Cervical Discopathy in Idiopathic Trigeminal Neuralgia: More than a Coincidence?

Background Data: The most common cause of trigeminal neuralgia is neurovascular compression. However, several patients present with unknown etiology. Purpose: This study aims to investigate the relationship between trigeminal neuralgia and cervical pathology in patients previously diagnosed with idiopathic trigeminal neuralgia. Study Design: We designed an observational case-control study in our tertiary center. Patients and Methods: A study group consisting of patients previously diagnosed with idiopathic trigeminal neuralgia and a control group consisting of patients with tension-type headaches were included in the study. A blinded neuroradiologist reevaluated cranial MRIs of trigeminal neuralgia patients. Once it was confirmed that no signs of neurovascular compression or any secondary causes were present, a cervical MRI was performed to evaluate cervical pathologies. Cranial and cervical MRIs of the controls were evaluated by the same neuroradiologist. Results: Twenty patients who had prior diagnoses of idiopathic trigeminal neuralgia and 20 controls were investigated. The mean age of trigeminal neuralgia patients was 64.9 ± 12.6, and the mean age of the control group was 61.3 ± 9.1 ( p = 0.305). The male/female ratio in trigeminal neuralgia patients was 2.3 and 1.8 in the control group ( p = 0.736). While indentation on the trigeminal spinal tract above the C4 spinal level was observed in 12 out of 20 patients, none of the controls had any involvement in the same region ( p < 0.001). Conclusion: The results of this study suggest that extramedullary indentation on the trigeminal spinal tract caused by upper cervical discopathy may be one of the possible etiological factors in trigeminal neuralgia. (2021ESJ244)


INTRODUCTION
Trigeminal neuralgia (TN) is an extremely debilitating condition characterized by a unilateral sudden stabbing, shock-like, and electrocutiontype paroxysmal pain in one or more divisions of the trigeminal nerve triggered by innocuous stimuli. Under the International Classification of Headache Disorders (ICHD-3) diagnostic criteria, TN is divided into classical, secondary, and idiopathic trigeminal neuralgia. 30 New diagnostic criteria are developed based on several clinical pieces of research. 4,16,30,33 Classical trigeminal neuralgia, caused by neurovascular compression, is the most common form of TN. 16,48 Secondary TN, which accounts for approximately 15% of cases, results from an external cause, such as a tumor or multiple sclerosis. 16,17,30 TN of unidentified etiology is labeled idiopathic. 30 The trigeminal nerve, the largest cranial nerve with three main branches, provides sensory innervations of the teeth, intracranial structures, neck, face, and head. In addition, it has motor branches that innervate the masticatory muscles, including the masseter, lateral pterygoid, and temporalis muscles. The sensory root, which extends from the ganglion, enters the pons and terminates three major nuclear complexes within the brainstem. 31,45,54 Clinical Rationale for the Study It is well-known that vascular contact has not been observed in a wide range (4%-89%) of TN patients. 1,5,17,29,48 Similarly, a considerable number of patients in our clinic were diagnosed with idiopathic TN due to no etiological factors being present. A recent new hypothesis suggests that pathological changes in the upper cervical region create a change in the trigeminal spinal tract that results in TN. It has been argued that TN can result from pathology in the subnucleus oralis because the distribution of the trigger zone in the facial area is in line with the subnucleus oralis. 49 Additionally, several case reports have identified that the lesion in the upper cervical region can cause TN. 52,55 As far as we know, no studies have illustrated upper cervical discopathy resulting in TN. This study aims to investigate whether there is a relationship between TN and cervical discopathy.

PATIENTS AND METHODS
The study was designed as an observational case-control study. It was conducted on patients admitted to the outpatient neurology clinic of a university hospital between 2018 and 2019. Patients who had a prior diagnosis of idiopathic TN and a control group consisting of patients with tension-type headaches were included in the study. Both patient groups were examined by the same experienced neurologist, and radiological findings were evaluated by a blinded neuroradiologist. Inclusion criteria were as follows: a prior diagnosis of "idiopathic TN" according to ICHD-3, 18 years of age and above, no pathological findings on cranial MRI, written consent given, and no systemic illnesses. Evaluation of clinical characteristics: all patients' data, including age, gender, duration of disease, side and involved branches of TN, pain severity (Visual Analogue Scale (VAS)), pain frequency (per day), and medical treatment, were recorded. Clinical symptoms of upper cervical discopathy such as neck pain, shoulder pain, chest pain, pain in the auricular area, and occipital area were evaluated and recorded. Patients previously diagnosed with idiopathic TN were reexamined; their cranial MRIs were reevaluated by a neuroradiologist. After confirming that no signs of neurovascular compression or any secondary causes were present, a cervical MRI was performed to evaluate cervical pathologies. Evaluation of MRI findings: MRI images were taken using a 1.5 Tesla magnet. Cervical MRI evaluation was carried out using sagittal fast spin-echo T1 and T2 and axial T2 weighted images. Section thickness was 3 mm. During cervical MRI evaluation, the spinal trigeminal tract was determined using Afshar's stereotactic atlas. 2 Assuming that the spinal trigeminal nucleus extends to the level of C4 and continues in Lissauer's tract and the medulla spinalis, the levels of the lesions were divided into two: above C4 level and below C4 level. 44 The level at which indentation was most pronounced was considered the level of the lesion. Three items related to disc degeneration were assessed (nucleus signal, prolapses, and bone marrow signal). The classification was done according to Frobin. Disc degeneration is divided into 12 categories (ABC…L); while category A contains a normal disc with no findings, category L contains a disc in the state of maximal degeneration. We divided Frobin's classification into mild, moderate, and severe (ABCD mild, EFGH moderately, IJKL as severe). 25 This study was performed in line with the principles of the Declaration of Helsinki. Ethical approval was obtained from the local ethics committee (approval number: 2011-KAEK-2/2019/147). Informed consent was obtained from all individual participants included in the study. Statistical Analysis: Statistical analysis was performed using SPSS software (version 21.0 SPSS Inc., Chicago, IL, USA) for Windows. Frequency distribution, percentage, mean, standard deviation, median, and range were calculated where appropriate. The Chi-square test (x2) was used for categorical variables, while the t-test was used for continuous variables under parametric conditions. Results were considered to be statistically significant at the level of p < 0.05.

RESULTS
Twenty patients with a prior diagnosis of idiopathic TN and a control group consisting of 20 patients with tension-type headaches were included in the study. The mean age of TN patients was 64.9 ± 12.6 years, and the mean age of the control group was 61.3 ± 9.1 years (p = 0.305). The male/ female ratio in TN patients was 2.3 and 1.8 in the control group (p = 0.736). All patients with TN had at least one of the additional following symptoms: ipsilateral neck pain, ear-auricular pain, periorbital pain, chest pain, or shoulder pain. The symptoms of the patients are illustrated in Table 1. One patient had no signs of any lesions. The radiological findings are shown in (Table 2). MRI examples of patients are shown in Figures 1, 2, 3, and 4. Cervical degenerative findings of the patients and controls: ten out of 20 patients with TN had severe disc degeneration findings. Eight of 20 patients had medium-degree disc degeneration findings, and two had mild-degree degenerative findings.
In the control group, eight had severe degenerative changes and 11 had medium and one had mild degenerative changes. No statistical difference was found between the two groups (p = 0.598). A comparison of the two groups is shown in Table 3. MRI examples of disc degeneration are shown in Figure 5.

DISCUSSION
This study illustrates that two-thirds of patients who did not have intracranial findings on MRI and had a previous diagnosis of idiopathic TN have an ipsilateral extramedullary indentation on the spinal trigeminal tract. The severity of intervertebral disc degeneration is not directly associated with spinal trigeminal tract injury. Compression caused by upper cervical discopathy can lead to TN in two different ways: either by direct indentation of the trigeminal spinal tract or by indirect anatomical, biochemical, or functional impairment of the trigeminocervical complex coming from the dorsal roots and dorsal horn. As far as we know, there is no research investigating the relationship between upper cervical discopathy and TN. However, there are some case reports which indicate that any pathology on the upper cervical region can cause TN. One case reported that cervical discopathy on the level of C3-C4 resulted in trigeminal sensory neuropathy by affecting the spinal trigeminal tract. Surgical removal of the disk resulted in an immediate and complete resolution of TNlike symptoms in the patient. 7 Francois et al. demonstrated TN in 3 cases after posttraumatic cervical discopathy. Patients' symptoms of TN were reported to have disappeared after surgical decompression. It has been claimed that the cause of the pain may be due to compression of the spinal trigeminal tract. They argue that the spinal trigeminal nucleus can also extend to the lower cervical region. 23 Similarly, in our study, 25% of patients had an indentation on the Lissauer's tract, which is the continuation of the trigeminal spinal tract. In another paper, Samim et al. demonstrated 6 cases that had orofacial neuralgia associated with whiplash trauma. The pain of these patients has been described as typical TN. Two out of six patients had bulging between C2-C6 levels. 53 Many studies are reporting that neuropathic pain develops due to spinal cord injuries. It has been reported that any pathology in the spinal cord may cause hyperexcitability in the dorsal horn. 26,60 This might occur through dysregulation of glutamate release, uptake, and receptor expression; 21,26,40,50, 51 dendritic spine remodeling; 58,61 loss of local inhibitory (GABAergic) tone; 6,8,20,39,42,46 descending (particularly serotonergic) inhibitory input to spinal nociceptive circuitry; 28,34,40 or increased expression of calcium channel subunit. 11 Within a few months of spinal cord injury, NADPHdiphosphorase abnormality is seen in the nucleus cuneatus, nucleus gracilis, and spinal trigeminal tract of rats. 32 Neuropathic pain may be experienced by about 80% of individuals who sustain spinal cord injury. 22,56,57 Some studies have pointed out the role of dorsal root ganglion in neuropathic pain. It is reported that chronic dorsal ganglia involvement can induce long-lasting N-methyl-D-aspartate receptor subunit 2B and neuronal nitric oxide synthase (nNOS) upregulation in the spinal dorsal horn. This upregulation may contribute to nociceptors activity-induced spinal plasticity and the development of central sensitization, and a close correlation between nNOS and neuropathic pain has been demonstrated. 14,43 After peripheral afferent fiber injury, a cascade of events within the dorsal root ganglion and upstream within the

EGYPTIAN SPINE
Journal dorsal horn of the spinal cord leads to a constitutive release of cytokines, production of abnormal ion channels, abnormal ion currents, early and late gene changes, and the development of chronic neuropathic pain. 37,38 It has been observed that compression with disc herniation may cause the spread of neuropathology from the dorsal part to the ventral area of the spinal cord. 41 The studies that report cervical discopathies may also bring about neuropathic pain, suggesting that the cause of neuropathic pain may result from degenerative changes in the lamina I cell in the dorsal horn of the cervical disc. Ascending projection from the superficial dorsal horn of mammals is mainly sourced in the lamina I providing ascending trigeminal and spinothalamic tract projections that are key in sensations such as pain, itching, and temperature. 15,27,59 Animal studies show neuroplastic changes in various regions, including the primary synapses, spinal trigeminal tract, and the spinal dorsal horn, where the anatomical changes play a role in the production, modulation, and continuation of pain. 3,12,36 It is well-known that the trigeminocervical complex plays the main role in many primary headaches. Kerr 35 was first to describe the trigeminocervical complex, which is formed by the association of the caudal trigeminal nucleus and the upper cervical segments. The pathogenic mechanism is hypothesized to involve the convergence of the upper cervical afferents from the C1, C2, and C3 spinal nerves and trigeminal afferents in the trigeminocervical nucleus of the upper cervical cord. 9,10 Functional convergence of the upper cervical and trigeminal sensory pathways seem to allow the bidirectional (afferent and efferent) referral of pain to the occipital, frontal, temporal, and/or orbital areas. 10 However, several previous studies have reported that lower cervical spine diseases (below C4) can also cause headache; to this end, it is not clear whether the middle-lower cervical roots also project into the trigeminocervical nucleus in humans. 9,19,24, 47 The excitability of the second-order neurons within the trigeminal subnucleus caudalis has been shown to be responsible for pain perception and processing in migraine and TN. 18 Our study shows that patients with upper cervical discopathy have a wide range of symptoms that can be mistaken for diseases such as ear, eye, or heart pathologies in clinical practice. Chen et al. also reported that various symptoms, including headache, perioral hyperesthesia, dizziness, and tinnitus, could be found in patients with upper cervical discopathy. 13 Limitation of the study: the main limitation of this study is that it is not prospective. It does not observe the results of surgical procedures that may have been done to patients, such as cervical decompression, which is a major limitation. Second, such a small sample size might not be enough to prove our theory. Another limitation is that the MRI device used is a low-level Tesla. Additionally, a standard rather than specialized MRI protocol is used to investigate the cranial and cervical regions. It is very difficult to locate and explore the cervical region in a routine MRI scan because it is anatomically small in humans.