Trigeminal neuralgia (TGN)

General

AKA tic douloureux

Other than sensory division of CN5, other possible pain pathways include:

Motor branch of CN5 (portio minor),
CN7
CN8

Most common of all the cephalic neuralgia

A Clinical diagnosis. Investigation are to find a cause

Definition

Paroxysmal lancinating electric-like pain lasting a few seconds,

Triggered by sensory stimuli,

Distribution at one or more branches of the trigeminal nerve on one side of the face,

With no neurologic deficit (mild sensory loss)

Characterized by periods of remission and initial response to carbamazepine

Terminology

Classical trigeminal neuralgia (75% of cases)

Significant neurovascular compression (NVC) on MRI or during surgery — not just simple contact.
Trigeminal neuralgia developing without apparent cause other than neurovascular compression.
Classical trigeminal neuralgia, purely paroxysmal (Typical TGN)

Classical trigeminal neuralgia without persistent background facial pain.

Classical trigeminal neuralgia with concomitant continuous pain (Atypical TGN)

Classical trigeminal neuralgia with persistent background facial pain.

Secondary trigeminal neuralgia (15% of cases)

An underlying disease that can cause trigeminal neuralgia has been demonstrated (except NVC).
Trigeminal neuralgia caused by an underlying disease
Trigeminal neuralgia attributed to multiple sclerosis

TGN criteria +
Multiple sclerosis (MS) has been diagnosed +
An MS plaque at the trigeminal root entry zone or in the pons affecting the intrapontine primary afferents has been demonstrated by MRI, or its presence is suggested by routine electrophysiological studies showing impairment of the trigeminal pathways

Trigeminal neuralgia attributed to space-occupying lesion

TGN criteria +
A space-occupying lesion in contact with the affected trigeminal nerve has been demonstrated +
Pain has developed after identification of the lesion, or led to its discovery

Trigeminal neuralgia attributed to other cause

TGN criteria +
A disorder other than those described above, but known to be able to cause trigeminal neuralgia, has been diagnosed
Pain has developed after onset of the disorder, or led to its discovery

Idiopathic trigeminal neuralgia (10% of cases)

Diagnostic tests have excluded a lesion or disease that can cause trigeminal neuralgia (no NVC).
Trigeminal neuralgia with neither electrophysiological tests nor MRI showing significant abnormalities.
Idiopathic trigeminal neuralgia, purely paroxysmal
Idiopathic trigeminal neuralgia with concomitant continuous pain

Typical TGN

Recurrent unilateral brief electric shock- like pains, abrupt in onset and termination, limited to the distribution of one or more divisions of the trigeminal nerve, and triggered by innocuous stimuli
No background of facial pain

Atypical TGN

Coexist a background of continuous facial pain

Primary: absence of apparent cause

Classical: absence of apparent cause (other than a neurovascular compression)

Usually due to MVC at REZ -often SCA

Idiopathic: unknown origin even after MRI

Secondary: a result of a neurological or other disease.

HIS-3 diagnostic criteria

(A) Recurrent paroxysms of unilateral facial pain in the distribution(s) of one or more divisions of the trigeminal nerve, with no radiation beyond, and fulfilling criteria B and C

(B) Pain has all of the following characteristics:

Lasting from a fraction of a second to 2 minutes

Severe intensity

Electric shock-like, shooting, stabbing or sharp in quality

(D) Not better accounted for by another ICHD-3 diagnosis.

Epidemiology

Annual incidence: 5/100,000.

Prevalence 70/100,000

F: M= 1.8:1

Aetiology

Vascular compression

90.5% of primary TGN have a neurovascular compression

90.7% arterial
9.3% venous

Venous alone 1/4
Venous & Arterial compression 3/4

Location of the Neurovascular compromise

Transition zone: 3mm from brain stem

84% pt has vessel in contact with nerve within <3mm from brainstem
19% pt has vessel in contact with nerve within >3mm from brainstem

REZ: 50%
Midcisternal portion of the root in 40%,
Porus of MC in 10%

Compression Grading (Sindou et al., 2007)

Grading	Description	Percentage of cases	Success rate at 15 years of FU
I	The vessel was in contact with the root without any visible indentation to the root	17.2%	65%
II	Displacement and/or distortion of the root,	33.2%	79%
III	A marked indentation in the root.	49.2%	88%

Tumour

Difference

	Tumour	Vascular compression
Pain	Atypical (constant)	Fluctuating
Neurological deficit	Present (early: no deficit; sensory loss that present late)	Not present
Age	Younger	Older

16/> 2000 patients harbored tumor (< 0.8% incidence).

All had hyperalgesia and atypical facial pain (AFP).
3 tumors outside cranial vault included nasal carcinoma and skull base mets;
6 middle fossa tumors included

Patients with true TGN initially responded to carbamazepine, none with AFP did.

2 of 7 VSs had tumors contralateral to the neuralgia (presumably due to brainstem shift).
Vestibular schwannoma (VS) is most common.

7 Posterior fossa tumors are the most likely to cause symptoms that most closely resemble true TGN;

1 pituitary adenoma.
2 schwannomas (1 primary tumor of Gasserian ganglion)
2 meningiomas

Association with MS

2% of patients with MS have TGN,
≈ 18% of patients with bilateral trigeminal neuralgia have MS.

There is no correlation with herpes simplex infection.

Natural history

There is a tendency for spontaneous remission, with pain-free intervals of weeks or months being characteristic, regardless of treatment.

Pathophysiology

Pain due to ephaptic transmission in trigeminal nerve from large-diameter partially demyelinated A fibres to thinly myelinated A-delta and C (nociceptive) fibres.

Ephaptic transmission: electrical activity crossing from one demyelinated neuron to another resulting in a false synapse.

Pathogenesis may be due to:

Vascular compression of the trigeminal nerve at the root entry zone

NB: compression may be seen in up to 50% of autopsies in patients without TGN
Compression at its medial portion (60%)
SCA (80%)
AICA (<25%)
Dolichoectatic basilar artery/vertebral artery (37.8%)
Persistent primitive trigeminal artery
Saccular aneurysm, AVM, petrous vein

Posterior fossa tumour
MS, plaque within brainstem may cause TGN that is often poorly responsive to microvascular decompression

The motor root is rarely affected.

Associated anatomical abnormalities of the trigeminal root or the posterior fossa → keep an eye out during surgery planning

42% the CN5 had a significant degree of global atrophy,

One to two- thirds reduction in calibre

Signifying coexisting neuropathy from likely degenerative origin.

18.2%, arachnoid was thickened, with strong adhesions to the root.
12.6% the root had a marked angulation on crossing over the petrous ridge at exit from Merkel Cave,

Signifying cerebellum was atrophic
Corresponds to the so-called sagging phenomenon

3.9% the root was compressed by being squeezed between the pons and the petrous bone within a ‘virtual’ cerebellopontine angle cistern due to the small size of the posterior fossa

Evaluation

A clinical diagnosis

History

Accurate description of pain localization to determine which divisions of trigeminal nerve need to be treated

Determine

Character of pain (Burchiel's classification) - two types can overlap in same patient

Type 1: lancinating type
Type 2: constant, aching, or burning

Time of onset of TGN
Trigger mechanisms
Severity of pain

Use of facial pain and QoL scales

Penn-FPS – seven items

Eating a meal, touching your face (grooming), brushing or flossing your teeth, smiling or laughing, talking, opening your mouth wide, eating hard foods like apples
Response scale: 0–10 NRS (does not interfere to completely interferes)
Recall period “past week”
For each item you ask them to give a pain score out of 10

Although some mild sensory abnormalities may be found especially in longstanding TN, absence of sensory deficit is essential for the diagnosis.
Presence and length of pain-free intervals (lack of any pain-free interval is atypical for TGN)
Responses to medication tried (typically response to carbamazepine initially)

Duration,
Side effects,
Dosages,

Inquire about symptoms that may indicate the presence of conditions other than TGN: e.g.

History of herpetic vesicles,
Excessive tearing of the eye (may indicate SUNCT (p.496)),
Facial twitching (tic convulsif),
Tongue pain (glossopharyngeal neuralgia),
Sensory loss (tumor…),
Progressive relentless pain (tumor, herpes…),
Symptoms that suggest MS

When very severe, the pain often evokes contraction of the muscles of the face on the affected side (tic douloureux).

Rarely, TGN manifests as status trigeminus, a rapid succession of tic-like spasms triggered by seemingly any stimulus. IV carbamazepine (where available) or phenytoin may be effective for this.

Exclude other facial pain syndromes

Trigeminal deafferentation pain

Result of previous treatment,

SUNCT (short- lived, unilateral neuralgic headache with conjunctival injection and tearing)

Particularly following treatment failure and consideration of reintervention.

Secondary causes like tumour and MS

Physical exam

The exam should be normal in TGN,

Any neurologic deficit (except very mild sensory loss) in previously unoperated patient should prompt search for structural cause, e.g. tumor.
This exam also serves as a baseline for post-op comparison

Assess

Sensation

All 3 divisions of trigeminal nerve bilaterally
Include corneal reflexes

Motor

Masseter function (bite)
Pterygoid function (on opening mouth, chin deviates to weak side)

Extra-ocular muscle function

Radiological

MRI is often used to evaluate these patients for possible intracranial tumors or MS plaques, especially in cases with atypical features. The yield in typical cases is low.

3T > 1.5T

1.5 T MRI depict NVC with a sensitivity of 96.7% and a specificity of 100% (Leal et al., 2010).

3D T2 high- resolution,

CISS/FIESTA sq

TOF MR- angiography

Visualizes only high- flow vessels

T1 with gadolinium,

Nerve atrophy and and displacement highly specific (96%) on MRI for TGN

CT pre and post contrast if you cannot do MRI

Neurophysiology

Check reflex massetter and corneal reflex

Normal in typical trigeminal neuralgia

Treatment

McMillan 2021.pdf

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Medical

Emergency

Indication

Uncontrollable exacerbations of pain,
Pain that is sufficiently severe to impair eating and drinking.

To provide a period of symptomatic remission e.g. 24 hours to enable a neurology review and rapid oral agent titration or a more definitive procedure such as percutaneous rhizotomy.
Acute pain management
They are then likely to require HDU admission for rescue therapy and intravenous re-hydration.
Options

Lidocaine - can be used acutely as an adjuvant to systemic medications should there be a defined ‘trigger point’:

Lidocaine 10mg per actuation nasal spray –

2 sprays into the nostril on the affected side (when pain is maxillary) as required

Lidocaine 5% ointment

Applied directly to trigger point on face or inside mouth as required

Infiltration/block anaesthesia to trigger point (provided by dentally trained clinicians)

Lidocaine 2% 1:80 000 adrenaline;
Can consider combination with a longer acting agent eg bupivacaine, ropivacaine

Sumatriptan

In cases where there is no defined ‘trigger point’, sumatriptan can be used acutely as an adjuvant to systemic medications; 6mg subcutaneous injection

Botulinum toxin type A

There is weak evidence that botulinum toxin may reduce pain intensity when used alongside other systemic drugs. There is no consensus on the dose or method of administration. Due to the delayed onset of action, botulinum toxin type A should only be considered for the medium-term management of TN

Infusion therapy

Lidocaine

1.5mg/kg intravenous infusion over 1 hour

(Hospital admission with full monitoring; in 2020 the UK lidocaine infusion safety group published a recommendation for a reduced dosage of lidocaine (from 5mg down to 1.5mg/kg) subject to a review of efficacy)

Fosphenytoin

15mg/kg intravenous infusion (hospital admission with full monitoring)

Phenytoin

10mg/kg intravenous infusion (hospital admission with full monitoring)

Over 1 hr

Need cardiac and BP monitoring

Hypotension

90% obtained immediate pain relief.

Long term management

1st line

Carbamazepine 800-1200mg/day split to QDS

NNT is 2
HLA-B*1502 allele testing in individuals of Han Chinese or Thai origin (risk of Stevens-Johnson syndrome in presence of HLA-B*1502 allele).

Oxcarbazepine 1200mg – 1800mg/day split to QDS

Indication:

Should there be medication interaction issues with carbamazepine.

HLA-B*1502 allele testing in individuals of Han Chinese or Thai origin (risk of Stevens-Johnson syndrome in presence of HLA-B*1502 allele).
Monitoring of plasma sodium concentration in patients at risk of hyponatraemia (hyponatraemia tends to be dose related

2nd line

Add on or switch to lamotrigine 400mg/day

Lamotrigine may increase the concentration of carbamazepine

Baclofen 40-80mg/day

Useful in patients with multiple sclerosis who are already using it for spasticity.

Pimozide 4-12mg/day

Alternative treatment option

Pregabalin 150-600mg/day

Gabapentin 900-3600mg/day

Topiramate 100-400mg/day

Tocainide 20mg/day

Valproate 600-2400mg/day

Summary

Drug	Level of Evidence	Effect	Adverse Effects	Suggested Dose	Comment
Carbamazepine (the only first-line agent)	Systematic review of four randomized controlled trials (n = 160)	NNT for pain relief is 1.9; 72% of patients had excellent or good response	Drowsiness, ataxia, nausea, constipation (minor); NNT, 3.7	100 mg twice daily; increase as necessary by 50-100 mg every 3-4 days; target range 400-1000 mg/day	Dose may need to be adjusted after 3 weeks because of enzyme induction.
Baclofen	One controlled trial compared baclofen with placebo (n = 10)	7/10 improved with baclofen; 0/10 improved with placebo (P = .05)	Drowsiness, hypotonia; avoid abrupt withdrawal	10 mg three times daily; increase as necessary by 10 mg/day; target dose 50-60 mg daily	May be useful in patients with multiple sclerosis, in whom its antispasticity effects can be harnessed.
Gabapentin	Five uncontrolled studies (n = 123)	Good to excellent pain relief in 40%; any pain relief in 53%	Drowsiness, ataxia, diarrhea (minor); NNT, 2.5	300 mg once daily; increase as necessary by 300 mg every 3 days in divided doses (three times daily); target dose 900-2400 mg daily	Widely used for TN although evidence is weak; evidence base in other types of neuropathic pains much stronger.
Lamotrigine	One randomized controlled trial with lamotrigine as add-on to carbamazepine or phenytoin (n = 14)	10/13 improved on lamotrigine; 8/14 improved on placebo; ns	Drowsiness, dizziness, constipation, nausea; no different from placebo	25 mg twice daily; increase by 50 mg weekly; target dose 200-600 mg daily	Probably better tolerated than carbamazepine but needs slow titration; may therefore have a role in the elderly or patients with multiple sclerosis who have less severe disease.
Oxcarbazepine	Two uncontrolled studies (n = 21)	Pain relief in all 21 patients	Dizziness, fatigue, rash, and hyponatremia	300 mg twice daily; increase by 600 mg weekly; target dose 600-2400 mg daily	Evidence weak; structurally similar to carbamazepine, although probably better tolerated.
Phenytoin	Three uncontrolled studies (n = 30)	77% of patients reported some pain relief	Drowsiness, ataxia, dizziness, gum hypertrophy	300 mg/day; dose altered to achieve therapeutic plasma concentration	First drug used in the successful management of TN; little evidence but rapid dose titration and once-daily administration are advantages.

Surgical

Indication

Reserved for cases refractory to medical management, or when side effects of medications exceed risks and drawbacks of surgery.

Types

Peripheral nerve procedure

Treating the terminal branches of the trigeminal nerve, and hence depend on accurate assessment of which nerve branch is acting as the trigger area.

Pros

Under local anaesthesia
Do not require the patients to be medically fit for surgery

Options

Injected with alcohol,
Surgically exposed and treated with cryotherapy or neurectomy

Percutaneous trigeminal rhizotomy (PTR)

Indication:

If MR imaging show no neurovascular compression AND medical management is insufficient.
Patient at high risk for general anesthesia

Elderly

Patient wish to avoid “major” surgery,
Have unresectable intracranial tumors,
Have MS,
Have impaired hearing on the other side, or
Have limited life expectancy (< 5 yrs).
For “atypical facial pain,”

Denervating the painful region of the face benefits <20% of patients, and worsens 20%.

Recurrences are easily treated by repeat procedures. May be used to treat failures of peripheral nerve ablation

Types: Recurrence rates and incidence of dysesthesias are comparable among the various lesioning techniques.

Radiofq rhizotomy (RFR)

Pros

Can target V2 and V3 separately by asking patient if they feel tingling or odd sensation

Cons

Patient have to be awake

Percutaneous gasserian ganglion neurolysis

Injection of glycerol into the CSF of the trigeminal cistern, inside the Meckel's cave

Performed under local anaesthesia

Metrizamide fluoroscopic control for an accurate placement into the cistern.

Advantage

Technique is easy to perform
Low cost

Widely performed around the world

Disadvantage

Control of diffusion of glycerol outside the trigeminal cistern is somewhat hazardous.
Frequent side effects are Herpes Zoster eruption,
Highest

Anesthesia dolorosa
Paraesthesia's and keratitis

Lack of predictability in terms of topography of effect and of long- term efficacy.

Percutaneous Ballon microcompression rhizolysis (PMC)

Cons

Incidence of intraoperative hypertension is less with PMC than with radiofrequency rhizotomy (RFR) lesion (no reports of intracerebral hemorrhage).
Bradycardia occurs regularly with PMC, which may not be harmful (some prophylaxis with atropine)

Disadvantage

Exception of a high rate of (most often transient) masticatory deficits.

Pearls and pitfalls

The lesion must not be made in the ganglion itself, but retrogasserian at the triangular plexus level to decrease the risk of trophic ulcerations by destroying the T cells of the ganglion
To obtain a marked hypoesthesia without important loss of tactile sensation and cover but not transpass the division(s) involved, an accurate placement of the electrode and a gradual lesioning process are required, which is demanding and time- consuming

Stereotactic radiosurgery (SRS)

Pros

Least invasive surgery

Recommended for patients with

Co-morbidities
High-risk medical illness
Pain refractory to prior surgical procedures
Those on anticoagulants (anticoagulation does not have to be reversed to have SRS

Low rate of complications.

Cons

Takes time for treatment to work

Several months (1-3 months)
However, this inconvenience is not a major problem for most patients with the exception of those referred for unbearable refractory pain

Target

Dorsal root entry zone of cranial nerve V near the pons.

Initial SRS directed at the gasserian ganglion produced inferior results.

Dose

80Gy as a single fraction

Results:

Pain reduction: 80–96%

Pain relief is experienced with a latency of approximately 1 month.

Not a suitable technique for acute TN crisis management

Pain free: 65%
Median latency to pain relief:

3 months (range: 1 d–13 months).

Recurrent pain occurs within three years in 10–25%.

Significantly lower dose of radiation must be employed to prevent

Post treatment numbness
Deafferentation pain (nerve damage pain), when combined with the TN pain can be debilitating

Patients with TN and multiple sclerosis are less likely to respond to SRS than those without MS.
SRS can be repeated, but only after four months following the original procedure.

Favourable prognosticators:

Higher radiation doses,
Previously unoperated patient,
Absence of atypical pain component,
Normal pre-treatment sensory function.

Side effects

Paresthesia is the most common side effect.
Hypesthesia occurred in 20% after initial SRS, and in 32% of those requiring repeat treatment (higher rates associated with higher radiation doses).

Method

4–5mm isocenter in the trigeminal nerve root entry zone identified on MRI.
Use 70–80Gy at the centre
Target should be at the retrogasserian cisternal portion of the CN5, in the order of 7.5 mm from exit to porus, rather than at the trigeminal root entry zone (TREZ), to minimize brainstem irradiation

Microvascular decompression (MVD)

Sindou 2007.pdf

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Indicated for patients

Inadequate medical control of pain
> 5 years anticipated survival
Able to tolerate a small craniotomy

Surgical morbidity increases with age

Pros

Pain relief 10 yrs in 70%.
Incidence of facial anesthesia is much less than with PTR
Anesthesia dolorosa does not occur.

Mortality: < 1%.

Side effects

Incidence of aseptic meningitis (AKA hemogenic meningitis): 20%.
5% risk of ipsilateral hearing loss
1–10% major neurologic morbidity
Failure rate: 20–25%.
1–2% of patients with MS will have a demyelinating plaque at the root entry zone;

This usually does not respond to MVD, and one should attempt a PTR.

Peduncular hallucinosis

Dandy vein injury
Hallucination

Mortality of 0.1%

Microscope vs endoscope

There is a meta-analysis showing the same outcome

Techniques

Offending vessels may be more than one in the same individual, (1/3 cases)

For not missing multiple conflicts, the entire root must be explored from REZ at brainstem to porus of MC and freed from all arachnoid adhesions.
If no vascular compression is found at the time of the surgery → Interposition of material to maintain the conflicting vessel away should not be ‘neocompressive internal neurolysis (‘nerve combing’ – the fascicles of the trigeminal nerve are longitudinally separated but not divided, in order to release the scarring between the nerve bundles)

Higher risk of sensory change after surgery;

Outcomes

Procedure	% Patients reported pain free	Mortality	Morbidity
Microvascular Decompression (Major surgery, non-destructive technique to decompress the trigeminal nerve, preserving its normal function)	Long-term – 90 1 year – 80 3 years – 75 5 years – 73	0.2–0.4%	- Major health problems (infarcts/hematoma) - Sensory loss - Hearing loss - Aseptic meningitis
Palliative destructive procedures (Ablative technique, penetrating the trigeminal ganglion to selectively destroy nerve fibres) - Radiofrequency thermocoagulation (RFT) - Glycerol injection (GI) - Percutaneous balloon compression (PCB)	Post-procedure (RFT, GI, PCB) – 90 1 year – 68 3 years – 54–64 5 years – 50 (RFT)	Low	- Sensory loss - Corneal numbness - Keratitis - Dysesthesias - Anaesthesia dolorosa
Stereotactic radiosurgery (Gamma Knife surgery) (Non-invasive procedure focusing low intensity radiotherapy at specific areas of trigeminal nerve tissue)	Post-procedure – 90 1 year – 69 3 years – 52	Nil	- Delayed pain relief - Sensory complications - Paraesthesia - Facial hypaesthesia

Surgery low complications and works immediately

Palliative destructive procedures

Percutaneous procedure outcome isn't the greatest

Summary of surgical outcomes (Bendtsen et al. 2019)

Intervention	No. of studies	Total patients	Median follow up (years)	Pain free at follow up (%)
MVD	21	5149	3–10.9	62–89
Stereotactic radiosurgery	8	1168	3.1–5.6	30–66
Radiofrequency thermocoagulation	7	4533	3–9.3	26–82
Balloon compression	5	755	4.2–10.7	55–80
Glycerol rhizolysis	3	289	4.5–8	19–68
Internal neurolysis	1	26	3.6	72

Factors affecting outcome in MVD Sindu

Duration of pain pre op no

Kaplan–Meier curve (at 15 years of follow-up) of pain-free patients according to preoperative duration of neuralgia. No statistical significance was found (p = 0.67).

Severity of compression YES

Kaplan–Meier curve (at 15 years of follow-up) of pain-free patients according to degree of compression; the more severe the degree, the better the outcome (p = 0.001).

Recurrence after

MVD 15.% at 5 years and 30.% at 10 years,

Glycerol rhizotomy 54% at 4 years,

SRS 20% at 3 years.

Differential diagnosis

Craniofacial pain syndromes

Cluster headache

Longer lasting pain
Located orbital/supraorbitally
May wake patient from sleep
Has autonomic symptoms

Dental pain (caries, craked tooth, pulpitis)

Localized;
Related to biting or hot or cold foods;
Visible abnormalities on oral exam

Giant cell arthritis (persistent pain)

Persistent pain
Often bilateral
Has jaw claudication

Glossopharyngeal neuralgia

Pain in tongue, mouth or throat
Brough on by swallowing, talking or chewing

Migrane

Longer-lasting pain
Assciated with photo and/or phonophobia
Family history

Otitis media

Pain localized to ear
Abnormalities on examination and tympanogram

Paroxysmal hemicrania

Pain in forehead or eyes
Autonomic symptoms

“Atypical facial pain” (AFP)