The trigeminal nerve is a mixed nerve, containing both general somatosensory and specific visceral motor nerve fibers. The sensory nerve divides the sensation of the face, mouth and top of the head, while the motor nerve innervates the movement of the masticatory muscles.
From the trigeminal nerve node, three large branches composed of three peripheral prominences emanate forward to the ophthalmic nerve, maxillary nerve and mandibular nerve in order of inward and outward, which are distributed in the skin of the head and face and the mucous membranes of the eyes, nose and mouth. The motor fibers of the trigeminal nerve originate from the motor nucleus of the trigeminal nerve in the cerebral bridge, and send fibers out of the brain in the lateral part of the cerebral bridge and exit the skull through the foramen ovale, traveling in the mandibular nerve, which innervates the masticatory and tympanic tensor muscles, mainly responsible for masticatory and mouth opening movements.
Trigeminal neuralgia is a rare, episodic facial pain that presents as electric shock-like, lightning-like, or knife-like pain, and when the pain attack is severe, the face can be distorted or frozen. Because the pain is located in two lower branches of the trigeminal nerve, it is often misdiagnosed as a dental condition, resulting in patients receiving unnecessary dental treatment and even causing some irreversible damage. Some small doses of antiepileptic drugs (e.g., carbamazepine) are more effective in providing pain relief if administered early rather than any pain medication.
However, up to 10% for antiepileptic drugs are ineffective in treating trigeminal neuralgia, and in rare cases, trigeminal neuralgia can be secondary to brain tumors, multiple sclerosis, or vascular abnormalities, which can only be identified by neuroimaging. If quality of life is impaired and trigeminal neuralgia is not controlled by medication, then patients should consider neurosurgery.
Studies in Europe have shown that in cases of neuropathic pain, trigeminal neuralgia can severely interfere with daily life and activities and can even lead to suicide. This clinical review, based on limited research evidence and expert opinion, aims to describe the characteristics, pathophysiology, biochemical studies, diagnosis, imaging, and treatment (drugs, surgery) of trigeminal neuralgia.
(I) Epidemiology
Trigeminal neuralgia is rare and, therefore, it is difficult to obtain high quality epidemiological data. Data validated from the United States in the 1990s showed an annual incidence of 5.7/100,000 women and 2.5/100,000 men, with a peak incidence at the age of 50-60 years and a progressive increase in its incidence with age. A survey on neurological disorders in London showed that. Subsequent data analysis of the UK GP database showed a prevalence of 27 per 10,000 person-years, as did initial data from the Netherlands, but when experienced experts went to validate the data, it was examined and found to be 12.6 per 100,000 person-years. In a community-based study in Germany, the lifetime prevalence was 0.3% after face-to-face interviews with experienced neurologists.
(ii) Vulnerable population
Comparative analysis of data from the United States indicates that women are more likely to develop trigeminal neuralgia than men, and the association would be stronger if women survived longer than men. If a patient has multiple sclerosis, she/he may be more likely to develop trigeminal neuralgia. Hypertension and stroke are also associated with trigeminal neuralgia, but this may be due to a matter of odds, as the prevalence of hypertension and other degenerative diseases is similar.
(iii) Potential pathophysiological mechanisms
Many large surgical series from different centers have confirmed that for the treatment of trigeminal neuralgia, trigeminal nerve visualization microvascular decompression is the most effective and longest lasting. There is strong evidence that trigeminal neuralgia is caused by vascular compression of the trigeminal nerve in approximately 95% of patients; however, the pathophysiological mechanisms of how vascular compression of the trigeminal nerve causes trigeminal neuralgia are still unknown.
Currently, it is believed that various causes of localized demyelination of the trigeminal nerve produce ectopic impulses, and pseudosynaptic formation or short-circuiting of adjacent axonal fibers results in the transmission of minor nociceptive stimuli to the center through the short-circuiting, and the transmission of central efferent impulses through the short-circuiting, thus causing trigeminal neuralgia attacks by superposition.
Some recent studies have shown that this demyelination leads to impairment of the pain system, and these patients appear to lose central inhibition of the pain system often with background pain, and some form of abnormal somatosensory function remains even after successful surgery. Other factors also include biological factors due to a genetic basis may be important and, although rare, there are familial aggregations.
The remaining small percentage of trigeminal neuralgia cases are associated with multiple sclerosis plaques, lacunar infarct-related brainstem trigeminal nervous system or cerebellopontine lesions. Demyelinating MS plaques have been reported to involve the brainstem trigeminal nucleus; however, after studying consecutive cases with MS it was learned that MRI showed the presence of bundle-forming trigeminal nerve root fiber lesions in all patients, and this research evidence further supports the role of central nerve root demyelination in trigeminal neuralgia.
(iv) Diagnosis
The following are the main clinical features and red flags of trigeminal neuralgia. The diagnosis of trigeminal neuralgia and other unilateral neuralgia is generally based on the patient’s history, but the diagnostic criteria have not been confirmed by case-control studies and are based mainly on expert consensus, headache specialists and epidemiological studies starting in the 1990s.
Location of pain: Pain occurs unilaterally in the area of trigeminal distribution; bilateral pain occurs in only 3% of patients, and both sides rarely occur simultaneously.
Periodicity: The pain occurs suddenly, lasts for a few seconds or minutes and then stops abruptly, and can recur many times a day. There is a period of inactivity for each pain. The pain may enter a remission period that lasts several weeks or months; the interval between pain-free episodes gradually shortens with time.
Associated factors: Rarely associated with a history of chronic pain and migraine, some patients with trigeminal neuralgia may also experience persistent background pain after a major episode of pain. Rarely, autonomic symptoms are present.
Red flags: abnormal sensation, deafness or other ear disorders, difficulty with pain control, poor response to carbamazepine, any skin injury or oral lesion that may lead to perineural spread, transcranial branches of the eye or bilateral suggesting benign or malignant lesions or multiple sclerosis, age less than 40 years at onset, optic neuritis, family history of multiple sclerosis.
Trigeminal neuralgia tends to occur suddenly and with time, pain relief becomes shorter and pain episodes longer. 65% of patients with a first diagnosis of trigeminal neuralgia will have a second episode no more than 5 years later, and 77% of patients will have a second episode of trigeminal neuralgia within 10 years.
Pain relief lasts at least 6 months in 50% of patients, and some patients have trigeminal neuralgia attacks as infrequently as 3-4 times/day and as often as 70 times/day. Trigeminal neuralgia also has a period of inactivity, when pain episodes cannot be evoked. 1/3 of patients have pain that occurs at night. Trigeminal neuralgia rarely occurs in the ophthalmic branch of the trigeminal nerve.
Some patients have persistent background pain with a 50% reduction in pain intensity, a condition called atypical trigeminal neuralgia, which is classified in the new International Classification of Headache Disorders as type 2 – trigeminal neuralgia with accompanying persistent facial pain. Some patients have self-limiting symptoms, such as conjunctival congestion, tearing, nasal congestion or runny nose, eyelid edema, ptosis, and facial sweating.
If autonomic symptoms are present, it is difficult to determine whether the condition is trigeminal neuralgia, transient hemianalgia-like with autonomic symptoms (SUNA), or transient persistent unilateral neuralgia-like headache with conjunctival congestion and lacrimation syndrome (SUNCT). In a retrospective study, up to 67% of patients who underwent significant microvascular decompression reported the presence of one autonomic symptom and 14% of patients had four or more autonomic symptoms, and these patients with autonomic symptoms were similarly difficult to benefit from significant microvascular decompression. Emphasis should be placed on examining the target and oral cavity, as well as the cranial nerves, and once abnormalities are identified, the treatment plan needs to be adjusted in the context of the patient’s specific situation.
(v) Investigations still to be completed
Trigeminal neuralgia is a purely clinical diagnosis in its own right; however, investigations need to be explicit about the red flags in the table above as well as indications based on case reports. In the differential diagnosis with trigeminal neuralgia, these investigations will help identify other craniofacial pain syndromes, as well as identify trigeminal neuralgia caused by non-vascular compression, and obtain baseline laboratory test values to assist in drug toxicity monitoring prior to initiation of drug therapy. Patient self-assessment tools could also be developed to facilitate a sensitive and specific diagnosis of trigeminal neuralgia, but unfortunately based on current evidence are still insufficient for development.
In a small study, investigators investigated patients with trigeminal neuralgia or atypical facial pain using the McGill Pain Questionnaire (a universal pain questionnaire for pain due to all conditions) and had a 90% correct diagnosis rate. In another study, the investigators used an extended version of the Brief Pain Questionnaire to identify the effects of differences in daily life in 114 patients with typical trigeminal neuralgia and 42 patients with atypical trigeminal neuralgia. Neither of these pain rating tools has been validated in a large study of patients with trigeminal neuralgia.
(vi) Imaging
The most favorable diagnostic tool is the brain scan with/without contrast MRI, which is used to rule out potential pain-causing causes if the diagnosis cannot be definitively ruled out or if danger signals in the table are present. sclerosis, intrinsic brain lesions occurring in the thalamic and brainstem trigeminal pathways (e.g., foci of lacunar infarction), and cerebellopontocerebellar keratopathy (e.g., tumors, or arachnoid cysts, aneurysms, or arteriovenous malformations).
The selection of the trigeminal nerve imaging sequence is very important because of the complex intracranial travel of the trigeminal nerve and the structures in the pontocerebellar region with nerves, blood vessels, and cerebrospinal fluid. General imaging cannot show the trigeminal nerve and can only be used to show localized disease. To show the neurological and vascular conditions in patients with trigeminal neuralgia, sequences sensitive to both nerves and vessels must be selected. MRI is the most sensitive screening and diagnostic tool for the diagnosis of multiple sclerosis and has the highest positive predictive value.
Tumors of the brain can also be associated with trigeminal neuralgia, although they are rare. Tumors of the posterior cranial fossa are the ones most likely to be associated with the painful features typical of trigeminal neuralgia, most commonly vestibular nerve sheath tumors, meningiomas, or epidermoid cysts. In clinical experience, sometimes when a patient is diagnosed with trigeminal neuralgia, based on what they have learned online about trigeminal neuralgia, they ask their physician to perform an MRI to evaluate the vascular compression of the trigeminal nerve. MRI looks at the contact between the vessels and the trigeminal nerve.
These techniques are very expensive and are not included in the standard MRI protocols, which are only available in some specialized institutions. In addition, in many patients without trigeminal neuralgia, the vessel in question is a normal vessel, the vessel is in normal position in relation to the cranial nerve contact, and the radiologist reads “normal” on the vessel contact imaging.
A multidisciplinary evidence-based review of the published literature by the American Academy of Neurology (ANN) and the European Federation of Neurological Societies (EFNS) concluded that MRI is currently insensitive for routine use in detecting vascular compression of the trigeminal nerve. Some small studies using more advanced techniques have improved its relevance, but it cannot be used routinely at this time.
(vii) Biochemical studies
Depending on the drug of choice for trigeminal neuralgia, particularly antiepileptic drugs, which may cause lower white blood cell counts, elevated liver transaminases, and hyponatremia, blood tests, blood electrolytes, and liver function tests should be performed during treatment to detect potential drug toxicity over time. Regular blood tests are not recommended unless clinically indicated.
For patients taking enzyme-inducing drugs, the National Institute for Health and Clinical Excellence (NICE) in the UK recommends screening for complete blood count, electrolytes, liver drug enzymes, and vitamin D levels and other bone metabolism tests (e.g., serum calcium and alkaline phosphatase) every 2-5 years.
(viii) Pharmacological treatment measures
All drugs currently available for the treatment of trigeminal neuralgia were not originally developed for indications specific to trigeminal neuralgia, mostly epilepsy, and only a very small number of small sample randomized controlled trials have studied drugs for trigeminal neuralgia, many of which are outdated and methodologically flawed. The commonly used drugs for trigeminal neuralgia treatment are.
In the UK, the only one approved specifically for trigeminal nerve is carbamazepine, but this can only be used in neurogenic pain (trigeminal neuralgia is considered to be neurogenic pain). However, the updated NICE guideline on pain management in neurogenic pain states that carbamazepine should only be used in primary care and should be referred to specialist treatment if treatment fails. The guideline specifically excludes the use of other neurogenic drugs for trigeminal neuralgia in primary care. All medications should be started at the lowest dose and gradually increased at 3-7 day intervals until the lowest effective dose provides optimal pain control, and should be carefully monitored for toxic effects.
Based on four randomized controlled trials with small study quality, the drug of choice remains carbamazepine, with approximately 70% of patients achieving 100% pain relief initially. However, most patients experienced side effects after taking the drug, which manifested themselves mainly in the central nervous system, such as fatigue, poor concentration, and a high risk of drug interactions. As a second choice, oxcarbazepine, a ketone derivative of carbamazepine, was shown to be as effective as carbamazepine, but more easily tolerated and with a reduced risk of drug interactions, based on the results of three randomized controlled trials that included a total of 130 participants.
However, both drugs increase the risk of side effects, and lamotrigine dosing must be slow or rash will occur. A small randomized controlled trial of gabapentin with ropivacaine injected into the site of pain showed improved pain control as well as quality of life for patients, but these results were not replicated. In an open prospective trial that included 53 participants, results at 1 year of follow-up demonstrated the effectiveness of pregabalin. No combination drug treatment trials are continuing.
(ix) Surgical treatment measures
Surgical treatment of trigeminal neuralgia is generally divided into two categories: one is palliative destruction; the second is for microvascular decompression, which is aimed at decompressing the trigeminal nerve and dealing with 95% of trigeminal neuralgia that is not caused by damage/lesion.