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Project

Trigeminal nerve injuries - Evaluation and optimization of diagnostic methods

Introduction and background

The trigeminal nerve is an important cranial nerve in the human body and is responsible for sense of touch in the face, pain perception, taste sensation and motor skills. This nerve has a very extensive course, function and representation in the cerebral cortex. Its peripheral branches are at risk of damage with numerous dental and maxillo-facial procedures: endodontics (root canal treatment), extractions, removal of wisdom teeth, placement of implants, use of local anesthesia, orthognathic surgery, etc.1

If damage to these nerve branches occurs, there is a risk of developing a neuropathic pain that is considered very invalidating for patients, while interfering with daily activities (eating, drinking, speaking, kissing, etc.). As the injury is caused by relatively "minimally invasive" procedures, often preceded by a limited informed consent, meanwhile having a major impact on the patient’s quality of life, medico-legal actions are relatively common.2–4 The limited symptom control with current therapies of these post-traumatic neuropathies of the trigeminal nerve may lead to frustration and powerlessness of both patient and treating physician, potentially evolving in medical shopping. Considering the lack of a central registry and the absence of dedicated referral center for iatrogenic trigeminal injuries, there is a gap in scientific evidence and thus also in clinical management. 

The social cost of this is particularly high.5,6 Some patients end up with neurostimulators, others languishing in social isolation or in psychiatric institutions confronted with persistent, inevitable pain complaints.7

Currently, post-traumatic trigeminal neuropathic pain (PTNP) diagnosis is primarily based on the patient’s history and description of symptoms, together with results from physical and neurological examination.8 Therefore, diagnosis remains largely limited to subjective and non-standardized evaluations. Considering overlapping symptoms and the large number of conditions that can cause orofacial pain, obtaining a correct diagnosis is difficult. However, finding the cause of pain is crucial for setting up an efficient therapy plan.9

Many patients with PTNP eventually will undergo a magnetic resonance imaging (MRI) scan to rule out underlying pathologies such as a tumor or multiple sclerosis as the cause of their pain. Furthermore, MRI scans are used in a desperate hope to detect any damage of the peripheral nerve fibers, but often fail to do so. We suspect that current MRI sequences have a too low sensitivity and specificity, and therefore have no diagnostic value. New high-resolution MRI protocols are required to reveal the presence, location and severity of nerve damage in the maxillofacial region if we wish to increase diagnostic accuracy.10

MR neurography (MRN) is an MRI technique specifically developed to visualize nerve fibers. This technique makes it possible to adequately distinguish the fat-rich nerve trunks from their

environment. Recent progress in this technology has allowed visualization of large nerve bundles with diameters above 2 mm. Unfortunately, the majority of nerve-related pathologies, but also neuroregeneration, are only visible at microscopic level (dimensions of 1 mm and below). In a series of pilot experiments in collaboration with Prof. Dr. Jan Casselman, we were able to develop a new MRN sequence which allows us to visualize these small nerve bundles in fresh human cadavers and healthy subjects (pilot study, unpublished). The next logical steps are to validate this protocol and to translate it to clinical practice by correlating it to the outcomes of physical and neurological examinations.

The following proposed research topics and aims are new to our research group. Dr. Van der Cruyssen has already started on some of the required work and several ethical committee dossiers have already been submitted in preparation of this doctoral thesis. 

General hypothesis and specific aims of the project

We assume the following hypotheses. Firstly, the impact of PTPN is underestimated and causes a significant impact on QoL of patients with a substantial health care cost. Secondly, diagnostic features differ between sensory profiles and may predict outcomes. Lastly, magnetic resonance neurography is accurate in detecting trigeminal nerve injuries and has the potential to aid diagnosis and treatment. 

Methodology

Part 1. Diagnostic and outcome data on PTNP patients

We aim to gain insights in the “burden of disease” of post-traumatic trigeminal neuropathy by performing a retrospective study analyzing patient records of all cases of post- traumatic, including iatrogenic, injury to branches of the trigeminal nerve seen at the department of Oral & Maxillofacial Surgery at UZ Leuven between January 2010 and October 2018. Subsequently we will gather prospective data in a similar way to assess these endpoints longitudinally. The primary endpoints are: 1) Are symptoms or clinical exam parameters predictive of a temporary or permanent injury? If so, which parameters can be withheld? 2) Is there a correlation between quality of life measured with EQ5D questionnaire and cause of injury, temporary versus permanent injuries? Two ethical committee dossiers have been approved to allow these studies: “S62333: post-traumatic neuropathy of the trigeminal nerve: a retrospective analysis” and “S61077: post-traumatic neuropathy of the trigeminal nerve: a prospective observational study of QoL”. Since there are no comparable studies available, it is difficult to make a power analysis. However, based on the most pessimistic models using repeated measures with within- and between-group variance powered at 80% (α=0.05) a sample size of 250 patients was calculated. Statistic measures are described in the study protocol (S61077).

Part 2. Costs of illness

Using the same retrospective dataset gathered in part 1 we will evaluate healthcare costs, medication use and productivity loss in relation to the injury and Quality of Life (QoL) measured using the EQ5D survey. To achieve this goal, we will cooperate with the National Christian Sickness Fund (Christelijke Mutualiteiten, CM hereafter). This study was already approved by the ethical committee (S62333: post-traumatic neuropathy of the trigeminal nerve: a retrospective analysis). Primary endpoints are: 1) What are the healthcare cost of patients with PTNP? 2) What is the average productivity loss? 3) Amount of medication use per medication class in patients with PTNP? 4) Is there a correlation between quality of life measured with EQ5D questionnaire and healthcare costs, productivity loss or medication use? Data will be handled in a similar way as part 1(please see above) as this is part of the same study protocol (S62333).

Part 3.1 Retrospective analysis of magnetic resonance imaging for patients diagnosed with PTNP

Before the start of the prospective study, a retrospective analysis of all commissioned MRI’s by the department of Oral and Maxillofacial Surgery UZ Leuven will be performed to assess diagnostic accuracy of MRI in post-traumatic trigeminal neuropathy and its ability to change the management of the trigeminal pain. This will be evaluated based on the medical records of the consultations following the MRI.

Statistical analysis will include descriptive statistical analysis of the grouped and subgroup data. Comparison between subgroups will be performed using the unpaired parametric t-test. A contingency table will be constructed for the total trigeminal pain group and for each subgroup.

Ethical committee approval for this retrospective study was already granted (S62823: the diagnostic value of magnetic resonance imaging in post-traumatic trigeminal neuropathy).

Part 3.2 Validation of magnetic resonance neurography in PTNP

Required sample size was calculated based on the pilot experiments suggesting a minimum sample size of 20 participants when assuming 95% power and α of 0.05. Twenty patients with current PTN symptoms will be recruited through the Oral & Maxillofacial Surgery department of University Hospitals Leuven, Belgium. Impact of post-traumatic trigeminal neuropathy will be confirmed based on a combination of clinical and neurophysiological tests. Twenty age- and gender-matched subjects without any history of peripheral nerve and/or neurologic disease will serve as controls. Magnetic resonance neurography examinations will be acquired at the radiology department, University Hospitals Leuven on an Ingenia 3-Tesla MR scanner (Philips Medical Systems, Best, The Netherlands) using a 32-channel standard head coil. All participants will receive the same examination protocol. Contrast agent will not be administered. Different levels of observers will rate the MR images independentlyblinded to the diagnosis. Signal- and contrast-to-noise ratios will be calculated for all branches on predetermined positions for image quality evaluation. In addition, the nerve visibility will be rated on a 5-point scale according to Fuji et al. (American Journal of Neuroradiology, 2015). Moreover, quality assessment of the produced MR images will also be included. McNemar tests will be used to test independent evaluator consistency in MRI results against the truth (control or PTN patient). To assess test reliability, Cohen’s kappa will be calculated for interrater differences. Interrater differences will be calculated after two separate evaluations within one-month interval. Image quality parameters will be compared using mixed models. 

Conclusion:

Some projects are already ongoing, necessary contacts with third parties (radiology department of AZ Sint-Jan, King’s College London, Christelijke Mutualiteiten, dep. of biostatistics and Leuvens Instituut voor Gezondheidszorgbeleid) are made and partnerships agreed upon. The MRN pilot study is in a final phase before moving on to validation of the protocol. These factors should allow for successful delivery of the proposed endpoints. We expect to achieve the following results:

1. Prove that PTNP has a significant burden on patients. This will be done on a large cohort of patients retrospectively and verified prospectively.

2. PTNP comes with a high societal and personal cost for certain subgroups. Identifying and early prediction of patients within these subgroups could have major implications in clinical management. Preventing injury in these groups could reduce societal costs. 

3. Standard MRI sequences are of no use in diagnosing PTNP, instead magnetic resonance neurography (MRN) techniques have the potential to accurately diagnose peripheral trigeminal nerve lesions. MRN could become the new gold standard of diagnostic tools in PTNP and improve diagnostic accuracy. 

 

Date:9 Sep 2019 →  12 Jun 2023
Keywords:Trigeminal nerve injuries, Orofacial pain, Microsurgical nerve repair
Disciplines:Oral and maxillofacial surgery
Project type:PhD project