Professional Documents
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5
5
a
Department of Neurology, Faculty of Health and Medical Sciences, Danish Headache Center, Rigshospitalet-Glostrup, University of
Copenhagen, Glostrup, Denmark; bPain Management Centre, National Hospital for Neurology and Neurosurgery, London; cEastman
Dental Hospital, UCLH NHS Foundation Trust, London; dTrigeminal Neuralgia Association UK, Oxted, Surrey, UK; eClinic of
Neurology, University of Tartu, Tartu, Estonia; fDepartment of Human Neuroscience, Sapienza University, Rome, Italy; gHeadache and
Pain Department, CHU La Timone, APHM, Marseille, France; hDepartment of Neurosurgery, Oslo University Hospital-Rikshospitalet,
Correspondence: L. Bendtsen, Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, Faculty of Health and Medical
Sciences, University of Copenhagen, 2600 Glostrup, Denmark (tel.: +45 38633065; fax: +45 38633839; e-mail: lars.bendtsen@regionh.dk).
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© 2019 EAN
EAN GUIDELINE ON TRIGEMINAL NEURALGIA 833
© 2019 EAN
834
Table 1 Diagnostic accuracy of clinical features for distinguishing secondary TN (STN) from primary (classical and idiopathic) TN (PTN)
L. BENDTSEN ET AL.
CC, case–control; CI, 95% confidence interval; CO, cohort survey; CS, case series; MS, multiple sclerosis; P assoc, probability of statistically significant association between the presence of the
characteristic and the presence of STN; P, prospective data collection; Pos LR, positive likelihood ratio; PTN, primary (idiopathic and classical) trigeminal neuralgia; R, retrospective or not
described data collection; Sen, sensitivity (sensitivities calculated for the presence of the characteristic in STN); Spe, specificity (specificities calculated for the absence of the characteristic in STN);
STN, secondary trigeminal neuralgia. aApproximate estimates based on symptom duration extracted from current age; bbilateral trigeminal neuralgia excluded a priori.
© 2019 EAN
EAN GUIDELINE ON TRIGEMINAL NEURALGIA 835
sought. Also papers addressing the role of laboratory 51% respectively. These findings indicate that mas-
tests in detecting trigeminal afferent damage in other seter inhibitory reflex testing, showing an almost abso-
neuropathic facial pain conditions were sought. Eight lute specificity, reliably demonstrates nerve damage,
studies reported the trigeminal reflex findings in whereas the relatively low sensitivity makes the finding
patients with TN [6,14–20] (Table 2). The diagnostic of a normal masseter inhibitory reflex by no means
accuracy of trigeminal reflexes for identifying sec- sufficient to exclude nerve damage. J€ a€
askel€ainen and
ondary TN patients was relatively high with sensitivity colleagues [28] found abnormal mental and lingual
59%–100% and specificity 93%–100%; pooled sensi- nerve blink reflexes in 38% of patients with trigeminal
tivity 94%; pooled specificity 88%. Six studies neuropathy due to surgical procedures. Trigeminal
reported the evoked potential findings in patients with reflex recording is particularly helpful in rare cases
TN [17,19,21–24] (Table 3). In contrast to the trigemi- of trigeminal isolated sensory neuropathy and facial-
nal reflexes, evoked potentials may be altered even in onset sensory motor neuropathy syndrome [29] that
idiopathic or classical TN. A pooled sensitivity of may manifest, in early stages, with unilateral paroxysmal
84% and a pooled specificity of 52% were found. pain.
Two studies reported trigeminal reflex and evoked
potential findings in patients with post-herpetic Clinical guide
neuralgia [25,26]. The diagnostic accuracy of neuro- Magnetic resonance imaging is the first-choice tool for
physiological tests for identifying trigeminal afferent diagnosing secondary TN. If MRI is contraindicated or
damage in the affected side was high with pooled unavailable, testing of trigeminal reflexes is useful to
sensitivity 100%; pooled specificity 100% and 88% distinguish secondary TN from primary TN. Trigemi-
respectively. One study reported masseter inhibitory nal reflexes and evoked potentials are also needed to
reflex findings in iatrogenic damage to the mandibular detect trigeminal afferent damage in patients with
nerves [27]. Specificity and sensitivity were 99% and different neuropathic facial pain conditions.
Table 2 Diagnostic accuracy of trigeminal reflex testing for distinguishing secondary TN (STN) from primary TN (PTN)
First author Year STN A/T PTN A/T P assoc Spe (CI) Sen (CI)
A/T, abnormal/total; CI, 95% confidence interval; NS, not significant; P assoc, probability of statistically significant association between the
presence of the characteristic and the presence of STN; PTN, primary (idiopathic and classical) trigeminal neuralgia; Sen, sensitivity (sensitivi-
ties calculated for the presence of abnormal trigeminal reflexes in STN); Spe, specificity (specificities calculated for the absence of abnormal tri-
geminal reflexes in STN); STN, secondary trigeminal neuralgia.
Table 3 Diagnostic accuracy of evoked potentials for distinguishing secondary TN (STN) from primary TN (PTN)
First author Year Method STN A/T PTN A/T P assoc Spe (CI) Sen (CI)
Leandri [21] 1988 Electrical TEPs 18/23 9/38 <0.0001 76% 78%
Cruccu [17] 1990 Electrical TEPs 4/4 9/30 <0.05 70% 100%
Cruccu [22] 2001 Laser EPs 20/20 24/47 <0.0001 49% 100%
Mursch [23] 2002 Electrical TEPs 6/10 13/37 NS 65% 60%
Squintani [19] 2015 Laser EPs 11/11 NS 0
Obermann [24] 2007 PREPs 24/24 NS 0
Pooled 48/57 90/187 <0.0001 52% (45–59) 84% (73–91)
A/T, abnormal/total; CI, 95% confidence interval; EPs, evoked potentials; NS, not significant; P assoc, probability of statistically significant associa-
tion between the presence of the characteristic and the presence of STN; PREPs, pain-related evoked potentials; PTN, primary (idiopathic and classi-
cal) trigeminal neuralgia; Sen, sensitivity (sensitivities calculated for the presence of abnormal evoked potentials in STN); Spe, specificity (specificities
calculated for the absence of abnormal evoked potentials in STN); STN, secondary trigeminal neuralgia; TEPs, trigeminal evoked potentials.
© 2019 EAN
836 L. BENDTSEN ET AL.
89 (83–93)
NVC in primary TN); Symp NVC, number of neurovascular contacts of any kind on the symptomatic (painful) side; T, tesla; TN, trigeminal neuralgia. Morphological changes were defined as com-
Asymp NVC, number of neurovascular contacts of any kind on the asymptomatic (pain-free) side; CI, 95% confidence interval; MRI, magnetic resonance imaging; NCV + MC, neurovascular con-
tact with morphological changes; No., number of patients; Sen, sensitivity (sensitivities calculated for the presence of NVC in primary TN); Spe, specificity (specificities calculated for the absence of
pression, distortion, dislocation or atrophy of the trigeminal nerve at the site of a neurovascular contact. aThe study is based on 18 patients but in two patients NVC status could not be judged due
Spe (CI) %
Final recommendations
In cases where MRI is contraindicated or unavailable, a
Table 4 Prevalence, associations, sensitivity and specificity of MRI-verified neurovascular contact of any type and with morphological changes in patients with primary (idiopathic and classical)
strong recommendation is given about the use of
100
87
92
trigeminal reflexes to distinguish secondary TN from
primary TN. For patients with TN, abnormal trigemi-
Sen (CI) %
54 (46–61)
nal nerve evoked potentials are probably associated
with an increased risk of secondary TN. However, there
44
53
67
to artefacts; to enable calculation of the odds ratio for NVC + MC 0.5 was added to each cell; bfor the purpose of this guideline the authors provided the original datasets.
is too much overlap in patients with primary TN and
0.023
˂0.001
0.001
˂0.001
secondary TN for this predictor to be considered clini-
value
cally useful. A strong recommendation is given against
P
using evoked potentials to identify secondary TN. In
patients with different neuropathic facial pain condi-
Odds ratio
13.3 (5.8–
tions, trigeminal reflexes and evoked potentials are
30.6)
15.0
11.6
15.0
needed to detect trigeminal afferent damage.
NVC + MC
Clinical question 1.3: What role does NVC play in
Asymp
primary TN?
0
18
20
Search strategy and results
NVC + MC
Reports of prospective studies of broad-spectrum pri-
mary TN patients were sought, comparing the blinded
Symp
symptomatic and asymptomatic side by high resolu-
7
71
16
94
tion MRI and grading the NVC as to whether there
are morphological changes of the trigeminal nerve.
Spe (CI) %
31 (25–39)
‘Broad spectrum’ was defined to be TN patients from
neurological settings. Three studies were identified ful-
62
22
63
filling the search criteria [30–32]. All three studies
were prospective cohort studies.
Sen (CI) %
86 (80–91)
Neurovascular contact of any kind was a frequent
finding on the asymptomatic side (120/175 asymp-
63
89
88
tomatic nerves) (Table 4), whilst NVC with morpholog-
ical changes was a rare finding on the asymptomatic
0.221
0.014
0.006
˂0.001
value
7.0
Asymp
Clinical guide
NVC
9
105
120
10
120
21
151
16
135
24
175
1.5 T
MRI
field
1995
2014
2014
confidence
Masur [30]
TN (PTN)
Maarbjerg
interval
Author
Pooled
[32]b
© 2019 EAN
EAN GUIDELINE ON TRIGEMINAL NEURALGIA 837
Table 5 Association between neurovascular contact without morphological changes and the symptomatic side in idiopathic TN and association
between neurovascular contact with morphological changes and the symptomatic side in classical TN
Idiopathic TN Classical TN
Asymp NVC, number of neurovascular contacts of any kind on the asymptomatic (pain free) side; NCV + MC, neurovascular contact with
morphological changes; No.: number of patients; Symp NVC, number of neurovascular contacts of any kind on the symptomatic (painful) side;
TN, trigeminal neuralgia. Morphological changes were defined as compression, distortion, dislocation or atrophy of the trigeminal nerve due
to a neurovascular contact. aThe study is based on 18 patients but in two patients NVC status could not be judged due to artefacts; for the cal-
culation of odds ratio for NVC + MC 0.5 was added to each cell; bfor the purpose of this guideline the authors provided the original datasets.
without morphological changes does play a role in No randomized controlled trials (RCTs) were
some idiopathic TN patients who are therefore not identified. Fifteen studies were found investigating the
truly ‘idiopathic’. In idiopathic TN, and probably also accuracy of preoperative imaging examination to
to a lesser degree in classical TN, other currently predict the presence of NVC [34–48]. All studies com-
unknown aetiological factors probably play an impor- pared the preoperative imaging analysis with surgical
tant role. data. Nine studies were performed using a 1.5-T MR
scanner [34,36,38,40–43,45,46], six with a 3-T scanner
Final recommendations [35,37,39,44,47,48], five studies applied an imaging
Based on a high quality of evidence, a strong indication protocol with only 3D TOF-MRA [34,37,40,43,45]; five
is given that idiopathic TN is moderately associated with a combination of 3D T2-weighted and 3D TOF-
with NVC without morphological changes and that MRA [36,38,39,42,46]; two with a combination of 3D
classical TN is highly associated with NVC with T2-weighted, 3D TOF-MRA and 3D T1-Gad [41,48];
morphological changes. Therefore, demonstration of two with a combination of 3D TOF-MRA and 3D T1-
NVC should not be used to confirm the diagnosis of Gad [35,47]; and one study with a combination of 3D
TN. Rather, it may help to decide if and when a T2-weighted and 3D fluid-attenuated inversion recov-
patient should be referred for an MVD. ery (FLAIR) [44]. The sensitivity and the specificity of
the imaging protocol in detecting NVC varied, respec-
tively, from 67% to 100% and from 50% to 100%.
Clinical question 1.4: For patients with TN, which kind
of imaging should be done to demonstrate NVC and
Clinical guide
rule out other causes of TN?
Standard MRI can be used to exclude secondary
Search strategy and results intracranial pathology such as MS and tumours but
Trigeminal neuralgia studies evaluating NVC using has not proved to be sufficient to establish or exclude
MRI, three-dimensional (3D) imaging, 3D T2- vessel–nerve contact. High-spatial-resolution 3D T2
weighted imaging, 3D time-of-flight (TOF) magnetic sequences (driven equilibrium, DRIVE; construc-
resonance angiography (MRA) and 3D T1-weighted tive interference in steady state, CISS; fast imaging
gadolinium (T1-Gad) were sought. Studies using employing steady state, FIESTA) all allow excellent
imaging protocols were investigated to facilitate the contrast between the cerebrospinal fluid (hypersignal)
diagnosis of TN and to detect the presence of NVC and neurovascular structures (hyposignal) producing
in comparison to intra-operative data. The following high-performance cisternography [48]. The limitations
criteria for acceptable studies were set: (i) diagnostic are the lack of signal differentiation, not only between
criteria stated; (ii) a minimum of 20 patients who arteries and veins and between vessels and nerves, but
had undergone MVD to allow a comparison with also for the brain parenchyma. 3D TOF-MRA pro-
preoperative imaging analysis; (iii) MRI characteris- vides good visualization of the arteries in hypersignal,
tics (machinery and sequences) stated; (iv) blinded contrasting with the cerebrospinal fluid in hyposignal.
control studies; and (v) unequivocal data of sensitiv- Nerves are visible, but they are difficult to distinguish
ity and/or specificity for detection of NVC. because of their intermediate signal [48]. Veins,
© 2019 EAN
838 L. BENDTSEN ET AL.
because of their low flow, are not usually visible, espe- exacerbations of TN. It is clinical experience that intra-
cially if a band of presaturation filter is applied. 3D venous infusion of fosphenytoin and lidocaine is effective
T1-Gad allows the visualization of nerves in interme- for pain relief of acute exacerbations, but evidence is
diate signal in relation to cerebrospinal fluid and lacking. The intravenous infusion should be performed
shows both arteries and veins in hypersignal [48]. only under specialist supervision because hospital admis-
Three tesla is probably preferable over 1.5 T. Thin sion and cardiac monitoring are required.
slices should be used. It should be described whether
a vessel contact causes morphological changes of the Final recommendations
nerve. It is recommended that the neuroradiologist is Given the very low quality of evidence there is weak
blinded to the side of pain in order to avoid bias recommendation for the use of intravenous fospheny-
in evaluation of NVC. If MRI is unavailable or toin and lidocaine in acute exacerbations of pain.
contraindicated a computed tomography scan with
contrast should be considered to rule out tumours.
Clinical question 2.2: For patients with primary TN,
which drugs have been demonstrated to be effective
Final recommendations
for the treatment of pain in the long term?
Magnetic resonance imaging should be performed in
all patients to exclude secondary causes of TN. A PICO
combination of three high-resolution sequences – 3D Population: patients with primary TN
T2-weighted, 3D TOF-MRA and 3D T1-Gad – aids Intervention: most used drugs
the detection of a possible NVC. The neuroradiologist Comparison: no treatment or most used drugs
should be blinded to the side of pain. It should be Outcome: reduction of pain to an acceptable level
described whether a vessel contact causes morphologi- with acceptable side effects for the patient (grade
cal changes of the nerve. These recommendations are of importance: critical).
based on low quality of evidence. Search strategy. Criteria for inclusion were published
systematic reviews and RCTs, at least single-blinded
and containing more than 10 individuals, of whom
Section 2: Pharmacological treatment
more than 80% were followed up. For GRADE eval-
uation see Table 6. Results for each of the relevant
Clinical question 2.1: For patients with primary TN,
drugs are as follows.
which interventions are effective in the treatment of
acute exacerbations of pain?
Carbamazepine
Search strategy and results Results. From the systematic reviews [53] and RCTs
Reports on the use of intravenous drugs in the emer- [54–58], carbamazepine seems to be more effective at
gency management of TN were sought. relieving pain compared with placebo but more patients
One RCT on the use of intravenous lidocaine in withdrew when using carbamazepine than placebo
acute exacerbation was found [49]. In this trial, a sin- because of side effects. All the RCTs were small and short
gle dose of intravenous lidocaine (5 mg/kg over term although some converted to open label follow-up,
60 min) was superior in reducing pain intensity com- used simple measures for pain outcomes and reported no
pared to placebo during the first 24 h after the infu- quality of life outcomes. One RCT showed improved
sion. The most common side effect was somnolence. outcome if ropivacaine injections were added [59].
Three reports were found, totalling five patients with Clinical guide. Carbamazepine is considered the gold
acute exacerbations of TN, responding to intravenous standard for the initial medical treatment of TN. Car-
infusion of phenytoin or fosphenytoin, with pain relief bamazepine has been shown to increase pain relief com-
lasting 2 days [50–52], but no RCT has been con- pared with placebo, but also causes adverse effects such
ducted. No reports supporting the use of opioids in as drowsiness, dizziness, rash, liver damage and ataxia
acute exacerbations of TN were found. and has the potential for multiple drug interactions.
Consensus expert opinion suggests that carbamazepine
Clinical guide may have a 50% failure rate for long-term (5–10 years)
In acute exacerbations, in-hospital treatment may be nec- pain control [58,60]. Based on the strength of published
essary for titration of anti-epileptic drugs and rehydra- evidence, carbamazepine remains the best supported
tion. Acute pain relief is crucial for affording a window standard medical treatment for TN.
of opportunity to adjust oral drugs and to control pain in Recommendation. Based on a moderate quality of
consideration of a possible neurosurgical intervention. It evidence, a strong recommendation is given that
is clinical experience that opioids are not effective in acute carbamazepine is used for long-term treatment of TN.
© 2019 EAN
EAN GUIDELINE ON TRIGEMINAL NEURALGIA 839
GRADE
Studies Effect quality of
(participants) Outcome Comparison Design Quality size evidence Direction Strength Comment
Wiffen (208) Pain Carbamazepine RCT 3 +2 Moderate For Strong Quality points deducted for
[53] relief up to 2400 mg crossover design and short
vs. placebo follow-up; directness point
deducted for inclusion of
different pain severities and
uncertainties about
diagnostic criteria and
outcomes measured; effect
size points added for
RR = 5 or higher
Liebel (48) Pain Oxcarbazepine RCT 3 0 Very low For Strong Quality points deducted for
[61] relief 750 mg vs. sparse data, incomplete
carbamazepine reporting of results, and no
direct comparison between
groups
Zakrzewska Pain Lamotrigine RCT 3 0 Very low For Weak Quality points deducted for
(14) [64] relief 400 mg as add- sparse data and crossover
on vs. placebo design with no pre-
crossover results; directness
point deducted for
concurrent use of other
medications
Yuan (1331) Pain Gabapentin up RCT 3 +1 Low For Weak High risk of bias, wide
[65] relief to 3600 mg vs. confidence limits
carbamazepine
Morra (178) Pain Botox vs. RCT 3 0 Very low For Weak Variable techniques and
[66] relief placebo, dosages, varying time
variable doses periods, quality points
deducted for risk of bias,
small sample sizes, similar
age and duration of
symptoms but other drug
usage unknown, missing data
RCT, randomized controlled trial; RR, relative risk; TN, trigeminal neuralgia.
© 2019 EAN
840 L. BENDTSEN ET AL.
be escalated slowly in order to avoid rashes, and it is rehydration and intravenous infusion of fosphenytoin
therefore not appropriate for acute management of TN. or lidocaine. For long-term treatment carbamazepine
Recommendation. Based on a very low quality of evi- (200–1200 mg/day) or oxcarbazepine (300–1800
dence, a weak recommendation is given that lamotrig- mg/day) remain the most effective medications espe-
ine is used either as monotherapy or as add-on cially in the early stages of TN. Sometimes even
therapy for long-term treatment of TN. higher doses are needed. Retard (slow release) prepa-
rations are available but there are no studies to com-
Gabapentin pare them with the conventional forms. However, if
Results. One systematic review was found [65] which these drugs become ineffective or result in poor toler-
was based on 16 RCTs, all published in Chinese, com- ability, then other drugs need to be considered.
paring gabapentin with carbamazepine. However, the Based on low to very low quality of evidence, lamot-
diagnostic criteria used were not clarified and the rigine, gabapentin, botulinum toxin type A, prega-
dosages used varied. Gabapentin is probably associated balin, baclofen and phenytoin may be used either as
with fewer adverse effects than carbamazepine and monotherapy or combined with carbamazepine or
oxcarbazepine. oxcarbazepine when first-line drugs fail due to either
Clinical guide. Clinical experience shows that gabapen- efficacy or tolerability. Patients should be encouraged
tin has a lower effect but also fewer adverse events to alter the dosages depending on pain severity and
than carbamazepine and oxcarbazepine. Gabapentin side effects, as periods of partial or complete remis-
can be used in patients who cannot tolerate carba- sion do occur [68]. However, it is crucial that
mazepine and oxcarbazepine, or in addition to carba- patients are instructed to increase and decrease
mazepine or oxcarbazepine when the latter become dosages slowly over several days. It is not essential
less effective. to try out all the drugs prior to referral for a neuro-
Recommendation. Based on low quality of evidence, a surgical opinion. It remains the responsibility of the
weak recommendation is given that gabapentin is used managing doctor to ensure that the patient is aware
either as monotherapy or as add-on therapy for long- of neurosurgical options and can take an informed
term treatment of TN. decision about choice of treatment.
© 2019 EAN
EAN GUIDELINE ON TRIGEMINAL NEURALGIA 841
GRADE
Clinical guide
Based on expert opinion, medical management with
Low
Low
Low
Low
Low
adequate doses and regular monitoring is recom-
mended before offering surgery for TN. Existing data
indicate that not all patients need surgery, but also
(1.4–4.6)
that some patients may be referred for surgery too
late. No data indicate how many drugs must be tested
3.35
2.25
RR
before surgery should be offered.
Final recommendations
K–M curve
P = 0.0002
P = 0.089
P = 0.003
P = 0.006
Based on a very low quality of evidence, medical man-
log rank,
agement is recommended before offering surgery for
TN. Patients should be offered surgery if their pain is
not sufficiently controlled medically or if medical
K–M, Kaplan–Meier; RR, relative risk. aOutcome, percentage of patients pain-free on no medication; bposterior fossa exploration; 91% had MVD.
treatment is poorly tolerated and should be informed
MVD 61–80%
GKS 33–56%
of the possibility at an early stage.
MVD 80%
MVD 61%
GKS 33%
GKS 47%
Outcomea
4–5 years
Outcome
5-years
Clinical question 3.2: Which surgical technique gives
the longest pain-free period with the fewest
complications?
MVD 77%
Search strategy and results
GKS 56%
Outcomea
4-years
Trials involving MVD, other posterior fossa surgery
[partial sensory rhizotomy (PSR) and internal neuroly-
sis (IN)], gamma knife surgery (GKS), radiofrequency
Table 7 Prospective trials comparing microvascular decompression (MVD) and gamma knife surgery (GKS)
MVD 68–88%
GKS 50–71%
MVD 88%
1–2 years
Outcome
comparative trials involving any two of the above
2-years
MVD 84%
MVD 83%
GKS 58%
GKS 66%
GKS 71%
Outcomea
MVD (287)
MVD (91)b
GKS (120)
GKS (274)
GKS (61)
MVD (24)
MVD (36)
MVD (N)
GKS (44)
GKS (49)
© 2019 EAN
842 L. BENDTSEN ET AL.
Table 8 Retrospective trials comparing microvascular decompression (MVD) and gamma knife surgery (GKS)
MVD (N)
Author GKS (N) Outcome time point Outcome GRADE
Oh 2008 [81] MVD (27) 33 months (mean) MVD 63% Very low
GKS (18) GKS 56%
Dai 2016 [78] MVD (87) 2 years MVD 72% Very low
GKS (115) GKS 60%
Nanda 2015 [79] MVD (20) 5.3 years (median) MVD 75% Very low
GKS (49) GKS 37%
Inoue 2017 [80] MVD (179) 3.3 years (median) MVD 80% Very low
GKS (52) 5.0 years (median) GKS 39%
the superiority of MVD over GKS with a substantial Single intervention trials. No RCTs were identified.
effect size at both medium and long term (Table 7). Forty-five non-randomized cohort studies fulfilling the
At 1–2 years postoperatively, 68%–88% of patients search criteria (seven, three, five, eight, one and 21
who underwent MVD reported being free from pain studies for RFTC, GR, BC, GKS, IN and MVD,
with no need for medication (BNI I), whilst 24%– respectively) were found (Table 9). Accepting some
71% did so after GKS. At 4–5 years, the percentages variability in the duration of observation periods
were 61%–88% for MVD and 33%–56% for GKS. across procedures, there appears to be a trend in
Four non-randomized retrospective studies involving favour of MVD with a median of 77% (range 62%–
a total of 957 patients demonstrated a similar superi- 89%) of patients being pain free at long-term follow-
ority of first-time MVD over GKS both at medium up. The same percentages for IN, GKS, BC, RFTC
and long term (Table 8) [78–81]. Three systematic and GR are 72%, 58% (30%–66%), 68% (55%–
reviews comparing published results from independent 80%), 58% (26%–82%) and 28% (18%–59%) respec-
treatment cohorts using various inclusion criteria tively. None of the case series on the effectiveness of
demonstrated a longer postoperative pain-free status PSR fulfilled the inclusion criteria. For more details
for MVD compared to GKS [82–84]. One non- see Appendix S1 and Tables S1–S12.
randomized prospective study evaluated the outcomes Complications. Reported complication rates from
at 3 years after MVD versus GR or RFTC [85], show- cohort studies are summarized in Table 10. For more
ing that MVD provided a greater percentage of pain- details see Appendix S1 and Tables S1–S12. Only
free status at 36 months compared to GR and RFTC. MVD is associated with reported mortality, although
A retrospective study with 2–3 years’ follow-up anecdotally it is known that RFTC and BC have in the
showed that significantly more patients were com- past very rarely resulted in the patient’s death. The dis-
pletely pain-free after MVD than BC [86]. tribution of complications reflects the nature of the
Comparison of neuroablative treatments. It was not operation. The small number of complications associ-
possible to find any randomized or non-randomized ated with GKS is noteworthy. Most of the reported
studies fulfilling the above inclusion criteria that com- complications are transitory and severe permanent
pared long-term effectiveness between GKS, GR, BC adverse effects are rare. It should also be emphasized
and RFTC. that facial hypaesthesia following neuroablative
BC, balloon compression; F/U, follow-up; GKS, gamma knife surgery; GR, glycerol rhizoly-
sis; IN, internal neurolysis; MVD, microvascular decompression; RFTC, radiofrequency ther-
mocoagulation.
© 2019 EAN
EAN GUIDELINE ON TRIGEMINAL NEURALGIA 843
AD, anaesthesia dolorosa; BC, balloon compression; CN, cranial nerve; CSF, cerebrospinal fluid; GKS, gamma knife surgery; GR, glycerol
rhizolysis; HS, herpes simplex; Hypaesth, hypaesthesia; IN, internal neurolysis; MVD, microvascular decompression; RFTC, radiofrequency
thermocoagulation; V, fifth cranial nerve. Cerebral: oedema, haemorrhage, stroke.
treatments tends to be associated with a better long- treatments or between them and MVD when an MRI
term response than any lack thereof. To help a com- scan fails to show significant nerve compression (idio-
parison of the diverse complications across all inter- pathic TN). Neuroablative treatments should be the
ventions, an attempt has been made to assess their preferred choice if MRI does not demonstrate any
impact on the patient’s health-related quality of life NVC.
[82]. The expected utility scores measuring this effect
were reported as similar between MVD and GKS [82].
Section 4: Management of secondary TN and
non-pharmacological and non-surgical
Clinical guide
management of TN
Although the quality of published studies reviewed
comparing MVD and GKS was low or very low, it is
Clinical question 4.1: Should patients with secondary
striking that they consistently showed the superiority
TN be offered the same pharmacological and surgical
of MVD over GKS in classical and idiopathic TN,
treatments of pain as patients with primary TN?
with comparable complication rates. In fully informed
patients with classical TN with no previous opera- Search strategy and results
tions, who have failed pharmacotherapy and who are Reports containing the keywords ‘secondary trigemi-
willing to and can safely undergo neurosurgery, MVD nal neuralgia’ or ‘symptomatic trigeminal neuralgia’
is likely to provide a longer lasting postoperative AND treatment or management were sought. One sys-
pain-free state than GKS. Low quality evidence from tematic review [87] but no RCTs were found for the
two comparative studies and indirect data from medical treatment of secondary TN, but a few small
cohort studies indicate that MVD may be considered case series reported successful treatment with lamot-
more effective in providing relief from pain than rigine [88–90], carbamazepine [89], misoprostol
RFTC, BC and GR. Due to limited and conflicting [91,92], gabapentin [93], topiramate [94,95] and botuli-
results, no preference can be shown for any one num toxin type A [96]. Most of these studies investi-
percutaneous neuroablative procedure over another. It gated TN secondary to MS. Surgical treatment was
should be underlined that they all do show consider- evaluated in secondary TN with only a small case
able effectiveness and should be considered for those series reporting treatment outcomes, with a general
patients who cannot or prefer not to undergo MVD. tendency toward lesser efficacy in this population.
Most authors recommend the use of Gasserian
Final recommendations ganglion procedures unless a definitive vascular com-
Based on low quality evidence but extensive clinical pression of the trigeminal nerve is identified on MRI.
experience, a strong recommendation is given that Radiofrequency thermocoagulation can be considered
MVD is preferred over GKS in patients with classical in secondary TN following dental procedures [97].
TN who are willing to and can undergo posterior Case reports conveyed a benefit of MVD for patients
fossa surgery. Based on low quality evidence, a weak with MS but suggest less efficacy than in non-MS
recommendation is given that MVD may be consid- patients [98,99]. A retrospective cohort study investi-
ered preferential over other neuroablative treatments gating 15 patients with MS over a median observation
(RFTC, BC, IN and GR). No recommendation can period of 55 months (range 17–99 months) reported
be given for choice between any neuroablative that seven (47%) were completely paroxysm-free and
© 2019 EAN
844 L. BENDTSEN ET AL.
that an additional four (27%) had significant relief anxiety. A small pilot study using a group cognitive
(>50%) of episodic pain. Amongst the eight patients behaviour programme has been run in the UK and
with a constant pain component, all were free of has been highly evaluated. This has now been sup-
their constant pain and four (50%) were free of their plemented by a telephone service offered by a clinical
episodic pain [100]. Electrical transcutaneous stimula- nurse specialist who can also prescribe, and patients
tion was reported to be effective in patients with have found this very helpful. These programmes
primary and secondary TN, but the authors did not enable patients to meet fellow sufferers and develop
clearly distinguish between patient types when evalu- strategies for coping with flare-ups, which may result
ating outcomes [101]. in fewer visits to emergency services and primary
care doctors. Support groups run by TN sufferers
Clinical guide were first established in the USA and UK and now
Patients with secondary TN generally respond less also run in Australia, Canada, Denmark, Germany,
well to conventional or surgical treatment. As no Spain and France. Sufferers report a great need for
treatment has sufficient evidence to prove its specific the support and advice that they can obtain from
efficacy in secondary TN patients, they should be trea- support group volunteers who understand the needs
ted similarly to patients with primary TN. Gasserian of this community. Regular contact with members
ganglion procedures can be considered. In patients and others through telephone and e-mail helplines,
with MS, when a definite NVC is present on MRI, an web-based forums, local groups, national meetings
MVD could be considered. and conferences can be very helpful for these
patients.
Final recommendation
Based on a very low quality of evidence, medical Final recommendations
treatment of patients with secondary TN should be Based on very low quality of evidence, it is recom-
similar to those with primary TN. Surgical interven- mended that patients are offered psychological and
tions should consider Gasserian ganglion procedures nursing support. Patients should be directed to
and MVD. national support groups where these are present.
Clinical question 4.2: For patients with primary TN, Conclusions and recommendations for future
what other non-pharmacological and non-surgical research
support can be provided?
The diagnostic criteria for TN have changed consider-
Search strategy and results ably since publication of the previous AAN-EFNS
Papers evaluating the overall disability caused by TN guideline, in order to avoid the differences between
and how this can be managed by means other than the criteria laid out by the International Headache
drugs and surgery were sought. There is increasing Society and the International Association for the
evidence that depression, anxiety and poor coping Study of Pain. The recent International Classification
mechanisms are common in patients with TN and of Headache Disorders diagnoses TN as primary TN,
result in poor quality of life [68,102–105]. These fea- either classical or idiopathic depending on the degree
tures are further compounded by the effects of the of NVC, or as secondary TN caused by other than
medications and complications after surgical treat- NVC. It is recommended that MRI is used as part of
ments. There is good evidence that cognitive beha- the work-up in TN patients, because no clinical
vioural therapy is effective for chronic pain [106] and characteristics can exclude secondary TN. Use of a
that self-management interventions for migraine and combination of three high-resolution sequences – 3D
tension-type headache can be better than the usual T2-weighted, 3D TOF-MRA and 3D T1-Gad – is
care provided [107]. An evaluation of three patient- recommended. The neuroradiologist should be blinded
organized national meetings in the UK, USA and to the side of pain and should describe whether a ves-
Australia showed that these are highly valued by suf- sel contact causes morphological changes of the nerve.
ferers as an opportunity to improve their knowledge If MRI is contraindicated or unavailable, trigeminal
and understanding [108]. reflexes can be used to distinguish secondary TN
from primary TN. NVC plays an important role in
Clinical guide primary TN, but demonstration of an NVC should
It is important to take into consideration that not be used to confirm the diagnosis of TN. Rather, it
patients with TN suffer not only from severe pain may help to decide if and when a patient should be
but also from other factors such as depression and referred for MVD.
© 2019 EAN
EAN GUIDELINE ON TRIGEMINAL NEURALGIA 845
In acute exacerbations of pain, in-hospital treat- improvements, making an update of this guideline
ment may be necessary for titration of anti-epileptic necessary in the not too distant future. It is likely that
drugs, rehydration and intravenous infusion of this guideline will need to be updated in 2025.
fosphenytoin or lidocaine. For long-term treatment
carbamazepine or oxcarbazepine are recommended
Acknowledgements
as drugs of first choice. Lamotrigine, gabapentin,
botulinum toxin type A, pregabalin, baclofen and The EAN has supported two face to face meetings
phenytoin may be used either as monotherapy or economically for preparation of the guideline. JZ
combined with carbamazepine or oxcarbazepine. undertook this work at UCL/UCLHT who received a
Patients should be encouraged to adjust the dosages proportion of funding from the UK Department of
depending on pain severity and side effects and Health’s NIHR Biomedical Research Centre funding
should be given specific instructions on titration. It is scheme.
recommended that patients should be offered surgery
if pain is not sufficiently controlled medically or if
Disclosure of conflicts of interest
medical treatment is poorly tolerated. MVD is rec-
ommended as first-line surgery in patients where The authors declare no financial or other conflicts of
NVC with morphological changes has been demon- interest.
strated (classical TN). No recommendation can be
given for choice between any neuroablative treat-
Supporting Information
ments or between them and MVD when an MRI
scan fails to show NVC with morphological changes Additional Supporting Information may be found in
(idiopathic TN). Neuroablative treatments may be the online version of this article:
preferred if MRI does not demonstrate any NVC.
Table S1. Demographic of patients and pain relief
Treatment for patients with secondary TN should in
data of RFTC series
general follow the same principles as for primary
Table S2. Demographic of patients and pain relief data
TN. In addition to medical and surgical management,
of GR series
it is recommended that patients are offered psycho-
Table S3. Demographic of patients and pain relief data
logical and nursing support.
of Percutaneous Balloon Compression (PBC) series
Compared with the previous AAN-EFNS guideline,
Table S4. Demographic of patients and pain relief data
there are important changes regarding diagnosis and
of GKS series
imaging. This allows better characterization of
Table S5. Demographic of patients and pain relief data
patients and helps in decision making regarding the
of IN series
planning of medical and surgical management. Rec-
Table S6. Demographic of patients and pain relief data
ommendations on pharmacological and surgical man-
of MVD series
agement have been updated. Unfortunately, no
Table S7. Reported complications related to RFTC series
substantial progress in management has been made
Table S8. Reported complications related to GR series
since the previous guideline.
Table S9. Reported complications related to Percutaneous
There is a great need for future research in the patho-
Balloon Compression (PBC) series
physiology and prognosis of TN and for development
Table S10. Reported complications related to GKS series
of more standardized outcomes, including quality of
Table S11. Reported complications related to IN series
life, to allow for a more reliable comparison of results
Table S12. Reported complications related to MVD
from different studies. Pharmacological management
series
should be evaluated using modern standards and there
Appendix S1. Clinical question 3.2: Which surgical
is a huge need for development of more effective drugs
technique gives the longest pain-free period with
with fewer side effects than current medications.
fewest complications?
Prospective studies are needed to evaluate outcome
after surgery using independent assessors as well as
studies comparing the various surgical procedures, and
studies comparing these to pharmacological manage-
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