Gamma knife Radiosurgery for Trigeminal Neuralgia: Outcomes and prognostic factors in 151 patientsKeywords: trigeminal neuralgia, radiosurgery, pain, gamma knife, outcomeInteractive ManuscriptAsk Questions of this Manuscript: What is the background behind your study?
Microvascular
decompression and percutaneous ablation surgery have historically been the
treatments of choice for medical refractory trigeminal neuralgia (TGN). Gamma Knife surgery has been utilized as an alternative,
minimally invasive treatment in trigeminal neuralgia. What is the purpose of your study?
Our purpose was to evaluate the long-term results of Gamma surgery for the treatment of
trigeminal neuralgia. Describe what you did.
From 1996 to 2003, we treated 151 cases of trigeminal
neuralgia with Gamma Knife surgery. In this group, radiosurgery was performed once in 136 patients, twice in
14 patients, and three times in one patient. Clinical outcomes and post-radiosurgical MR imaging studies were analyzed. Describe your patient group.
The median age of the patients was 68 (range 22-90) years
old, and the median time from diagnosis to Gamma surgery was 72 months (range 1
to 276 months). The types of
trigeminal neuralgia were as follows: 122 patients with typical TGN; 3 with atypical TGN; 4 with multiple
sclerosis associated TGN; and 7 patients with TGN and a history of a cavernous
sinus tumor. In each case, the
radiosurgical target was chosen 2 to 4 mm anterior to the entry of the
trigeminal nerve into the pons. The maximum doses ranged from 50 to 90 Gy. Describe your main findings.
The median follow-up was 19 (range 2 to 96) months. The mean time to relief of pain was 24
(range 1-180) days. The percentage of patients who were pain-free without
medication at 1, 2, and 3 years follow up was 47%, 45%, and 34%, respectively.
The percentage of patients who experienced some degree of improvement in their
pain was 90%, 77%, and 70% at
1, 2 and 3 years follow-up,
respectively. Thirty-three of 122 (27%) patients with initial improvement later
experienced pain recurrence at a median time of 12 months post-radiosurgery (range
2-34 months). Among those with recurrence of their symptoms, 14 patients
received additional Gamma surgery, 6 had a microvascular decompression, 4 had a
glycerol injection, and 1 patient had a percutaneous radiofrequency rhizotomy.
Twelve (9%) patients developed the onset of new facial numbness
post-radiosurgery. Post-radiosurgical MR imaging changes were noted in 9
patients (7%). In multivariate
analysis, both right-sided neuralgia (p=0.032) and age (p=0.05) were
statistically significant. New
onset of facial numbness following Gamma surgery correlated with more than one
radiosurgery (p=0.002). Describe the main limitation of this study.
The main limitation of this study is
its retrospective nature and lack of a specific control group. Describe your main conclusion.
At last follow-up,
Gamma Knife surgery effectuated pain relief in 44%. Some degree of pain improvement at 3 years post radiosurgery
was noted in 70% of patients with trigeminal neuralgia. Describe the importance of your findings and how they can be used by others.
Although less
effective than microvascular decompression, radiosurgery remains a reasonable
treatment option for those unwilling or unable to undergo more invasive
surgical approaches and offers a low risk of side effects. This data will
be of value for the design of randomized trials. What is the background of your topic?
Trigeminal neuralgia (TGN) is a paroxysmal lancinating pain
confined to a distribution encompassing one or more of the branches of the
trigeminal nerve on one side of the face. It frequently arises in conjunction with a vascular contact between an
artery or vein and the trigeminal nerve at the root entry zone (REZ). This fact led to the hypothesis of a
causal relationship between vessel compression and trigeminal neuralgia and the
devising of microvascular decompression surgery. 1 First line treatment for patients with
TGN is medical therapy. However,
many patients with this condition eventually fail medical therapy because of
refractory pain or intolerable medication side-effects. More invasive treatment options include
microvascular decompression (MVD), and neuronal modulating procedures such as
glycerol rhizolysis, radiofrequency rhizotomy, percutaneous balloon
microcompression, and peripheral nerve blocks. 1,12What is the importance to the reader/community? Radiosurgery has been employed to treat TGN
using high-resolution imaging guidance, typically magnetic resonance
imaging. Radiosurgery has been
viewed as a minimally invasive treatment option with few side effects. However,
questions remain about the efficacy, safety, and durability of Gamma Knife surgery
for TGN. What is your hypothesis? (What question(s) did you ask?)
Our hypothesis was that through
retrospective evaluation of a large clinical series , we could determine the
efficacy, safety, and durability of Gamma Knife surgery for TGN.
What was done in your study?
We evaluated our experience with Gamma Knife surgery
for the treatment of 136 patients with trigeminal neuralgia and atypical facial
pain and analyzed the factors associated with a pain free outcome. What are the main conclusions derived from prior reports? In various series, pain free outcomes have ranged from 21.8% to 75%, and
complication rates varied from 2.7% to 37%. 2,3,4,5,6,7,8,9,10, 11,13,14,15,16,17,18 What are the main limitations of your research method?
The main limitation of our study method
was that data was evaluated retrospectively using a prospective database. If your work has Institution Review Board or any other supervisory authority approval, state that now:
This study was approved by the University of Virginia
Institutional Review Board. State the source of funding for this study.
No external funding was provided for this study. Describe patient age (mean, range)
The mean age was 68 years. From 1996 until 2004, a total of 136 patients were treated,
and 122 had a diagnosis of trigeminal neuralgia while 14 had a diagnosis of
atypical facial pain (Table 1). Describe patient sex (number male and number female)
This patient population consisted of 66 males and 70
females. Describe other important patient features (symptoms (list); clinical presentation features, prior treatment, employment, etc)
Ninety-four patients had right sided pain while 42 patients
had left sided pain. The
distribution of pain in the divisions of the trigeminal nerve was as
follows: V1= 6.9% of patients; V2=
28.4%; V3= 23.3%; V1 and V2= 15.5%; V2 and V3= 15.5%; and V1 and V2 and V3=
11.2%. Pre-operative facial numbness was noted in 34 patients (25%). Describe disease features (example = tumor subtypes)
The vast majority of the patients had at some point been
treated with more than one pharmacological agent, and all patients were
refractory to medical treatment. In addition, seventy-four patients had undergone previous surgical
procedures for treatment of their facial pain. Twenty–three (17%) underwent MVD, 46 (34%) had glycerol
injections, 2 (1.5%) had radiofrequency rhizotomies, and 32 (24%) had
neurectomies. Describe the clinical intervention (ie. medications, devices, techniques)
A total of 151 Gamma Knife surgeries were performed on these 136
patients with 14 undergoing a second Gamma Knife surgery and one undergoing three
Gamma surgeries. Radiosurgery was
performed using the Model U (1989 to June 2001) and Model C (July 2001 to
present) Gamma Knifes (Elekta Instruments, Norcross, GA). The Leksell model G head frame was
applied in the main operating room under local anesthesia with light
intravenous sedation (typically propofol or fentanyl and versed). Most patients were treated with one
isocenter (median 1, range 1 to 7) delivered with the 4mm collimator helmet.
Maximal doses ranged from 50 to 90 Gy, and the median dose
was 80 Gy. The maximum
prescription doses were as follows: 50 Gy in 0.7% of procedures; 60 Gy in 0.7%;
70 Gy in 43%; 80 Gy in 55%; and 90 Gy in 0.7% of cases. In each case, the root entry zone (REZ)
was encompassed within the treatment plan to allow a low dose of radiation
(approximately 20 to 30 Gy) to the edge of the pons. The doses less than 70 Gy were only given at
retreatment. The center of the
targeting was typically chosen 2 to 4 mm anterior from the junction of the
trigeminal nerve and the pons. Targets
were categorized into two groups. The first group of targets is when the trigeminal nerve was covered with
the 50% isodose outside of the brainstem. The second category of targets was when the 50% isodose
curve was adjacent to the surface of the brainstem. Fifty-two percent of patients were
treated using the first target strategy and forty-three percent were treated
using the second strategy. Describe the tests used to perform your research (Imaging, Patient Outcomes, Other specific tests.)
The trigeminal nerve was typically imaged using a 1.5 Tesla
MRI unit. Localization was performed using T1-weighted and fast spin
echo T2-weighted axial images along with coronal images of the nerve. The axial volume acquisition of 512x216
matrices was divided into sections of 1 mm without gaps. T1 weighted images were also repeated
after administration of gadolinium. Two patients underwent computed tomography (CT) cisternography for targeting because of
medical conditions (e.g. a pacemaker) that prohibited MR imaging. However, CT cisternography is not ideal for targeting
purposes. What percent of study subjects completed each of the tests?
Clinical Follow-up of
Patients
136
of 151 patients were available for follow-up. Patients received direct clinical
follow-up every 3 to 6 months. If the patient failed to make his clinical
appointment, a questionnaire was sent to the patient. On that questionnaire, patients were asked to assess their
pain intensity, time to onset of pain relief, presence or absence of facial
numbness, pharmacological agents taken for pain, and whether they underwent
additional surgical interventions for treatment of facial pain. Patients were specifically asked if
they were pain free or had improvements in their pain following Gamma
surgery. They were also asked
about the presence of new or worsened facial numbness post-operatively.
Imaging Follow-up of Patients
Patients received routine MRI examinations 6 to
9 months after Gamma Knife surgery. T1-weighted sequences with and without contrast and T2-weighted images
were performed to evaluate for any adverse consequences. If a patient developed the onset of new
facial numbness post-radiosurgery, that patient underwent additional MRI
testing at the time of the onset of the numbness to evaluate for any brain
tissue changes.
Describe who conducted the tests. (Study investigators or other parties?)
All serial follow-up information was obtained via direct
contact with the patient or their referring physicians. Were the tests validated for use in this kind of study? The tests and scoring
methods were validated Describe your statistical methods or tests used Univariate and multivariate analysis were performed to assess for
variables that were predictive of a pain free outcome after Gamma Knife surgery. The following variables were
assessed: right sidedness of the
pain; typical or atypical pain; age; gender; number of isocenters; target
distance from nerve root entry zone (either the 50% isodose well outside of or
adjacent to the brainstem); maximal dose; presence of post-GK imaging changes;
presence of previous interventions; a previous MVD; previous glycerol
injection; previous neurectomy; increasing length of time from diagnosis to
Gamma surgery; distribution of the pain; the presence of pre-operative facial
numbness; the presence of post-operative facial numbness; and recurrence of
pain in those patients who were treated more than once with Gamma surgery. The unpaired Student’s t-test or
analysis of variance were used for continuous variables. Nominal or ordinal data was compared
using the two-tailed Fisher’s exact test. All statistical analyses were conducted with the aid of Statview 5.01
(SAS Institute, Cary, NC). Describe your study power calculation (if any)
We did not use a power calculation as
no control group was studied. Describe your chosen level of statistical significance P<.05 was chosen as the
level of statistical significance. Provide the results for the most important outcome of your research [i.e. Patient survival]
Clinical Outcome
Median follow-up in the 136 patients was 19
months. The median interval from
the treatment to symptom improvement was 24 (range 1-180) days. Few patients experienced a benefit more
than 2 months following radiosurgery. At the last time of follow-up, 44% of patients were pain free without
medication, and 56% still had some degree of pain. The percentage of patients who were
pain free without medication at specific time points was as follows: 47% at 1 year (of 118 patients with 1
year follow-up); 45% at 2 years (of 64 patients with 2 years follow-up); and
34% at 3 years (of 39 patients with 3 years follow-up). In a similar fashion, those who
experienced some improvement in pain post-radiosurgery were as follows: 90% at 1 year (of 118 patients with 1
year follow-up); 77% at 2 years (of 64 patients with 2 years follow-up); and
70% at 3 years (of 39 patients with 3 years follow-up). Forty-six percent of those with typical TN (n=122) were pain
free at last follow-up whereas only 29% of those with atypical TN (n=14) were
pain free (p=0.35, t-test).
During follow-up, 33 patients had recurrence of
their pain after some initial relief. The median time to recurrence of facial
pain was 12 months. Among those
patients with recurrence of pain, 14 patients underwent an additional Gamma
Knife surgery, 6 patients had a microvascular decompression, 4 patients a glycerol
injection, 1 patient a radiofrequency rhizotomy, and 5 patients refused any
further treatment. Discuss any additional outcomes of your study [i.e. Imaging findings, Patient functional outcomes, Complications]
Clinical Complications
Twelve patients (9%) experienced new
post-operative numbness following Gamma Knife surgery. In our study, 4 patients out of 14 who
had repeat Gamma surgery (29%) had new facial numbness. Eight out of 122 patients who had only
one Gamma Knife surgery (7%) developed new facial numbness. There was a statistically significant difference in the
incidence of new facial numbness in these two group (p=0.002, t-test). We were unable to establish a
significant relationship between radiation dose and post-operative facial
numbness. No patient experienced
the new onset of corneal reflex loss or anesthesia dolorosa.
A total of 26 patients had either new or
worsened facial numbness after Gamma surgery. The severity of the numbness was as follows: 12 patients with mild numbness; 10 with
somewhat disturbing numbness; and 4 with severe numbness. Twenty-one of 122 patients (17%)
receiving only one Gamma surgery developed new or worsened facial numbness
while 5 out of 14 patients (36%) receiving more than one Gamma surgery
experienced new or worsened symptoms. The difference was not statistically significant (p=0.14, T-test). In addition, 12 of 46 patients (26%)
with a history of glycerol injection experienced new or worsened facial numbness
as compared to 14 out of 90 patients (16%) without a history of glycerol
injection (p=0.14, T-test). One
patient described that the facial numbness was worse than the original TGN pain
because it led to drooling. She did not have anesthesia dolorosa.
Imaging Outcome
Nine patients (6.6%) had post-radiosurgical imaging changes
including focal contrast enhancement or focal T2-weighted signal change. Among those nine patients who
had post-operative imaging changes, 4 had no numbness, 3 had mild numbness, and
2 had severe numbness. Discuss Statistical Outcomes [i.e. Multivariate analyses]
In
order to evaluate the efficacy of Gamma radiosurgery in a rigorous fashion, we
chose to consider factors that were statistically related to a pain free
outcome at the last time of follow-up. Seventeen factors in all were tested. In univariate analysis, right sidedness
to the pain (p=0.0002) and a previous neurectomy (p=0.04) were statistically
related to a pain free result. In
multivariate analysis, again right sidedness (p=0.032), and this time
increasing age (p=0.05) were related to a pain free result. No other factors were significantly
related (i.e. p>0.05) to a pain free result following Gamma Knife surgery. Provide the background and reason for your work and briefly summarize important prior research.
The
underlying etiology of trigeminal neuralgia has been the subject of intense
investigation for more than a century. Research by Pfluger (1859) and Heidenhain (1861) demonstrated that the
proximal end of a nerve was more excitable than the distal end and that the
excitability of the nerve increased near the region of a cross section.
By 1941, Olivecrona described that
mechanical pressure along the root or at the level of the ganglion could be the
cause of trigeminal neuralgia. Granit, Leksell, and Skoglund (1944) demonstrated that local
pressure on nerve fibers could result in painful afferent discharges from the
injured neural segment. Jannetta and others have suggested that vascular compression of the
trigeminal nerve may be a causal agent in trigeminal neuralgia. 1,12
Following the successful long-term outcome of two patients
who had trigeminal neuralgia radiosurgery using ortholvoltage x-rays Leksell
and Hakanson treated 48 patients between 1970 and 1978, and follow-up
information was available on 46 of these patients . In the first 24 patients, plain
stereotactic skull X-rays were used for targeting, and 33% were pain free at 6
months while only 8.3% were pain free at a mean follow up of 26 months
(Personal communication, Sten Hakanson, 2004). In the second set of 22 patients, the position of the
Gasserian ganglion was determined by transoval cisternography using tantalum
dust. For that group, the
percentages of patients who were pain free at 6 and 26 months were 59% and 18%,
respectively.
Overall, the treatment of choice for trigeminal neuralgia
remains microvascular decompression. However, for patients who are ineligible for or unwilling to undergo
more invasive neurosurgical procedures, Gamma Knife surgery offers a reasonable
alternative. Gamma Knife surgery also
does not carry the same type and degree of risks that microvascular
decompression does. For instance,
in a long-term series of microvascular decompression patients, there were the
following risks from the series by Dr. Jannetta: 0.2% death; 0.1% brain stem infarct; and 1% hearing loss. 1 None of these complications were
observed in our series nor were they associated with radiosurgical treatment of
trigeminal neuralgia in other major centers. Ultimately, the patient must choose the type of intervention
he or she is willing to undergo. Discuss the most important findings in your study.
Measuring Pain Relief
We believe it is better to grade patient outcome in a
straightforward fashion by reporting pain free outcomes off medications. Such an endpoint is readily
understandable to patients, neurosurgeons, and referring physicians of all
backgrounds. Reporting outcomes in
terms of subjective degrees of pain relief may lead to confusion for patients
and physicians alike. As a means
of comparing our results to other studies which report pain relief rather than
pain free outcomes, we do note the numbers of patients who reported
improvements in their trigeminal neuralgia. In our study, pain relief meant that the patients were still
on medications but thought their pain was improved after Gamma Knife surgery. This result is arguably very meaningful
to patients with severe pain and can translate into a significant improvement
in the quality of life.
The variable history of trigeminal neuralgia is
the other major difficulty in analyzing results from small to medium size
retrospective studies. Trigeminal
neuralgia can be characterized by spontaneous partial or complete
remissions. The characteristic
waxing and waning nature as well as the subjectivity of pain, sensory loss, and
paresthesias makes a longer follow-up period and straightforward endpoints
essential.
Prognostic Factors for Pain Relief
In our study, multivariate analysis revealed
that right sided pain and age correlated with a pain free outcome. In our study, it is notable that a pain
free outcome was not related to dose, sensory loss, slight differences in
target selection, or the type of pain (i.e. either atypical or typical
trigeminal neuralgia).
The relationship between a previous
neurectomy and Gamma Knife surgery in terms of a pain free outcome suggests the
efficacy of the Gamma Knife may not be reduced after a peripheral neurectomy. Clearly, the Gamma Knife and a peripheral
neurectomy target proximal and distal portions of the symptomatic trigeminal
nerve, respectively. In a subset
of patients, it is possible that both proximal and distal portions of the nerve
should be lesioned to provide adequate pain relief. The effect of age on outcome may in part be due to the
generally older age of the patient treated with Gamma Knife (median age of 68)
and the fact that many of these patients had had Gamma surgery as a first line
treatment.
Other studies have reported different factors
that were associated with a better response to Gamma Knife surgery. These include typical trigeminal
neuralgia rather than atypical pain from multiple sclerosis or other causes 13,
higher doses of radiation 3, a target closer to the brainstem,
and no prior surgery 6. Another favorable prognostic factor in patients with no prior surgical
intervention is MRI evidence of blood vessel contact with the trigeminal nerve. 4 In the present study, we did not find
these factors related to a pain free outcome.
Discuss the various aspects of your work (for example, treatment-related complications, comparisons to other approaches or techniques, cost-effectiveness analysis)
Complications of Gamma Knife surgery
The most frequent complication following radiosurgical
treatment of trigeminal neuralgia is facial numbness. The incidence of new trigeminal dysfunction varies from 6%
to 66%. 2,3,4,5,8,14,15 In this series, 12 out of 136 patients (9%) developed new facial numbness
following Gamma Knife surgery. In
our study, only 1 patient received a dose of 90 Gy and no facial numbness was
noted in this case. Fortunately,
we did not observe cases of anesthesia dolorosa or absence of the corneal
reflex in the 136 patients.
In our study, 29% of patients who had repeat
Gamma Knife surgery had new facial numbness whereas 7% of patients who had only one
Gamma Knife surgery developed new facial numbness (p=0.002, t-test). In a series of 18 patients who underwent
repeat radiosurgery, Herman et al. (2004) noted an 11% incidence of new or
worsened facial numbness which was not substantially elevated over the risk of
facial numbness for those having only one Gamma Knife surgery. 7 However, Hasegawa et al. (2002) noted an increased risk of facial numbness associated
with repeat Gamma surgery. 6 Discuss Future Work and Recommendations.
Gamma
Knife surgery is a relatively safe and effective treatment option for patients
with medically refractory trigeminal neuralgia. The improvements in pain
following Gamma surgery diminish somewhat with time, but this is true for other
treatments as well. Studies of
long term durability are important. Future work should consider randomized trials between the
different therapeutic options in patients appropriate for randomization.
Microvascular
decompression and percutaneous ablation surgery have historically been the
treatments of choice for medical refractory trigeminal neuralgia (TGN). Gamma Knife surgery has been utilized as an alternative,
minimally invasive treatment in trigeminal neuralgia.
Our purpose was to evaluate the long-term results of Gamma surgery for the treatment of
trigeminal neuralgia.
From 1996 to 2003, we treated 151 cases of trigeminal
neuralgia with Gamma Knife surgery. In this group, radiosurgery was performed once in 136 patients, twice in
14 patients, and three times in one patient. Clinical outcomes and post-radiosurgical MR imaging studies were analyzed.
The median age of the patients was 68 (range 22-90) years
old, and the median time from diagnosis to Gamma surgery was 72 months (range 1
to 276 months). The types of
trigeminal neuralgia were as follows: 122 patients with typical TGN; 3 with atypical TGN; 4 with multiple
sclerosis associated TGN; and 7 patients with TGN and a history of a cavernous
sinus tumor. In each case, the
radiosurgical target was chosen 2 to 4 mm anterior to the entry of the
trigeminal nerve into the pons. The maximum doses ranged from 50 to 90 Gy.
The median follow-up was 19 (range 2 to 96) months. The mean time to relief of pain was 24
(range 1-180) days. The percentage of patients who were pain-free without
medication at 1, 2, and 3 years follow up was 47%, 45%, and 34%, respectively.
The percentage of patients who experienced some degree of improvement in their
pain was 90%, 77%, and 70% at
1, 2 and 3 years follow-up,
respectively. Thirty-three of 122 (27%) patients with initial improvement later
experienced pain recurrence at a median time of 12 months post-radiosurgery (range
2-34 months). Among those with recurrence of their symptoms, 14 patients
received additional Gamma surgery, 6 had a microvascular decompression, 4 had a
glycerol injection, and 1 patient had a percutaneous radiofrequency rhizotomy.
Twelve (9%) patients developed the onset of new facial numbness
post-radiosurgery. Post-radiosurgical MR imaging changes were noted in 9
patients (7%). In multivariate
analysis, both right-sided neuralgia (p=0.032) and age (p=0.05) were
statistically significant. New
onset of facial numbness following Gamma surgery correlated with more than one
radiosurgery (p=0.002).
The main limitation of this study is
its retrospective nature and lack of a specific control group.
At last follow-up,
Gamma Knife surgery effectuated pain relief in 44%. Some degree of pain improvement at 3 years post radiosurgery
was noted in 70% of patients with trigeminal neuralgia.
Although less
effective than microvascular decompression, radiosurgery remains a reasonable
treatment option for those unwilling or unable to undergo more invasive
surgical approaches and offers a low risk of side effects. This data will
be of value for the design of randomized trials.
Trigeminal neuralgia (TGN) is a paroxysmal lancinating pain
confined to a distribution encompassing one or more of the branches of the
trigeminal nerve on one side of the face. It frequently arises in conjunction with a vascular contact between an
artery or vein and the trigeminal nerve at the root entry zone (REZ). This fact led to the hypothesis of a
causal relationship between vessel compression and trigeminal neuralgia and the
devising of microvascular decompression surgery.1 First line treatment for patients with
TGN is medical therapy. However,
many patients with this condition eventually fail medical therapy because of
refractory pain or intolerable medication side-effects. More invasive treatment options include
microvascular decompression (MVD), and neuronal modulating procedures such as
glycerol rhizolysis, radiofrequency rhizotomy, percutaneous balloon
microcompression, and peripheral nerve blocks.1,12 Radiosurgery has been employed to treat TGN
using high-resolution imaging guidance, typically magnetic resonance
imaging. Radiosurgery has been
viewed as a minimally invasive treatment option with few side effects. However,
questions remain about the efficacy, safety, and durability of Gamma Knife surgery
for TGN.
Our hypothesis was that through
retrospective evaluation of a large clinical series , we could determine the
efficacy, safety, and durability of Gamma Knife surgery for TGN.
We evaluated our experience with Gamma Knife surgery
for the treatment of 136 patients with trigeminal neuralgia and atypical facial
pain and analyzed the factors associated with a pain free outcome. In various series, pain free outcomes have ranged from 21.8% to 75%, and
complication rates varied from 2.7% to 37%.2,3,4,5,6,7,8,9,10, 11,13,14,15,16,17,18
The main limitation of our study method
was that data was evaluated retrospectively using a prospective database.
This study was approved by the University of Virginia
Institutional Review Board.
No external funding was provided for this study.
The mean age was 68 years. From 1996 until 2004, a total of 136 patients were treated,
and 122 had a diagnosis of trigeminal neuralgia while 14 had a diagnosis of
atypical facial pain (Table 1).
This patient population consisted of 66 males and 70
females.
Ninety-four patients had right sided pain while 42 patients
had left sided pain. The
distribution of pain in the divisions of the trigeminal nerve was as
follows: V1= 6.9% of patients; V2=
28.4%; V3= 23.3%; V1 and V2= 15.5%; V2 and V3= 15.5%; and V1 and V2 and V3=
11.2%. Pre-operative facial numbness was noted in 34 patients (25%).
The vast majority of the patients had at some point been
treated with more than one pharmacological agent, and all patients were
refractory to medical treatment. In addition, seventy-four patients had undergone previous surgical
procedures for treatment of their facial pain. Twenty–three (17%) underwent MVD, 46 (34%) had glycerol
injections, 2 (1.5%) had radiofrequency rhizotomies, and 32 (24%) had
neurectomies.
A total of 151 Gamma Knife surgeries were performed on these 136
patients with 14 undergoing a second Gamma Knife surgery and one undergoing three
Gamma surgeries. Radiosurgery was
performed using the Model U (1989 to June 2001) and Model C (July 2001 to
present) Gamma Knifes (Elekta Instruments, Norcross, GA). The Leksell model G head frame was
applied in the main operating room under local anesthesia with light
intravenous sedation (typically propofol or fentanyl and versed). Most patients were treated with one
isocenter (median 1, range 1 to 7) delivered with the 4mm collimator helmet.
Maximal doses ranged from 50 to 90 Gy, and the median dose
was 80 Gy. The maximum
prescription doses were as follows: 50 Gy in 0.7% of procedures; 60 Gy in 0.7%;
70 Gy in 43%; 80 Gy in 55%; and 90 Gy in 0.7% of cases. In each case, the root entry zone (REZ)
was encompassed within the treatment plan to allow a low dose of radiation
(approximately 20 to 30 Gy) to the edge of the pons. The doses less than 70 Gy were only given at
retreatment. The center of the
targeting was typically chosen 2 to 4 mm anterior from the junction of the
trigeminal nerve and the pons. Targets
were categorized into two groups. The first group of targets is when the trigeminal nerve was covered with
the 50% isodose outside of the brainstem. The second category of targets was when the 50% isodose
curve was adjacent to the surface of the brainstem. Fifty-two percent of patients were
treated using the first target strategy and forty-three percent were treated
using the second strategy.
The trigeminal nerve was typically imaged using a 1.5 Tesla
MRI unit. Localization was performed using T1-weighted and fast spin
echo T2-weighted axial images along with coronal images of the nerve. The axial volume acquisition of 512x216
matrices was divided into sections of 1 mm without gaps. T1 weighted images were also repeated
after administration of gadolinium. Two patients underwent computed tomography (CT) cisternography for targeting because of
medical conditions (e.g. a pacemaker) that prohibited MR imaging. However, CT cisternography is not ideal for targeting
purposes.
Clinical Follow-up of
Patients
136
of 151 patients were available for follow-up. Patients received direct clinical
follow-up every 3 to 6 months. If the patient failed to make his clinical
appointment, a questionnaire was sent to the patient. On that questionnaire, patients were asked to assess their
pain intensity, time to onset of pain relief, presence or absence of facial
numbness, pharmacological agents taken for pain, and whether they underwent
additional surgical interventions for treatment of facial pain. Patients were specifically asked if
they were pain free or had improvements in their pain following Gamma
surgery. They were also asked
about the presence of new or worsened facial numbness post-operatively.
Imaging Follow-up of Patients
Patients received routine MRI examinations 6 to
9 months after Gamma Knife surgery. T1-weighted sequences with and without contrast and T2-weighted images
were performed to evaluate for any adverse consequences. If a patient developed the onset of new
facial numbness post-radiosurgery, that patient underwent additional MRI
testing at the time of the onset of the numbness to evaluate for any brain
tissue changes.
All serial follow-up information was obtained via direct
contact with the patient or their referring physicians. The tests and scoring
methods were validated Univariate and multivariate analysis were performed to assess for
variables that were predictive of a pain free outcome after Gamma Knife surgery. The following variables were
assessed: right sidedness of the
pain; typical or atypical pain; age; gender; number of isocenters; target
distance from nerve root entry zone (either the 50% isodose well outside of or
adjacent to the brainstem); maximal dose; presence of post-GK imaging changes;
presence of previous interventions; a previous MVD; previous glycerol
injection; previous neurectomy; increasing length of time from diagnosis to
Gamma surgery; distribution of the pain; the presence of pre-operative facial
numbness; the presence of post-operative facial numbness; and recurrence of
pain in those patients who were treated more than once with Gamma surgery. The unpaired Student’s t-test or
analysis of variance were used for continuous variables. Nominal or ordinal data was compared
using the two-tailed Fisher’s exact test. All statistical analyses were conducted with the aid of Statview 5.01
(SAS Institute, Cary, NC).
We did not use a power calculation as
no control group was studied. P<.05 was chosen as the
level of statistical significance. Table 1: Table 1: Summary of Patients Treated with Gamma Surgery for Trigeminal NeuralgiaAttribute | Number | Range |
---|
| | | Total number of patients | 136 | | Male | 66 | | Female | 70 | | Age (years) | 68 | 22 to 90 | Median Follow-up (months) | 19 | 2 to 96 | Median Time from Diagnosis to Gamma Surgery | 72 | 1 to 276 | number of patients w/ previous treatment for TGN | 74 | | Microvascular decompressions | 23 | | Glycerol injections | 46 | | Radiofrequency rhizotomies | 2 | | Neurectomies | 32 | | Patients with Typical trigeminal neuralgial pain | 122 | | Patients with Atypical facial pain | 14 | | Atypical trigeminal neuralgia pain | 3 | | Multiple sclerosis associated trigeminal neuralgia | 4 | | Cavernous sinus tumor and trigeminal neuralgia | 7 | | Right Sided Pain | 94 | | Left Sided Pain | 42 | | Median Number of Isocenters | 1 | 1 to 7 | Median Dose (Gy) | 80 | 50 to 90 | Number of Patients undergoing Gamma Knife Surgeries | | | One Gamma Surgery | 136 | | Two Gamma Surgeries | 14 | | Three Gamma Surgeries | 1 | | Pre-operative numbness | 34 | | New post-operative numbness | 12 | | New or worsened post-operative numbness | 26 | | Number of patients w/ recurrence of TGN | 33 | | Median time to recurrence of TGN (months) | 12 | 2 to 34 |
Clinical Outcome
Median follow-up in the 136 patients was 19
months. The median interval from
the treatment to symptom improvement was 24 (range 1-180) days. Few patients experienced a benefit more
than 2 months following radiosurgery. At the last time of follow-up, 44% of patients were pain free without
medication, and 56% still had some degree of pain. The percentage of patients who were
pain free without medication at specific time points was as follows: 47% at 1 year (of 118 patients with 1
year follow-up); 45% at 2 years (of 64 patients with 2 years follow-up); and
34% at 3 years (of 39 patients with 3 years follow-up). In a similar fashion, those who
experienced some improvement in pain post-radiosurgery were as follows: 90% at 1 year (of 118 patients with 1
year follow-up); 77% at 2 years (of 64 patients with 2 years follow-up); and
70% at 3 years (of 39 patients with 3 years follow-up). Forty-six percent of those with typical TN (n=122) were pain
free at last follow-up whereas only 29% of those with atypical TN (n=14) were
pain free (p=0.35, t-test).
During follow-up, 33 patients had recurrence of
their pain after some initial relief. The median time to recurrence of facial
pain was 12 months. Among those
patients with recurrence of pain, 14 patients underwent an additional Gamma
Knife surgery, 6 patients had a microvascular decompression, 4 patients a glycerol
injection, 1 patient a radiofrequency rhizotomy, and 5 patients refused any
further treatment.
Clinical Complications
Twelve patients (9%) experienced new
post-operative numbness following Gamma Knife surgery. In our study, 4 patients out of 14 who
had repeat Gamma surgery (29%) had new facial numbness. Eight out of 122 patients who had only
one Gamma Knife surgery (7%) developed new facial numbness. There was a statistically significant difference in the
incidence of new facial numbness in these two group (p=0.002, t-test). We were unable to establish a
significant relationship between radiation dose and post-operative facial
numbness. No patient experienced
the new onset of corneal reflex loss or anesthesia dolorosa.
A total of 26 patients had either new or
worsened facial numbness after Gamma surgery. The severity of the numbness was as follows: 12 patients with mild numbness; 10 with
somewhat disturbing numbness; and 4 with severe numbness. Twenty-one of 122 patients (17%)
receiving only one Gamma surgery developed new or worsened facial numbness
while 5 out of 14 patients (36%) receiving more than one Gamma surgery
experienced new or worsened symptoms. The difference was not statistically significant (p=0.14, T-test). In addition, 12 of 46 patients (26%)
with a history of glycerol injection experienced new or worsened facial numbness
as compared to 14 out of 90 patients (16%) without a history of glycerol
injection (p=0.14, T-test). One
patient described that the facial numbness was worse than the original TGN pain
because it led to drooling. She did not have anesthesia dolorosa.
Imaging Outcome
Nine patients (6.6%) had post-radiosurgical imaging changes
including focal contrast enhancement or focal T2-weighted signal change. Among those nine patients who
had post-operative imaging changes, 4 had no numbness, 3 had mild numbness, and
2 had severe numbness.
In
order to evaluate the efficacy of Gamma radiosurgery in a rigorous fashion, we
chose to consider factors that were statistically related to a pain free
outcome at the last time of follow-up. Seventeen factors in all were tested. In univariate analysis, right sidedness
to the pain (p=0.0002) and a previous neurectomy (p=0.04) were statistically
related to a pain free result. In
multivariate analysis, again right sidedness (p=0.032), and this time
increasing age (p=0.05) were related to a pain free result. No other factors were significantly
related (i.e. p>0.05) to a pain free result following Gamma Knife surgery.
The
underlying etiology of trigeminal neuralgia has been the subject of intense
investigation for more than a century. Research by Pfluger (1859) and Heidenhain (1861) demonstrated that the
proximal end of a nerve was more excitable than the distal end and that the
excitability of the nerve increased near the region of a cross section.
By 1941, Olivecrona described that
mechanical pressure along the root or at the level of the ganglion could be the
cause of trigeminal neuralgia. Granit, Leksell, and Skoglund (1944) demonstrated that local
pressure on nerve fibers could result in painful afferent discharges from the
injured neural segment. Jannetta and others have suggested that vascular compression of the
trigeminal nerve may be a causal agent in trigeminal neuralgia.1,12
Following the successful long-term outcome of two patients
who had trigeminal neuralgia radiosurgery using ortholvoltage x-rays Leksell
and Hakanson treated 48 patients between 1970 and 1978, and follow-up
information was available on 46 of these patients . In the first 24 patients, plain
stereotactic skull X-rays were used for targeting, and 33% were pain free at 6
months while only 8.3% were pain free at a mean follow up of 26 months
(Personal communication, Sten Hakanson, 2004). In the second set of 22 patients, the position of the
Gasserian ganglion was determined by transoval cisternography using tantalum
dust. For that group, the
percentages of patients who were pain free at 6 and 26 months were 59% and 18%,
respectively.
Overall, the treatment of choice for trigeminal neuralgia
remains microvascular decompression. However, for patients who are ineligible for or unwilling to undergo
more invasive neurosurgical procedures, Gamma Knife surgery offers a reasonable
alternative. Gamma Knife surgery also
does not carry the same type and degree of risks that microvascular
decompression does. For instance,
in a long-term series of microvascular decompression patients, there were the
following risks from the series by Dr. Jannetta: 0.2% death; 0.1% brain stem infarct; and 1% hearing loss.1 None of these complications were
observed in our series nor were they associated with radiosurgical treatment of
trigeminal neuralgia in other major centers. Ultimately, the patient must choose the type of intervention
he or she is willing to undergo.
Measuring Pain Relief
We believe it is better to grade patient outcome in a
straightforward fashion by reporting pain free outcomes off medications. Such an endpoint is readily
understandable to patients, neurosurgeons, and referring physicians of all
backgrounds. Reporting outcomes in
terms of subjective degrees of pain relief may lead to confusion for patients
and physicians alike. As a means
of comparing our results to other studies which report pain relief rather than
pain free outcomes, we do note the numbers of patients who reported
improvements in their trigeminal neuralgia. In our study, pain relief meant that the patients were still
on medications but thought their pain was improved after Gamma Knife surgery. This result is arguably very meaningful
to patients with severe pain and can translate into a significant improvement
in the quality of life.
The variable history of trigeminal neuralgia is
the other major difficulty in analyzing results from small to medium size
retrospective studies. Trigeminal
neuralgia can be characterized by spontaneous partial or complete
remissions. The characteristic
waxing and waning nature as well as the subjectivity of pain, sensory loss, and
paresthesias makes a longer follow-up period and straightforward endpoints
essential.
Prognostic Factors for Pain Relief
In our study, multivariate analysis revealed
that right sided pain and age correlated with a pain free outcome. In our study, it is notable that a pain
free outcome was not related to dose, sensory loss, slight differences in
target selection, or the type of pain (i.e. either atypical or typical
trigeminal neuralgia).
The relationship between a previous
neurectomy and Gamma Knife surgery in terms of a pain free outcome suggests the
efficacy of the Gamma Knife may not be reduced after a peripheral neurectomy. Clearly, the Gamma Knife and a peripheral
neurectomy target proximal and distal portions of the symptomatic trigeminal
nerve, respectively. In a subset
of patients, it is possible that both proximal and distal portions of the nerve
should be lesioned to provide adequate pain relief. The effect of age on outcome may in part be due to the
generally older age of the patient treated with Gamma Knife (median age of 68)
and the fact that many of these patients had had Gamma surgery as a first line
treatment.
Other studies have reported different factors
that were associated with a better response to Gamma Knife surgery. These include typical trigeminal
neuralgia rather than atypical pain from multiple sclerosis or other causes13,
higher doses of radiation3, a target closer to the brainstem,
and no prior surgery6. Another favorable prognostic factor in patients with no prior surgical
intervention is MRI evidence of blood vessel contact with the trigeminal nerve.4 In the present study, we did not find
these factors related to a pain free outcome.
Complications of Gamma Knife surgery
The most frequent complication following radiosurgical
treatment of trigeminal neuralgia is facial numbness. The incidence of new trigeminal dysfunction varies from 6%
to 66%.2,3,4,5,8,14,15 In this series, 12 out of 136 patients (9%) developed new facial numbness
following Gamma Knife surgery. In
our study, only 1 patient received a dose of 90 Gy and no facial numbness was
noted in this case. Fortunately,
we did not observe cases of anesthesia dolorosa or absence of the corneal
reflex in the 136 patients.
In our study, 29% of patients who had repeat
Gamma Knife surgery had new facial numbness whereas 7% of patients who had only one
Gamma Knife surgery developed new facial numbness (p=0.002, t-test). In a series of 18 patients who underwent
repeat radiosurgery, Herman et al. (2004) noted an 11% incidence of new or
worsened facial numbness which was not substantially elevated over the risk of
facial numbness for those having only one Gamma Knife surgery.7 However, Hasegawa et al. (2002) noted an increased risk of facial numbness associated
with repeat Gamma surgery.6
Gamma
Knife surgery is a relatively safe and effective treatment option for patients
with medically refractory trigeminal neuralgia. The improvements in pain
following Gamma surgery diminish somewhat with time, but this is true for other
treatments as well. Studies of
long term durability are important. Future work should consider randomized trials between the
different therapeutic options in patients appropriate for randomization. The Author(s) wish to thank: Ladislau Steiner
This work was presented in part in a prior work with the JOURNAL OF NEUROSURGERY.
No external funding was utilized for this study.Project Roles:
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