|Disease DB 13363|
Trigeminal neuralgia (TN), or tic douloureux, is a chronic neurological condition characterized by severe, lancinating pains to the face that are transient, unilateral, and stimulus-evoked. It is a debilitating disease with a high prevalence of depression and anxiety. TN is the most common facial pain syndrome with an annual incidence ranging from 4-13 per 100,000. The majority of cases of TN are due to neurovascular compression of the trigeminal nerve root, and neuroimaging is recommended to identify the etiology and direct management. First-line medical and surgical management of TN consists of membrane stabilizing agents (e.g., carbamazepine and oxcarbazepine) and microvascular decompression. Ophthalmic complications, such as corneal anesthesia, may be seen following surgical treatments.
The trigeminal nerve (V) consists of three branches that join to form the trigeminal ganglia within Meckel’s cave in the cranial cavity. The ophthalmic branch (V1) provides sensory innervation to the face between the scalp and upper eyelids and includes the cornea and meninges. The maxillary branch (V2) innervation extends between the lower eyelids and upper lip and includes the maxillary teeth and surrounding mucosa. The mandibular branch (V3) innervates the muscles of mastication and provides sensation to the mandibular teeth, buccal mucosa, anterior tongue, lower lip, and rest of the face. Sympathetic and parasympathetic fibers that innervate sweat, salivary, lacrimal, and other glands run along these nerves as well.
The International Classification of Headache Disorders, Third Edition (ICHD-3) and the International Association for the Study of Pain (IASP) has delineated three types of trigeminal neuralgia based on the etiology.
• Classical TN is the most common type and is often due to vascular compression of the sensory components of the trigeminal nerve at the nerve root entry zone into the pons. Compression is most often caused by the superior cerebellar artery, a branch of the basilar artery.
• Secondary TN is responsible for 15% of cases, has an underlying cause, including neurologic disease (e.g., demyelination in multiple sclerosis), arteriovenous malformations, saccular aneurysms, or cerebellopontine angle tumors. These patients are more likely to be younger, have bilateral pain, and have sensory loss to the face.
• Idiopathic TN makes up 10% of cases and has no identifiable cause. Proposed causes include neural inflammation, gain-of-function mutations to voltage-gated ion channels, and non-demyelinating, non-specific brain stem lesions.
Magnetic resonance imaging (MRI) with gadolinium is advised after initial diagnosis to help distinguish systemic causes (e.g., multiple sclerosis) and identify possible compressive vascular or non-vascular lesions.
TN is more common in women with a male-to-female ratio ranging from 1:1.5 to 1:1.7. Incidence increases with age, and most patients are over the age of 50. Multiple sclerosis is the strongest risk factor, increasing the risk of disease by a factor of 20 compared to the general population. Patients with a history of stroke are also at an increased risk of TN. Although rare, cases of familial inheritance have also been described.
The entry of the trigeminal nerve into the pons has a transition of myelination from Schwann cells to oligodendroglia. This transition zone is susceptible to damage and demyelination by compression or multiple sclerosis plaques. Particularly at risk are the large, non-nociceptive Aβ fibers. Demyelination and subsequent changes in the electrochemical gradient cause hyperexcitability of nerve fibers resulting in ectopic and ephaptic (nerve fiber cross-talk) impulses and persistent signaling after the termination of a stimulus. These abnormal, high-frequency impulses via non-nociceptive Aβ fibers may be interpreted in the brain stem as pain. Another explanation is the stimulation of nociceptive fibers due to direct apposition and emphatic impulses between demyelinated Aβ and Aδ fibers. Familial occurrence of TN due to abnormalities in voltage-gated ion channels may be more common than previously considered, but the clinical significance has yet to be fully elucidated.
TN is a clinical diagnosis, and currently, there is no gold standard testing to confirm the diagnosis. Diagnostic workup is often complex and requires clinical expertise and neuroimaging interpretation along with history and physical examination. The ICHD-3 has established three main criteria for diagnosis, which are similar to the IASP guidelines.
A) Recurrent paroxysms of facial pain unilaterally in the distribution of trigeminal nerve and fulfilling criteria B and C.
B) Pain has all of the following characteristics:
- lasting from <1 second to 2 minutes
- severe intensity
- electric shock-like, shooting, stabbing or sharp in quality
C) Pain is triggered by innocuous stimuli within the affected trigeminal territory
D) Not better accounted for by another ICHD-3 diagnosis.
Triggered paroxysmal pain is the key and characteristic feature for TN and is reported by 91 to 99% of patients. Cruccu et al. found common triggers among a group of 120 patients with classical TN include in order of frequency: talking, washing face, chewing, brushing teeth, drying face, eating, drinking, shaving, applying makeup, combing or washing hair. A cool breeze contacting the face is another classic trigger. Patients may have specific extra- and intraoral trigger zones that correspond to areas of pain. Common zones include alveolar gingiva, cheeks, lips, nasolabial areas, and the chin. Spontaneous pain episodes are also seen in 68-98% of patients. The pain is unilateral and more commonly seen on the right side of the face. Rarely, it may present bilaterally, which warrants a high suspicion and workup for an underlying cause.
The frequency of pain episodes a patient experiences may vary from several to hundreds of attacks a day. After a pain episode, there is usually a refractory period where an additional episode cannot occur. Episodes may remit for months to years at a time with unpredictable recurrence.
In 24-49% of patients, there is continuous or long-lasting pain experienced between attacks. Therefore, TN may be further classified as either Type 1 with pain only during attacks or Type 2 with continuous pain between attacks also called atypical trigeminal neuralgia. This continuous pain does not respond well to medical or surgical treatment and has been hypothesized to be due to central sensitization.
The maxillary (V2) and mandibular (V3) division, both extra- and intraorally, are the most common branches affected. However, isolated V1 TN occurs in 3% of patients. In addition to paroxysmal pains, some patients experience ophthalmic manifestations during attacks such as photophobia, lacrimation, excessive blinking, or redness in the ipsilateral eye. Photophobia is much more common in isolated V1 TN.
Most cases of TN are diagnosed by history alone and the examination is typically normal. Examination during an attack, however, might demonstrate a blink or small mouth movement or forceful contractions of facial muscles known as “tic convulsive”. Sensory exam is typically normal, but subjective mild hypoesthesia of the face may be present in 29% of patients. Hypoesthesia, or other neurological abnormalities should prompt consideration of alternative diagnoses and neuroimaging investigation.
Although not included in the diagnostic criteria, neuroimaging is generally recommended to subclassify TN. MRI with contrast is the recommended imaging modality often in combination with 3D T2-weighted, 3D time-of-flight, and MR angiography with gadolinium-based contrast sequences. In classical TN, MRI findings may show distortion or atrophy of the trigeminal nerve due to vascular compression by a tortuous artery or arterial loop. Intracranial masses, multiple sclerosis plaques, or other abnormalities causing secondary trigeminal neuralgia may also be found with MRI imaging. When MRI imaging is contraindicated, such as patients with metal implants, computed tomography with contrast to rule out tumors may be considered.
• Herpes Zoster
• Cluster headache
• Temporomandibular joint pain or other dental problem
• Cerebral aneurysms
• Intracranial hemorrhage
• Trigeminal neuropathies due to trauma or rheumatologic diseases such as systemic lupus erythematosus or sclerodema.
First-line therapy for trigeminal neuralgia due to any cause is membrane stabilizing agents like carbamazepine or oxcarbazepine, assuming no contraindications. Meaningful control of pain is achieved in nearly 90% of patients with these medications. Unfortunately, they are less effective at treating concomitant continuous pain. These agents help stabilize the hyperexcited neuronal membranes via inhibition of voltage-gated sodium channels. Dosages should be titrated to control the pain while monitoring for side-effects. Side-effects include dizziness, diplopia, ataxia, elevated aminotransferases, and hyponatremia. Oxcarbazepine may be better tolerated with a lower potential for drug–drug interaction. However, failure to tolerate oxcarbazepine does not exclude potential benefit from carbamazepine, so when one drug fails due to nonallergenic side-effects, the other should be tried. Contraindications include cardiac conduction problems and allergic reactions. Add-on or second-line medical therapy includes gabapentin, pregabalin, lamotrigine, baclofen, phenytoin, botulinum toxin type A injections, topiramate, local anesthesia, or greater occipital nerve blocks.
Acute treatment for TN exacerbations with high attack frequency includes lidocaine injection into trigger zones or intravenous infusion of lidocaine and fosphenytoin. These treatments, however, do not have substantial scientific evidence, and intravenous infusions should only be done in the setting of high-dependency units.
When symptoms are not controlled on the standard dosage of medications or when side effects are intolerable, surgical intervention may reduce the frequency and severity of paroxysmal attacks.
• Microvascular Decompression
Microvascular decompression (MVD) is the first-line surgical treatment for classical trigeminal neuralgia who fail maximum medical treatment. MVD involves the placement of a sponge between the pulsating artery and nerve root via open posterior fossa surgery. Between 62-89% of patients are pain-free after 3-11 years of follow-up. Complications of MVD include cranial nerve palsies, facial hypoesthesia, CSF leak, anaesthesia dolorosa, hearing loss, stroke, meningitis, Teflon granuloma, or rarely death.
• Ablative Treatments
In the absence of neurovascular compression on neuroimaging, percutaneous ablative treatments to damage the trigeminal ganglion in Meckel’s cave or exiting nerve branches should be considered. These include radiofrequency thermocoagulation, mechanical balloon compression, and injection of glycerol to cause chemical destruction. Stereotactic (e.g., Gamma Knife) radiosurgery is also used to create a lesion at the trigeminal nerve root entry zone while carefully avoiding the pons. Complications of ablative treatments include facial hypoesthesia, corneal hypoesthesia, trigeminal motor weakness, meningitis, and anesthesia dolorosa.
Ophthalmic Surgical Complications
• Corneal anesthesia and subsequent neurotrophic keratitis may be seen after unintentional lesions to the V1 division of the trigeminal nerve after MVD or ablative procedures. Patients with preoperative V1 involvement appear to be at an increased risk of postoperative corneal anesthesia. Radiosurgery has a low associated risk of corneal anesthesia, so this may be a preferred choice for cases of V1 division involvement.
• Herpetic keratitis may occur due to herpes simplex virus reactivation from manipulation of the trigeminal nerve, stress from surgery, or use of steroids.
• Exposure keratitis may result from transient or permanent facial nerve paresis.
• Diplopia can occur from ocular motor cranial nerve damage. The abducens nerve has a close proximity to the V1 division of the trigeminal nerve putting it at risk of damage, but trochlear and oculomotor nerve involvement has also been described.
• Optic nerve damage after facial pain surgery was found by a questionnaire of neurosurgeons as well as several case reports. Complications included transient visual loss, homonymous hemianopsia, central retinal artery occlusion, subhyaloid hemorrhage, and rarely blindness.
TN is often thought to be a recurrent, chronic, and progressive disease. Although resistance to medications, increased pain intensity, and the need for neurosurgical intervention is seen in some, most patients do not require substantial changes in medication dosage. Short duration of disease (<5 years) and additional chronic pain conditions have been negatively correlated with medical treatment prognosis. However, studies on the natural history of the disease are lacking in the literature.
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