

Long-Term Results

In our analysis of CTN treated by SRS, we formally excluded patients with TN secondary to MS, megadolichobasilar artery compression, or a second GKR treatment, which are reputed to have more variable responses to SRS. Preoperative MRI revealed the presence of a vascular compression in 278 cases (55.9%). Four hundred fifty-six patients (91.75%) were initially pain free in a median time of 10 days (range 1 to 180 days). The initially pain-free actuarial rates at 0.5, 1, 2, 3, 4, 5, and 6 months were 53.52%, 73%, 83.5%, 88.1%, 88.9%, 89.5%, and 91.75%, respectively. The hypoesthesia actuarial rate at 5 years was 20.4% and at 7 years reached 21.1% and remained stable through 14 years with a median delay of onset of 12 months (range 1 to 65). A facial hypoesthesia that was very bothersome was reported in only three cases (0.6%). Interestingly, the hypoesthesia rate was higher in cases with latter pain-free appearance (after 30 days), compared to those alleviated within the first 48 hours, or between 48 hours and 30 days, suggesting different radiobiological mechanisms. The probability of remaining pain free at 3, 5, 7, and 10 years was 71.8%, 64.9%, 59.7%, and 45.3%, respectively. Furthermore, the rate of recurrence sufficiently severe to require a new surgery was 67.8% at 10 years. Dhople et al. reported a series of 102 patients with a median follow-up period of 5.6 years. Although initial freedom from pain was as high as 81%, bothersome hypoesthesia was 6% and long-term freedom from pain without medication was only 22% at 7 years. Kondziolka et al. published the Pittsburgh series, with a rather low rate of hypoesthesia (10.5%) and a 10-year rate of being pain free without medication of 26%.

Some Particular Situations

Repeat SRS (second radiosurgery) is an option if the patient had been pain free after the first SRS and for a long period of time. However, this is marked in most of the series by higher hypoesthesia rates. The initial pain-free response is similar or higher compared to the first SRS, with even higher long-term pain-free rates. The North American consortium has recently addressed the issue of a third SRS (by GKR) procedure for recurrent cases. Pain recurred in 23.5% of patients, after a mean interval of 19.1 months. No patient sustained an additional sensory disturbance after a third GKR. Third GKR could be considered as an option in selected cases.

Multiple sclerosis (MS)-related TN is a frequent symptomatology in this particular disease, being usually bilateral. The initial pain-free rates of GKR are high, similar as for classical TN, but the maintenance of pain relief on long term is less, due to the particular pathophysiology of MS. ^, The recent multicentric study by Xu et al. analyzed outcomes for 263 patients. The median time to pain relief was 1 month. The actuarial reasonable pain control maintenance rates at 1, 2, and 4 years were 54%, 35%, and 24%, respectively. New facial numbness appeared in 10% of the cases. Our previous report also suggested lower rates of maintenance of pain relief on long-term basis, as compared to CTN.