Advances in diagnosis, classification, pathophysiology, and management of trigeminal neuralgia

doi:10.1016/S1474-4422(20)30233-7

The Lancet Neurology

Volume 19, Issue 9, September 2020, Pages 784-796

https://doi.org/10.1016/S1474-4422(20)30233-7 Get rights and content

Summary

Trigeminal neuralgia is a very painful neurological condition with severe, stimulus-evoked, short-lasting stabbing pain attacks in the face. The past decade has offered new insights into trigeminal neuralgia symptomatology, pathophysiology, and treatment, leading to a change in the classification of the condition. An accurate diagnosis is crucial because neuroimaging interpretation and clinical management differ among the various forms of facial pain. MRI using specific sequences should be a part of the diagnostic workup to detect a possible neurovascular contact and exclude secondary causes. Demonstration of a neurovascular contact should not be used to confirm a diagnosis but rather to facilitate surgical decision making. Carbamazepine and oxcarbazepine are drugs of first choice for long-term treatment, whereas microvascular decompression is the first-line surgery in medically refractory patients. Advances in neuroimaging techniques and animal models will provide further insight into the causes of trigeminal neuralgia and its pathophysiology. Development of more efficacious treatment options is highly warranted.

Introduction

Trigeminal neuralgia is a debilitating neuropathic pain condition that affects basic human psychological, physical, and social needs and activities, such as touching the face, talking, eating, and drinking.¹ An epidemiological study showed increased anxiety, depression, and poor sleep in patients with trigeminal neuralgia, highlighting the condition's effect on mental health.²

Trigeminal neuralgia is managed by both medical, dental, and surgical health-care professionals, which can result in major variations in treatment approach and lead to delays in accessing specialist care.³ The intense pain and the possible effective treatment options warrant prompt, pain-focused tests and treatment. The past decade has witnessed major scientific advances in trigeminal neuralgia symptomatology, aetiology, pathophysiology, classification, and treatment, which can be readily translated into clinical practice. As an example, conventional MRI studies have highlighted that a neurovascular contact with morphological changes of the trigeminal nerve is highly associated with the symptomatic side in trigeminal neuralgia.4, 5 By contrast, advanced imaging studies using diffusion tensor imaging have shown that the microstructure of the myelination of the trigeminal nerve is disrupted by dysmyelination or demyelination.6, 7, 8, 9, 10 These findings have led to a new classification system for trigeminal neuralgia, which has been endorsed by both the International Headache Society (IHS) and the International Association for the Study of Pain (IASP).1, 11, 12

In this Review, we provide an update on the diagnosis, classification, pathophysiology, neuroimaging, treatment, and prognosis of patients with trigeminal neuralgia. We also provide a proposal for the practical management of patients with trigeminal neuralgia in a specialist setting. We focus on idiopathic and classical trigeminal neuralgia, together termed primary trigeminal neuralgia. Secondary trigeminal neuralgia has not been studied as much as the primary form of the disease;13, 14 it is much less common and can be caused by tumours or multiple sclerosis, among other factors.13, 14, 15

Section snippets

Epidemiology and genetics

Population-based European studies found a lifetime prevalence of 0·16–0·3%16, 17 of trigeminal neuralgia and an incidence of 12·6–27·0 per 100 000 person-years.18, 19 For reasons that are still not clear, trigeminal neuralgia affects women (60%) more than men (40%).2, 3 The average age of onset was reported to be 53–57 years.2, 3

Studies of trigeminal neuralgia in childhood and familial clustering suggest that genetic alterations contribute to the pathophysiology of the disease.3, 20 Increased

Classification

In 2018, both the IHS and IASP published new classifications for trigeminal neuralgia in an effort to align the two classifications. Although the two classifications differ in format, the classifications are similar with regard to the clinical characteristics required for diagnosis (panel 1).1, 11, 12 According to the third edition of the International Classification of Headache Disorders, trigeminal neuralgia is defined by recurrent severe paroxysmal pain restricted to the trigeminal

Diagnosis

Trigeminal neuralgia is a clinical diagnosis as the diagnostic criteria are based on patient history and necessitate detailed history taking, followed by clinical examination, to avoid misdiagnosis (panel 1).1, 11, 12 Panel 2 outlines the most important differential diagnoses.

Generally, the physical and neurological examinations are normal in patients with trigeminal neuralgia. Any abnormal neurological findings should prompt further investigations because it raises suspicion of secondary

Clinical features

Trigeminal neuralgia pain is short lasting³ and the quality is commonly described as stabbing, sharp, shooting, electric shock-like, or ice-pick-like pain. In addition, 14–50% of patients also have a concomitant continuous pain in the same area as the stabbing pain.2, 30, 31, 32 This pain component is dull, throbbing, or aching in quality, is less intense than the paroxysmal pain, and lasts from hours to days.³⁰

Although the origin of trigeminal neuralgia is considered to be at the trigeminal

Pathophysiology

Remarkably, symptomatology of trigeminal neuralgia is essentially the same across all known causes—ie, classical, idiopathic, and secondary trigeminal neuralgia. There is converging evidence of neural pathology at the root entry zone resulting from its compression by a blood vessel or tumour.4, 5, 15 Within this zone, the transition of peripheral Schwann cell myelination to central oligodendroglia myelination takes place,³⁵ which is thought to make the entry zone particularly susceptible to

Acute treatment for severe exacerbations

Single trigeminal neuralgia attacks are generally too short to be treated by medical intervention.¹³ Acute trigeminal neuralgia exacerbations are characterised by a very high attack frequency and can often lead to dehydration and anorexia because intake of fluids and food can trigger the pain. In such severe cases, in-hospital treatment might be warranted for rehydration and titration of antiepileptic drugs. Acute pain relief can provide a window for adjustment of oral preventive medication and

Management

We propose that the multidisciplinary team of medical specialists, neurosurgeons, neuroradiologists, nurses, physiotherapists, and psychologists involved in trigeminal neuralgia care, form a small dedicated group with a special interest in trigeminal neuralgia (figure 2). This proposal was tested in a Danish setup with 186 patients, in which all patients with trigeminal neuralgia were first seen by a neurologist with a special interest in the condition, and then underwent a 3·0 T MRI evaluated

Prognosis

Natural history studies in patients with trigeminal neuralgia are scarce. It has previously been a common belief that trigeminal neuralgia is a progressive disease. However, findings from two studies contradict this belief. In one retrospective Italian study, based in a tertiary pain centre, with a mean follow-up of 9 months, only 15 (8%) of 171 patients developed resistance to trigeminal neuralgia medications or reported increased pain intensity. Of the 178 patients with trigeminal neuralgia,

Future directions

Better knowledge of the aetiology and pathophysiology of trigeminal neuralgia could lead to new therapeutic targets with a higher degree of tolerability and individualisation of treatment. It is highly probable that there are multifactorial causes for trigeminal neuralgia, which need to be especially explored in patients with the idiopathic condition. Compared with patients with classical trigeminal neuralgia, the gender distribution in the idiopathic condition is more in favour of female

Conclusions

The past decade has offered important scientific advances regarding trigeminal neuralgia. The classification of primary trigeminal neuralgia now includes two scientifically founded subgroups, idiopathic and classical trigeminal neuralgia, on the basis of imaging findings. The IHS and IASP classifications have been aligned, which will ensure that future trigeminal neuralgia studies are comparable.1, 11, 12 Clinical features of trigeminal neuralgia have been much better described and knowledge on

Search strategy and selection criteria

References for this Review were identified using PubMed and MEDLINE, Embase, and Cochrane Library. Searches were restricted to the English language. We focused on papers published between Jan 1, 2010, and April 30, 2020. We used the search terms “trigeminal neuralgia”, “diagnosis”, “neurovascular contact”, “aetiology”, “pathophysiology”, “medical management”, and “surgical management”. The references were chosen on the basis of their originality and relevance to the Review.

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Cited by (205)

Cannabidiol and it fluorinate analog PECS-101 reduces hyperalgesia and allodynia in trigeminal neuralgia via TRPV1 receptors
2024, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Trigeminal neuralgia (TN) is an intense and debilitating orofacial pain. The gold standard treatment for TN is carbamazepine. This antiepileptic drug provides pain relief with limited efficacy and side effects. To study the antinociceptive potential of cannabidiol (CBD) and its fluorinated analog PECS-101 (former HUF-101), we induced unilateral chronic constriction injury of the infraorbital nerve (IoN-CCI) in male Wistar rats. Seven days of treatment with CBD (30 mg/kg), PECS-101 (3, 10, and 30 mg/kg), or carbamazepine (10 and 30 mg/kg) reduced allodynia and hyperalgesia responses. Unlike carbamazepine, CBD and PECS-101 did not impair motor activity. The relief of the hypersensitive reactions has been associated with transient receptor potential vanilloid type 1 (TRPV1) modulation in the trigeminal spinal nucleus. CBD (30 mg/kg) and PECS-101 (10 and 30 mg/kg) reversed the increased expression of TRPV1 induced by IoN-CCI in this nucleus. Using a pharmacological strategy, the combination of the selective TRPV1 antagonist (capsazepine-CPZ – 5 mg/kg) with sub-effective doses of CBD (3 and 10 mg/kg) is also able to reverse the IoN-CCI-induced allodynia and hyperalgesia responses. This effect was accompanied by reduced TRPV1 protein expression in the trigeminal spinal nucleus. Our results suggest that CBD and PECS-101 may benefit trigeminal neuralgia without motor coordination impairments. PECS-101 is more potent against the hypernociceptive and motor impairment induced by TN compared to CBD and carbamazepine. The antinociceptive effect of these cannabinoids is partially mediated by TRPV1 receptors in the caudal part of the trigeminal spinal nucleus, the first central station of orofacial pain processing.
Alterations in the spinal cord, trigeminal nerve ganglion, and infraorbital nerve through inducing compression of the dorsal horn region at the upper cervical cord in trigeminal neuralgia
2024, Brain Research
Idiopathic trigeminal neuralgia (TN) cases encountered frequently in daily practice indicate significant gaps that still need to be illuminated in the etiopathogenesis. In this study, a novel TN animal model was developed by compressing the dorsal horn (DH) of the upper cervical spinal cord.
Eighteen rabbits were equally divided into three groups, namely control (CG), sham (SG), and spinal cord compression (SCC) groups. External pressure was applied to the left side at the C3 level in the SCC group. Dorsal hemilaminectomy was performed in the SG, and the operative side was closed without compression. No procedure was implemented in the control group. Samples from the SC, TG, and ION were taken after seven days. For the histochemical staining, damage and axons with myelin were scored using Hematoxylin and Eosin and Toluidine Blue, respectively. Immunohistochemistry, nuclei, apoptotic index, astrocyte activity, microglial labeling, and CD11b were evaluated.
Mechanical allodynia was observed on the ipsilateral side in the SCC group. In addition, both the TG and ION were partially damaged from SC compression, which resulted in significant histopathological changes and increased the expression of all markers in both the SG and SCC groups compared to that in the CG. There was a notable increase in tissue damage, an increase in the number of apoptotic nuclei, an increase in the apoptotic index, an indication of astrocytic gliosis, and an upsurge in microglial cells. Significant increases were noted in the SG group, whereas more pronounced significant increases were observed in the SCC group. Transmission electron microscopy revealed myelin damage, mitochondrial disruption, and increased anchoring particles. Similar changes were observed to a lesser extent in the contralateral spinal cord.
Ipsilateral trigeminal neuropathic pain was developed due to upper cervical SCC. The clinical finding is supported by immunohistochemical and ultrastructural changes. Thus, alterations in the DH due to compression of the upper cervical region should be considered as a potential cause of idiopathic TN.
Long-Term Patient-Reported Outcomes of Stereotactic Radiosurgery for Trigeminal Neuralgia
2024, World Neurosurgery
We aimed to evaluate patient-reported outcomes (PROs) of stereotactic radiosurgery (SRS) for TN in terms of treatment efficacy and toxicity.
We retrospectively analyzed patients who underwent Gamma Knife SRS for idiopathic or classic TN between January 2013 and February 2022. Questionnaires regarding pain relief, treatment toxicity, and post-SRS treatment were sent between late 2022 and early 2023, and the responses received were analyzed. The Faces Pain Scale (FPS, 0: best, 5: worst) was used for quantitative evaluation.
Responses were received from 51 patients (76%). The mean pre-SRS FPS score was 4.1 (standard deviation (SD) 1.1). Forty-three patients (83%) reported initial pain relief and the best post-SRS FPS score was 1.1 (SD 1.5) (P < 0.001). At a median follow-up of 50 months, the FPS score was still 1.1 (SD 1.6) (P < 0.001). Analysis of factors contributing to durable pain relief showed neurovascular compression to be associated with FPS score improvement (Odds ratio 5.7, 95% CI 1.1–29.7, P = 0.038). Facial dysesthesia had a mean pre-SRS FPS score of 1.7 (SD 2.0) and a mean score of 1.4 (SD 1.7) at the last follow-up (P = 0.32). Eight patients (15%) received post-SRS interventions and 21 (40%) no longer required pharmacotherapy without post-SRS intervention. Forty-four patients (85%) reported being satisfied with SRS.
We analyzed PROs of SRS for TN using the FPS and showed SRS to be a safe and effective treatment modality achieving long lasting pain relief.
Bibliometric Analysis of the Top 100 Cited Articles and Author H-Indexes on the Surgical Treatment of Trigeminal Neuralgia
2024, World Neurosurgery
Medically refractory cases of trigeminal neuralgia often require treatment escalation. Surgical options include microvascular decompression and percutaneous ablation. This paper provides a bibliometric analysis of the most influential articles on the surgical management of trigeminal neuralgia.
The Web of Science database was queried to identify the top 100 cited articles concerning surgical treatment of trigeminal neuralgia. The search terms used included ALL=((“trigeminal neuralgia” OR “tic douloureux” OR "Fothergill's disease” OR “Trifacial neuralgia") AND (“surgical treatment” OR “surgical management” OR “surgery” OR “neurosurgery") NOT (“radiosurgery” OR “gamma knife")). The extracted variables included the first and senior author names, journal, publication year, institution, and surgical modality.
Our bibliometric search yielded 2104 studies, with 41,502 citations overall. Within the top 100 articles, Zakrzewska had the most first author papers (n = 5), and Burchiel had the most senior author papers (n = 6). The Massachusetts General Hospital was the most represented institution (n = 5). The United States was the most represented country (51%). Microvascular decompression was the most studied surgical strategy (51%), followed by percutaneous radiofrequency coagulation (9%), balloon/nerve compression (7%), and glycerol rhizolysis (7%). Some studies assessed multiple treatment modalities (22%). The types of studies included retrospective articles (58%), prospective articles (26%), reviews (10%), anatomic studies (2%), and basic science (1%). Neurosurgery (35%) and the Journal of Neurosurgery (33%) were the most represented journals.
The current literature consists of retrospective reviews and mostly describes microvascular decompression for trigeminal neuralgia. Future studies should include further characterization of other surgical modalities such as percutaneous radiofrequency thermocoagulation, glycerol injection, and balloon compression.
Sex differences in carbamazepine effects in a rat model of trigeminal neuropathic pain
2024, European Journal of Pharmacology
Carbamazepine (CBZ) represents the first-line treatment for trigeminal neuralgia, a condition of facial pain that affects mainly women. The chronic constriction of the infraorbital nerve (CCI-ION) is a widely used model to study this condition, but most studies do not include females. Thus, this study aimed to characterize sensory and affective changes in female rats after CCI-ION and compare the effect of CBZ in both sexes. Mechanical allodynia was assessed 15 days after CCI-ION surgery in rats treated with CBZ (10 and 30 mg/kg, i.p.) or vehicle, together with the open-field test. Independent groups were tested on the Conditioned Place Preference (CPP) paradigm and ultrasonic vocalization (USV) analysis. Blood samples were collected for dosage of the main CBZ metabolite. CBZ at 30 mg/kg impaired locomotion of CCI-ION male and sham and CCI-ION female rats and resulted in significantly higher plasma concentrations of 10-11-EPX-CBZ in the latter. Only male CCI-ION rats showed increased facial grooming which was significantly reduced by CBZ at 10 mg/kg. CBZ at 10 mg/kg significantly reduced mechanical allodynia and induced CPP only in female CCI-ION rats. Also, female CCI-ION showed reduced emission of appetitive USV but did not show anxiety-like behavior. In conclusion, male and female CCI-ION rats presented differences in the expression of the affective-motivational pain component and CBZ was more effective in females than males. Further studies using both sexes in trigeminal neuropathic pain models are warranted for a better understanding of potential differences in the pathophysiological mechanisms and efficacy of pharmacological treatments.
Transplantation of olfactory ensheathing cells can alleviate neuroinflammatory responses in rats with trigeminal neuralgia
2024, Brain Research
Trigeminal neuralgia (TN) is a common form of facial pain, which primarily manifests as severe pain similar to facial acupuncture and electric shock. Olfactory ensheathing cells (OECs) are glial cells with high bioactivity; these cells are essential for the periodic regeneration of the olfactory nerve and have been utilized for the repair of nerve injuries. A member of the P2X receptor family, P2X7R, is an ion channel type receptor that has been confirmed to participate in various pain response processes. In this study, we transplanted OECs into trigeminal nerve–model rats with distal infraorbital nerve ligation to observe the therapeutic effect of transplanted OECs in rats. Additionally, we utilized the P2X7R-specific inhibitor brilliant blue G (BBG) to study the therapeutic mechanisms of cell transplantation. The facial mechanical pain threshold of these rats significantly increased following cell transplantation. The immunohistochemistry, immunoblotting, and RT-qPCR results demonstrated that the levels of P2X7R, (NOD)-like receptor protein-3 (NLRP3), nuclear factor-κB (NF-κB), interleukin (IL)-1β, and IL-18 in the trigeminal ganglion of rats treated with OEC transplantation or BBG treatment were significantly lower than those in the injured group without treatment. Overall, our results demonstrate that OEC transplantation can alleviate TN in rats, and it can reduce the expression of P2X7R related inflammatory factors in TN rats, reducing neuroinflammatory response in TG.

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ReviewAdvances in diagnosis, classification, pathophysiology, and management of trigeminal neuralgia

Summary

Introduction

Section snippets

Epidemiology and genetics

Classification

Diagnosis

Clinical features

Pathophysiology

Acute treatment for severe exacerbations

Management

Prognosis

Future directions

Conclusions

Search strategy and selection criteria

Pain

Pain

Pain

Pain

Pediatr Neurol

Neuroscience

Pain

Clin Neurol Neurosurg

Neurosci Lett

Pain

Pain

Pain

Neuroimage Clin

Neuroimage Clin

Br J Anaesth

Pain

J Allergy Clin Immunol

Br J Anaesth

Pain

World Neurosurg

Eur J Pain

Lancet Neurol

Lancet

Br J Anaesth

Headache classification committee of the international headache society (IHS). The international classification of headache disorders, 3rd edition

Cephalalgia

Evaluating the impact of trigeminal neuralgia

Pain

Trigeminal neuralgia–a prospective systematic study of clinical characteristics in 158 patients

Headache

Significance of neurovascular contact in classical trigeminal neuralgia

Brain

Loss of anisotropy in trigeminal neuralgia revealed by diffusion tensor imaging

Neurology

High-resolution diffusion tensor imaging for the detection of diffusion abnormalities in the trigeminal nerves of patients with trigeminal neuralgia caused by neurovascular compression

J Neuroimaging

Trigeminal neuralgia due to neurovascular compression: high-spatial-resolution diffusion-tensor imaging reveals microstructural neural changes

Radiology

Microstructural alterations in trigeminal neuralgia determined by diffusion tensor imaging are independent of symptom duration, severity, and type of neurovascular conflict

J Neurosurg

Trigeminal neuralgia: new classification and diagnostic grading for practice and research

Neurology

The IASP classification of chronic pain for ICD-11: chronic secondary headache or orofacial pain

Pain

European Academy of Neurology guideline on trigeminal neuralgia

Eur J Neurol

Trigeminal neuralgia secondary to multiple sclerosis: from the clinical picture to the treatment options

J Headache Pain

Clinical features and long-term surgical outcomes in 39 patients with tumor-related trigeminal neuralgia compared with 360 patients with idiopathic trigeminal neuralgia

Br J Neurosurg

The rare, unilateral headaches. Vågå study of headache epidemiology

J Headache Pain

Prevalence of trigeminal neuralgia and persistent idiopathic facial pain: a population-based study

Cephalalgia

A gain-of-function mutation in Nav1.6 in a case of trigeminal neuralgia

Mol Med

Trigeminal neuralgia—diagnosis and treatment

Cephalalgia

Field-testing of the ICHD-3 beta diagnostic criteria for classical trigeminal neuralgia

Cephalalgia

Quantitative sensory testing in classical trigeminal neuralgia—a blinded study in patients with and without concomitant persistent pain

Pain

Concomitant persistent pain in classical trigeminal neuralgia—evidence for different subtypes

Headache

Triggering trigeminal neuralgia

Review
Advances in diagnosis, classification, pathophysiology, and management of trigeminal neuralgia