The difference in clinical characteristics in the patients with unilateral oral cenesthopathy with and without the neurovascular compression of trigeminal nerve: A clinical chart review


 Background

Oral cenesthopathy (OC) is characterized by unusual sensation in the oral cavity without corresponding medical and dental evidence. Their complaints are vary and some patients show sever symptoms which decline their quality of life. The neurovascular compression (NVC) of trigeminal nerves is known as one of the factors to indicate abnormal sensation in facial area including oral cavity. The aim of the present study was to investigate the pathophysiology of OC by comparing the clinical characteristics of unilateral OC patients with and without trigeminal nerve NVC.
Methods

This is a retrospective study reviewing medical records of patients diagnosed with unilateral OC seen between April 2016 and February 2019. Magnetic resonance images (MRI) were performed to assess the presence of NVC.
Results

Among 321 patients who were diagnosed with OC, 87 patients showed unilateral OC. finally, 52 patients who were performed MRI were involved in the present investigation. In 48.1% subjects (25/52), NVC of trigeminal nerves was observed. In the patients without NVC, 85.2% (23/27) were female with significant difference (p = 0.010) compared to the patients with NVC (48.0%, 12/25). There was no significant difference in age, the presence of psychiatric history and psychosomatic dental comorbidity, and the scores of psychological questionnaires. However, in the patients without NVC, significantly higher scores were observed in the symptom severity and the functional impairment as follow; movement (p = 0.042), pain (p = 0.040), work (p = 0.013) and social activities (p = 0.015), compared to the group with NVC.
Conclusion

These results suggest that unilateral OC has two subtypes based on predominant involvement of peripheral or central nervous system (CNS). The unilateral OC with NVC may involve predominantly peripheral nervous system. Furthermore, the unilateral OC without trigeminal nerve NVC which showed severe functional impairment may be reflected predominant CNS involvement.

The difference in clinical characteristics in the patients with unilateral oral cenesthopathy with and without the neurovascular compression of trigeminal nerve: A clinical chart review Kazuya

Background
Oral cenesthopathy (OC) is characterized by unusual sensations in the oral cavity without corresponding medical and dental evidence. OC is also called "oral somatic delusion" or "oral dysesthesia". OC patients complaint various sensations. Some patients complaint of a slimy and sticky sensation or excessive mucus secretion in the oral cavity while some patients complain of real strange oral sensations such as coil and wire sometimes even accompanied by the movement. Their daily lives are sometimes eclipsed by bizarre symptoms. It remains still unclear the detailed pathophysiology of OC including the factors which affect variations and severities of symptoms.
OC is classi ed as "delusional disorder, somatic form" according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition [1], and classi ed as "persistent delusional disorder" or "other schizophrenia" in the classi cation of mental and behavioral disorders in International Classi cation of Diseases 10th revision [2]. Previously, the existence of the subtypes of OC have been suggested based on the etiology [3] and clinical mental manifestation [4]. Moreover, since the comorbidity of psychotic disorders such as schizophrenia and bipolar was found only 6% in the OC patients, the authors conclude the oral cenesthopathic sensation might not be merely a partial symptom of psychotic disorders that present delusional symptoms [5]. These results suggest that the pathophysiology of OC differ from psychotic disorders.
Recently, involvement of the central nervous system (CNS) was considered as one of the pathophysiology of OC. In the investigation by using single photon emission computed tomography (SPECT), cerebral blood ow (CBF) showed a right-dominant asymmetry in the callosomarginal, precentral, and temporal regions in the patients with OC [6]. Moreover, a signi cant right dominant asymmetry in the temporal and posterior cerebral regions was observed regardless of the presence of a history of depression [7]. The right dominant asymmetric CBF may affect the oral delusional symptoms.
As the peripheral nervous system, cranial nerves assume important roles. The trigeminal nerve is the largest cranial nerve and has a sensitive and motor composition for a facial area including oral cavity. It is called root entry zone (REZ) where trigeminal nerves entry into or exit from brainstem via the cisternal portion at the height of pons. The artery or vein compression of trigeminal nerves can be occurred at REZ. Neurovascular compression (NVC) of trigeminal nerves indicates abnormal pain sensation such as trigeminal neuralgia [8], persist idiopathic facial pain (PIFP) in some cases [9]. Since trigeminal nerves transit not only pain but also thermal, tactile and pressure, we hypothesized that NVC of trigeminal nerves may be involved in the pathophysiology of other abnormal oral sensation in OC patients. The trigeminal nerves mainly decussates and run to contralateral thalamic neuclei which project to cortical region through the thalamocortical tract [10]. Considering this anatomical nerve tract and asymmetric CBF in OC patients, other our hypothesis was built that unilateral OC has subtypes based on not only the presence of NVC but also the laterality of the symptoms and NVC.
The aim of the present study was to investigate the pathophysiology of OC by comparing clinical characteristics of unilateral OC patients with and without NVC of trigeminal nerves.

Subjects
This is a retrospective study reviewing the medical records of patients diagnosed with unilateral OC seen between April 2016 and February 2019 at the Psychosomatic Dentistry Clinic of Tokyo Medical and Dental University.
The OC was diagnosed by a specialist in psychosomatic dentistry who had certi ed by Japanese society of psychosomatic dentistry. The inclusion criteria were as follows: 1) unilateral symptoms of OC, 2) absence of corresponding abnormal ndings from a dental panoramic radiograph and intra-and extraoral examination. The exclusion criteria were patients who 1) did not give us informed consent, 2) referred to another clinic, 3) dropped out, 4) refused inspection, 5) could not take magnetic resonance images (MRI), 6) had a severe health condition and 7) were performed MRI in the another year during the study duration ( Fig. 1).
Clinical characteristics were obtained from the patients' medical charts, including demographic information (sex, age), the duration of illness, psychiatric history, comorbid psychosomatic dental symptoms, and the triggers of symptoms. All examiners in the present study were well experienced trained clinicians and researchers in our clinic.

MRI protocol and de nitions
All patients underwent MRI scan within one month after the rst medical examination. No patients had improved their oral symptoms on that day. All data were acquired on 3-Tesla 3D MRI scanner (Siemens Healthcare, Erlangen, Germany) with a 16-channel head coil. The MRI sequences were acquired at the level of REZ of trigeminal nerves with the same parameters with our previous study [9]. MR angiography (MRA) was acquired using 3D time-of-ight (3D-TOF) MRA with following parameters: repetition time (TR) / echo time (TE) 24/3.9 ms, ip angle 18°, eld of view (FOV) 160 × 160 mm, matrix 320 × 192, section thickness 0.5 mm, and number of slab 3, which was reconstructed to a voxel size of 0.5 × 0.5 × 0.5 mm, a slab thickness 44 mm. MR cisternography was obtained using 3D constructive interference in steady state (3D-CISS) with the following parameter: TR/TE 7.4/3.7 ms, ip angle 50°, FOV 160 × 160 mm, matrix 320 × 320, section thickness 0.5 mm, which was reconstructed to a voxel size of 0.5 × 0.5 × 0.5 mm, a slab thickness 44 mm.
All 3D-TOF and 3D-CISS were displayed in triplanar views (transverse, coronal and sagittal views) on the visualization system and evaluated the presence of NVC by experienced oral radiologists who were blinded to symptom side. The presence of NVC was de ned as contact between a blood vessel and trigeminal nerves at REZ without visible cerebrospinal uid between them in the triplanar views of 3D-CISS. The type of responsible blood vessel (artery or vein) was evaluated using the triplanar views and memory-in-pixel display of 3D-TOF MRA. If there was disagreement or uncertainty about whether there was a contact, it was considered as no NVC in the data analysis.

Assessment of OC and psychological state
The symptoms of OC was assessed using the oral dysesthesia rating scale (Oral DRS) which developed based on literature review and extensive clinical experience to reorganize and objectify the complicate symptoms [11]. Oral DRS consists of a symptom severity scale (SSS), functional impairment scale (FIS), and visual analog scale (VAS  [19]. Subgrouping for targeted treatment generic (STarT-G) were also performed to assess disability due to chronic sensation [20]. In addition, clinical global impression (CGI) severity was used for objective assessment of the severity of illness [21].

Analysis
All data were analyzed using student t-test,  (Fig. 1).

Demographic and clinical characteristics
The NVC on the trigeminal nerves were observed in 25 patients (48.1%) with unilateral OC (  (Fig. 3). Moreover, the numbers of corresponding symptoms in both SSS and FIS were signi cantly higher in the patients without NVC than those in the patients with NVC.

Discussion
This is the rst study investigated pathophysiological involvement of NVC of trigeminal nerves by comparing the clinical characteristics of unilateral OC patients with and without trigeminal NVC. The NVC of trigeminal nerves were observed in 48.1% patients, and the patients without NVC were found predominantly female and showed more complex symptoms and sever dysfunction in their daily lives.
OC patients complain of various discomfort or abnormal sensations in the oral cavity without dental and medical evidence. Some complaints are on the extension of understandable sensations such as sticky or slimy sensation, but some are more bizarre and realistic feeling as if wires, coil, small bubbles or eggs exist even the patients recognized they do not. The severity of the symptoms is also various. In some patients, their daily lives are eclipsed by the oral symptoms and their quality of life are declined. Several studies have proposed etiological hypotheses to explain clinical features and treatment effects.
The CNS involvement were suggested in previously. In a case report with OC, the asymmetric CBF pattern ameliorated after the treatment with aripiprazole [22]. The case report of the modi ed electroconvulsive therapy to the OC patients showed improved CBF asymmetry in the temporal region and reduced the symptoms of OC [23]. In addition, the investigation by using SPECT also revealed that CNS might be involved. The right-dominant regional CBF (rCBF) asymmetry was observed in the callosomarginal, precentral, and temporal regions in the patients with OC [6]. Moreover, a signi cant right dominant asymmetry in the temporal and posterior cerebral regions was observed regardless of the presence of a history of depression, while the mean rCBF values of patients with depression were lower in several regions [7].
To the peripheral, trigeminal nerve is the fth and the largest cranial nerve. It is composed of sensory and motor nerves extensively distribute to facial area including oral cavity. The NVC at the REZ of trigeminal nerves indicates abnormal pain sensation such as trigeminal neuralgia, PIFP. Since trigeminal nerves transit not only pain but also thermal, tactile and pressure, there is possibility that NVC of trigeminal nerves also indicate abnormal sensation which found in OC patients. In the present study, 48.1% of the unilateral OC patients showed NVC and the rate was similar with our previous study of the unilateral PIFP patients [9]. The patients without NVC of trigeminal nerves was found in 51.9% patients and predominantly female. The rate (85.2%) coincides with the previous studies of OC (73.8%) [5] and other psychosomatic dental symptoms [24][25] [26]. Moreover, the patients without NVC showed signi cantly more complexed oral symptoms with higher severity and functional impairment in working and social activity which decline the quality of life though no signi cance were observed in psychological questioners compared to the patient with NVC. These results suggest that the unilateral OC has two subtypes based on predominant involvement of central or peripheral nervous system. In speculate, the more complex mechanisms which involved in CNS may exist for the cases without NVC and may indicate various and severer symptoms. Additionally, some mechanisms which modulate the sensation may exist for the case with NVC.
The myelin sheath surrounding the cranial nerves to protect from damage and support metabolism. In the CNS, oligodendrocytes form the myelin while Schwann cell form in the peripheral nervous system [27]. The transit zone of these two types of myelin is more vulnerable. The chronic demyelination and aberrant re-myelination at the transit zone were noticed as the underling mechanism involved in the syndrome caused by NVC [8]. Interestingly, the myelin sheath of demyelinated and abnormally remyelinated were as thin as normal white matter [28], and uncertain degeneration case reduction of nerve conduction velocity [29]. The neural in ammation, edema and plasticity on the trigeminal nerves indicate the white matter abnormalities in the brainstem project to somatosensory cortices [10]. While these abnormalities may occur idiopathic sensation in facial area, is there any possibility to speculate that these degenerative changes effect to control the sensation of OC not to exacerbate.
In addition, most patients with trigeminal neuralgia complain unilateral symptoms, but the laterality, whether left or right, is not signi cant [30]. On the other hand, 234/321 OC patients showed bilateral symptoms who were excluded from the present study, and left side unilateral symptoms were found in 69.2% patients with unilateral OC. Although no signi cant was found in this study due to the small sample size, the left dominant symptom laterality and the ipsilateral NVC would be key points for the next investigations considering right dominant asymmetric CBF in the patients with OC [6] [7]. Further studies combined with CNS and peripheral nervous system were required to investigate highly complexed pathophysiology of OC.

Limitations
The present study has several limitations. First, the MRI scan were preformed within one month from the rst visit, and some patients had already underwent the psychopharmaco-treatment. However, there was no patient whose symptom had improved on the day of the MRI examination. Second, the comparison with the state after the treatment was not investigated. To compare them, further detailed involvement of NVC of trigeminal nerves will be revealed in the future. Third, the examination to assess the involvement of CNS were not performed. Besides SPECT, diffusion tensor imaging is also useful to investigate nerve bers connectivity in both peripheral and central nervous systems [30].

Conclusion
In the present study, the patients without NVC were found predominantly female and showed signi cantly higher severity and dysfunction in their daily activities compared to the patients with NVC. These results suggest that unilateral OC has two subtypes based on predominant involvement of peripheral or central nervous system.

Consent for publication
Consent for publication were obtained from all patients.

Availability of data and materials
The datasets used and analyzed during the present study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
The present study was supported by KAKENHI from Japanese Society for the Promotion of Science (JSPS), Grant Number 19K10328 to Prof. Toyofuku. The funder had no role in study design, data collecting, data analysis, decision of publishing and preparation of the manuscript.
Authors' contribution KW acquired and analyzed the data and wrote the rst draft of the manuscript. TS, TT, CH, ZL, CT, TY and MT acquired the data. JS, NY and TK acquired and analyzed the imaging data. MW, YU, HM analyzed the data and revised the manuscript. AT was contributed to study design and developed the methodology. All authors read and approved the nal manuscripts.  Flowchart showing the selection of patients with unilateral Oral Cenesthopathy for inclusion in the present study.