Body mass index and response to stereotactic radiosurgery in the treatment of refractory trigeminal neuralgia: A retrospective cohort study

Abstract

Stereotactic radiosurgery (SRS) is used as a noninvasive treatment option for patients with trigeminal neuralgia (TN), but the effect of obesity on pain relief post SRS, if any, is unknown. The primary goal of our study was to evaluate the association between obesity and response to SRS in patients with TN. We conducted an IRB-approved retrospective review of patients treated with SRS for TN between 2010 and 2017. Barrow Neurologic Institute (BNI) Score was assigned pre-and post-SRS to quantify pain level. Thirty-two patients (65% female) between the ages of 24 and 96 were studied with a median follow-up time of 11 months. Patients with BMI >25 were significantly less likely to have improvement in their symptoms with SRS (p = 0.005). Elevated BMI may be associated with worsened response to SRS in the treatment of TN.

Introduction

Trigeminal neuralgia (TN) is a rare pain syndrome characterized by sharp, sudden radiations of severe pain along the trigeminal nerve distribution resulting in debilitation and reduced quality of life. Treatment modalities consist of medical, surgical, and radiosurgical. Most patients attempt initial control with medical management such as carbamazepine and oxcarbazepine, but side effects often preclude long-term reliance on medications. Percutaneous procedures, such as balloon compression, radiofrequency ablation (RFA), and glycerol rhizotomy, can be performed without incision or anesthesia and typically provide immediate relief, but often require reintervention (1–3). Microvascular decompression has excellent reported outcomes, but is restricted in poor surgical candidates (4). Stereotactic radiosurgery (SRS) is a non-invasive, safe, cost-effective definitive treatment modality that is gaining increasing popularity in medication-resistant TN (5–10).

Management of this complex syndrome is multidisciplinary, and patients and providers have a variety of treatment pathways to contemplate pursuing. While SRS has demonstrated efficacy in the literature, with median reported rates of definitive cure without need for medication ranging between 40-50%, an uncertain subpopulation of patients does not derive significant benefit from SRS (11,12). An enhanced understanding of pre-treatment clinicopathologic parameters associated with poor responders may permit better personalization of diverse, complicated treatment pathways, thus sparing procedures, promoting quicker resolution of symptoms, and improving outcomes (13,14).

A current hypothesis is that patients with obesity may have a blunted response to TN therapy. Obesity is a well-established promoter of chronic pain, pain sensitization, and neuropathic pain (15–18). Animal studies have shown evidence for abnormal trigeminal sensory processing and nociceptive activation of the trigeminal system in obese mice (19,20). Recently, Arnone and colleagues showed an association between increased reoperation rates and poorer outcomes with MVD surgery in morbidly obese TN patients (21).

While SRS as a non-invasive modality is well-suited for overweight patients with multiple medical co-morbidities, the effect of obesity on pain relief after SRS, if any, is unknown. We investigated the relationship between pre-treatment obesity and SRS in patients treated at our institution. The primary goal of our study was to detect an association, if present, between obesity and SRS efficacy in refractory TN. We hypothesized that obesity would not affect pain relief post SRS. Secondary goals of study included reporting long-term outcomes of SRS and side effect profile of SRS.

Methods

Radiosurgical Patient Selection

Following institutional review board (IRB) approval (IRB #180127), we conducted a retrospective study of TN patients seen at our institution. Informed consent was waived by the IRB due to the minimal risk the study imposed. We identified patients treated in our Department of Radiation Oncology with SRS for intractable TN between 1996 and 2017. All patients were required to have a minimum of 3 months of documented follow-up with a neurologist, neurosurgeon, or radiation oncologist. Patients with previous SRS treatments for TN or patients lost to follow-up were excluded from analysis. Thirty-two patients treated from 2010-2017 met all of our inclusion criteria.

Electronic medical records were reviewed to describe patient characteristics including demographics, pertinent medical comorbidities, and history of neurologic disease (history of CVA and/or TIA, Charcot-Marie-Tooth, migraine, epilepsy, occipital neuralgia). Overweight patients were defined as those with a Body Mass Index (BMI) > 25 at the time of consultation with a radiation oncologist. BMI was calculated as weight (kg) divided by height squared (m²). Symptom onset, time to initial therapy, time to SRS, and time to initial relief were noted. TN subtype was qualified according to the scheme proposed by Eller and colleagues (22). Involvement of the ophthalmic, maxillary, or mandibular branches, as well as prior and subsequent medical and invasive therapies, was also documented.

Radiosurgery Technique

All patients underwent single-fraction SRS using the Novalis TX linear accelerator equipped with Brainlab ExacTrac Localization and iPlan Treatment Planning Software. Indications for SRS included patients with medically refractory disease, patients with medication intolerance, patients who had failed prior procedural therapies such as microvascular decompression, and/or patients who were not medically operative candidates. The treatment team included a radiation oncologist, neurosurgeon, medical physicist, and radiation therapist. After patient immobilization utilizing a non-rigid thermoplastic mask with a stereotactic head frame, simulation head CT was obtained in 1.5 mm thick serial axial slices and digitally fused to thin-slice (<1mm) T1-weighted post-contrast and T2 steady-state gradient Echo (FIESTA) MRI sequences for optimal targeting localization. A customized isocentric 6 MV radiosurgery plan was designed using the BrainLab iPlan system and reviewed by other physicians and medical physicists at a quality assurance conference. At the time of treatment delivery, kilovoltage (kV) images were obtained with the patient in the treatment position and confirmed with ExacTrac localization, and the isocenter alignment was verified by the treating physician. A prescription between 75 and 90 Gy was delivered to the ipsilateral trigeminal dorsal root entry zone (DREZ) in a single fraction utilizing a 4 mm and/or 6 mm cone collimator. Dosing was determined based on physician preference, institutional experience, and available data at the time of treatment (23). Additionally, the distance from the isocenter to the brainstem also influenced dosing; for example, a target nerve in a large prepontine cistern with sufficient separation from the brainstem may be treated with higher dose if brainstem constraints remained satisfactory. The brainstem, optic nerves, and optic chiasm were constrained to a point maximum dose less than 10 Gy.

Outcome Measures

Our primary endpoint was response to SRS based on quantified pain level via the Barrow Neurologic Institute (BNI) Pain Intensity Scale (8). BNI scores I and II were considered representative of well-controlled pain. A rating of III reflected moderate control; scores of IV and V indicated poorly-controlled and uncontrolled pain, respectively. As a measure of quality control, BNI score of a randomly selected subset of study patients was assigned by two blinded data collectors after independent review of abstracted text from the EMR. Out of 47 assigned scenarios, only 3 (6.4%) ratings differed between investigators, and each only by one BNI level. This strongly supports the inter-rater reliability of our retrospective scoring method (Spearman’s rank correlation coefficient R = 0.96, two-tailed p < 0.001).

Patients were retrospectively scored at consultation, at date of initial pain relief, and at last known follow-up. Response to therapy (R_SRS) was quantified as pre-SRS BNI score subtracted from post-SRS score. Treatment success was defined as R_SRS < 1, aka a decrease in BNI score; treatment failure was considered R_SRS > 0, representing an unchanged or increased level of pain. Secondary endpoints included last known BNI rating, short- and long-term neurologic sequelae associated with SRS, requirement for salvage therapy and relief at last follow-up after SRS with or without salvage interventions.

Statistical Analysis

Data collection was performed using Microsoft Excel. All statistical analysis was performed using SAS 9.4 (Cary, NC) or GraphPad Prism 7.0 (La Jolla, CA). Continuous variables were summarized with mean, median, and range, and compared using the Kruskal-Wallis test or linear regression. Categorical variables were summarized using counts and percentages, and compared using the Fisher’s exact or chi-square tests.

Results

Retrospective Cohort Analysis

From 2010-2017, a total of 32 patients between the ages of 24-96 years met selection criteria, including 10 patients (31%) with a normal BMI and 22 patients (69%) with a BMI greater than 25. There were 14 female overweight patients (14/21, 67%) and 8 male overweight patients (8/11, 73%). Most patients did not have a genetic predisposition (3%) or family history (3%), had unilateral symptoms (84%), and had at least one cardiovascular risk factor (66%). There were no significant differences in demographics or medical history between the normal and overweight groups (see Table 1 for details).

Table 1.

Patient characteristics grouped by body mass index (BMI) group – Abbreviations used in table: SRS (stereotactic radiosurgery); BNI (Barrow Neurological Institute). P-value based on Fisher’s exact or chi-square tests for categorical variables, and Kruskal-Wallis test for continuous variables.

	Total	Not overweight	Frequency	Overweight	Frequency	P-value
	N=32	N=10	(%)	N=22	(%)
Sex: Male	11	3	30	8	36	>0.99
Sex: Female	21	7	70	14	64
Laterality: Left	12	2	20	10	45	0.25
Laterality: Right	20	8	80	12	55
History
Genetic predisposition	1	0	0	1	5	>0.99
Bilateral symptoms	5	2	20	3	14	0.64
Multiple sclerosis	4	1	10	3	14	>0.99
Other neurologic disease	14	6	60	8	36	0.27
Family history	1	0	0	1	5	>0.99
Comorbidities
Diabetes mellitus	2	1	10	1	5	0.53
Hypertension	11	2	20	9	41	0.43
Smoking history	11	2	20	9	41	0.43
Use of steroids	3	1	10	2	9	>0.99
Pre-SRS sensory disturbance	8	3	30	5	23	0.68
Autonomic symptoms	1	0	0	1	5	>0.99
Pain class
Constant pain	4	1	10	3	14	>0.99
Lancinating pain	20	7	70	13	59
Multiple sclerosis	4	1	10	3	14
Trauma/surgery	4	1	10	3	14
Pain distribution						0.81
V1 only	4	1	10	3	14
V1, V2	3	1	10	2	9
V1, V2, V3	4	1	10	3	14
V2 only	5	2	20	3	14
V2, V3	13	3	30	10	45
V3 only	2	1	10	1	5
Medications before SRS
Carbamazepine	26	9	90	17	77	0.64
Oxcarbazepine	5	1	10	4	18	>0.99
Pregabalin	13	1	10	12	55	0.02
Gabapentin	15	8	80	7	32	0.02
Hydrocodone-acetaminophen	7	2	20	5	23	>0.99
Steroids	3	1	10	2	9	>0.99
Any of the above medications	31	10	100	21	95	>0.99
Medicine Count						0.91
0	1**	0	0	1	5
1	4	1	10	3	14
2	18	6	60	12	55
3	7	3	30	4	18
4	2	0	0	2	9
Alternative therapies before SRS*						0.88
Glycogen injection	3	0	0	3	10
Microvascular decompression	8	2	17	6	20
Nerve block	2	0	0	2	7
None	14	5	42	8	27
Radiofrequency ablation	8	3	25	5	17
Rhizotomy	8	2	17	6	20
None	13	5	42	8	27	0.46
1-3 procedures	29	7	58	22	73
Salvage therapy						0.053
None	18	3	30	15	68
Medicine	3	2	20	1	5
Invasive Procedure	8	5	50	3	14
Additional SRS	2	0	0	2	9
Additional SRS, then invasive procedure	1	0	0	1	5
Change in BNI from pre-SRS to last follow up	Median 2, Range 4 to 1	Median 2	Range 4 to 1	Median 1	Range 4 to 0	0.10
SRS dose (Gy)	Median 85, Range 75 to 90	Median 85	Range 80 to 90	Median 85	Range 75 to 90	0.26
Max dose (Gy)	Median 93, Range 75 to 99	Median 95	Range 85 to 99	Median 93	Range 75 to 98	0.33
Follow up since diagnosis (years)	Median 6, Range 0.8 to 32	Median 11	Range 3 to 32	Median 5	Range 0.8 to 27	0.22
Follow up since SRS (months)	Median 11, Range 3 to 88	Median 19	Range 3 to 46	Median 10	Range 3 to 88	0.30

^*Each patient had 0-3 alternative interventions prior to SRS.

^**This patient was prescribed both amitriptyline and fentanyl for pain control.

Most patients had lancinating pain classified as classical type 1 TN (63%). There was no difference in the quality (chi-square p>0.99) or distribution (chi-square p=0.81) of pain between the normal and overweight groups. The most common symptom distribution was in both cranial nerve V2 and V3 regions (41%).

Almost all patients had failed medical management before consideration for SRS after trying a median of 2 medications (range 1 to 4). There was no difference in pre-SRS use of carbamazepine, oxcarbazepine, hydrocodone-acetaminophen, or steroids. However, overweight patients were more likely to have tried pregabalin (55% vs 10%, chi-square p=0.02) and less likely to have tried gabapentin (32% vs 80%, chi-square p=0.02).

The normal and overweight groups were comparable in their use of pre-SRS interventional therapies (chi-square p=0.88). The number of interventions each patient had tried ranged from 0 to 3. Most commonly tried were microvascular decompression (25%), radiofrequency ablation (25%), and balloon rhizotomy (25%).

There was no significant difference in SRS treatment plan or delivery. Very few patients experienced acute side effects within 1 month of SRS (16%), with no difference between weight groups (chi-square p>0.99). No patients developed secondary malignancies after SRS.

There was no significant difference in the initial BNI score by weight group before SRS (Kruskal-Wallis p=0.45). After SRS (before salvage treatment), there was no difference in improvement between normal weight patients and overweight patients (Kruskal-Wallis p=0.08) (Table 2). After SRS and salvage therapies, all normal weight patients had achieved relief of trigeminal neuralgia, while 6 (27%) of overweight patients never achieved relief (Kruskal-Wallis p=0.14). Overweight patients also had a significantly smaller improvement in pain compared to normal weight patients (Kruskal-Wallis p=0.005) (Figure 1). Normal weight patients had a median improvement of 2 points on the BNI scale (range 4 to 1), compared to a median improvement of 1 point (range 4 to 0) in overweight patients at last follow-up. There was no linear relationship between BMI and treatment response (p=0.0577).

Table 2.

Barrow Neurological Institute (BNI) score before and after SRS

	Total	Not overweight	Frequency	Overweight	Frequency	P
	N=32	N=10	(%)	N=22	(%)
BNI score before SRS (range 1-5)						0.45
1	0
2	0
3	3	0	0	3	14
4	9	2	20	7	32
5	20	8	80	12	55
BNI score after SRS (range 1-5) at initial time of relief						0.08
1	6	3	30	3	14
2	4	2	20	2	9
3	14	3	30	11	50
4	2	2	20	0	0
5	1	0	0	1	5
N/A (never had relief)	5	0	0	5	23
Change in BNI score from pre-SRS to last follow up						0.005
-4 (complete relief)	5	2	20	3	14
-3 (significant improvement)	5	2	20	3	14
-2 (moderate improvement)	7	5	50	2	9
-1 (some improvement)	7	0	0	7	32
0 (no change)	7	0	0	7	32
1 (pain worsened)	1	1	10	0	0
BNI improvement after SRS						0.21
No	9	1	10	8	36
Yes	23	9	90	14	64
Relief at last follow up						0.14
No	6	0	0	6	27
Yes	26	10	100	16	73

Figure 1.

(a) Barrow Neurologic Institute (BNI) pain intensity score before SRS, at earliest post-SRS relief and at last follow-up. P-value <0.005 corresponds to comparison of pre-SRS to last follow-up scores. (b) Data depicted as a change in BNI score (ΔBNI) comparing final improvement in BNI pain intensity score from pre-SRS to post-SRS and any salvage therapies at last follow-up. All data grouped by normal weight (body mass index [BMI] <25) and overweight (BMI ≥25)

More than half of patients did not require any additional salvage therapy after SRS (56%). Of the 14 patients who did receive salvage treatments after SRS, 8 (57%) underwent at least one additional procedure, 3 (21%) received further medical management, 2 (14%) received additional SRS, and 1 (7%) received additional SRS and then MVD. Of the patients who received repeat SRS: one was treated with repeat SRS again without improvement but ultimately improved with MVD; one patient received SRS to the gasserian ganglion due to recurrent pain (not to the DREZ) with improvement, and one patient had worsened pain from BNI 2 to 3, but repeat SRS did not lead to improvement. After SRS, 70% of normal weight patients received salvage therapy, compared to only 32% of overweight patients, although this was not statistically significant in our cohort (p=0.053).

Discussion

Our retrospective cohort analysis shows for the first time that patients with elevated BMI undergoing SRS for refractory TN have a poorer response and lesser improvement in their BNI score as compared to their normal weight counterparts. Among all patients with poor response to SRS, overweight patients with a poor response to SRS were offered salvage therapies in fewer instances, though it is not clear why patients with a poorer response were less likely to receive salvage. Conversely, patients with normal range BMI had nearly universal benefit from SRS. In a similar vein, surgical data by Arnone et al. also showed that obese patients undergoing microvascular decompression from TN also had higher failure rates (21).

Recent animal studies by Rossi et al. were first to link obesity with nociceptive activation of the trigeminal system (19,20). In their study of obese mice, they showed increased pain-related neuronal activation in the trigeminal nucleus caudalis (TNC), which they postulated mechanistically may be related to TNF-alpha receptor activation of TRPV1 channels on peripheral nociceptors and the TNC. Dandona et al have shown that TNF alpha, an inflammatory mediator, has been shown to be elevated in the plasma of obese humans and can directly correlates with weight loss or weight gain (24). This poses an intriguing hypothesis for a similar mechanism for TNC activation and sensitization in obese humans. Considering our results presented here along with recent animal studies which have shown evidence for abnormal trigeminal sensory processing and nociceptive activation of the trigeminal system in obese mice, we postulate that our patients with higher BMI may have underlying trigeminal pain sensitization that may be mechanistically unique compared to normal BMI patients with TN. Sensitization of the TNC of our overweight patients may thus also be explained by a TNF-alpha mediated mechanism. Future studies may reasonably consider weight loss to reduce pain-sensitizing TNF-alpha serum levels, or the future use of TNF-alpha blockading therapy (such as infliximab) in conjunction with stereotactic radiosurgery for the treatment of TN in patients with higher BMIs to potentially yield a better response in this subset of patients.

Primary limitations to this study include its retrospective nature and small sample size. Due to the sample size, we were only able to perform univariate analysis, as a stratified analysis for covariates such as gender, age, pre-SRS medication, or pre-SRS procedure would not hold substantial meaning here, but does represent an approach for future investigation. Moreover, there was no statistically significant relationship between BMI and response. This was most likely the case because of our small sample size and outliers in our data (such as BMI=42) that did not correlate with greatest effect size, in part due to the subjective nature of pain response assessment. A larger study with prospective evaluation of pain at scheduled timepoints is indicated to validate and confirm the dose-response relationship between BMI and response to SRS proposed in our manuscript.

Conclusion

While the vast majority of normal weight TN patients had an improvement in BNI pain score, our study shows that TN patients with elevated BMI were less likely to achieve pain relief and received salvage therapies less often. Correlation with animal studies and other clinical data suggests a plausible TNF-alpha mediated mechanism for nociceptive sensitization of the trigeminal nucleus caudalis. Our data suggest that further investigation is warranted to guide better targeted management of overweight patients with TN in order to achieve better response.