Background
Dystonia is an involuntary, repetitive, sustained (tonic), or spasmodic (rapid or clonic) muscle contraction. The spectrum of dystonias can involve various regions of the body. Of interest to oral and maxillofacial surgeons are the cranial-cervical dystonias, in particular, orofacial dystonia (OFD). OFD is an involuntary, sustained contraction of the periorbital, facial, oromandibular, pharyngeal, laryngeal, or cervical muscles [
1]. OFD can involve the masticatory, lower facial, and tongue muscles, which may result in trismus, bruxism, involuntary jaw opening or closure, and involuntary tongue movement.
The etiology of OFD is varied and includes genetic predisposition, injury to the central nervous system (CNS), peripheral trauma, medications, metabolic or toxic states, and neurodegenerative disease. However, in the majority of patients, no specific cause can be identified. An association was found among painful temporomandibular disorders (TMDs), migraine, tension-type headache, and sleep bruxism, although the association was only significant for chronic migraine. The association between painful TMDs and sleep bruxism significantly increased the risk for chronic migraine, followed by episodic migraine and episodic tension-type headache [
2].
Bruxism is the most frequently occurring oral movement disorder, and can occur in subjects while awake and during sleep. Both forms are likely to have different etiologies, and their diagnosis and treatment require different approaches. Treatment is indicated when bruxism causes pain in the masticatory system or leads to damage such as tooth wear or fractures of teeth, restorations, or even of implants. A focused review on the etiology of bruxism [
3] concluded that there is a limited role for morphological factors in the etiology of bruxism, while psychological factors (e.g., stress) and pathophysiological factors (e.g., disturbances in central neurotransmitter systems) are more prominently involved.
Orofacial pain (OP), including pain from TMDs, exerts a modulatory effect on mandibular stretch reflexes [
4]. Electrophysiological studies have shown that experimentally induced pain from injections of 5% hypertonic saline solution into the masseter muscle causes an increase in the peak-to-peak amplitude of the jaw jerk. This facilitatory effect appears to be related to an increased sensitivity of the fusimotor system, which at the same time causes muscle stiffness [
5]. In addition, a number of animal studies of experimentally-induced muscle pain have shown that activation of the muscle nociceptors markedly influences the proprioceptive properties of the muscle spindles through a central neural pathway [
6], and that washing of the local algogenic substance causes a return to normal tendon reflexes.
However, few studies have attempted to characterize the pain associated with bruxism (i.e., to examine the neurobiological and physiological characteristics of the mandibular muscles). Some clinical cases and small-scale studies suggest that certain drugs linked to the dopaminergic, serotoninergic, and adrenergic systems can either suppress or exacerbate bruxism. Further, the majority of these pharmacological studies indicate that various classes of drugs can influence the muscular activity related to bruxism, without exerting any effect on OP [
7].
Therefore, the sensitization of the trigeminal nociceptive system and the facilitating effect on mandibular stretch reflexes and CNS hyperexcitability are neurophysiopathogenetic phenomena that can be correlated to pain in the craniofacial region. However, up to now, no correlation has been reported between OP, dysfunction of the mesencephalic nuclei, and facilitation of trigeminal nociception, except for a clinical study on a patient affected by pontine cavernoma, which highlighted a relative facilitation of the trigeminal nociceptive system through the blink reflex [
8].
Thus, in the present study we performed an electrophysiological evaluation of the excitability of the trigeminal nervous system in a patient affected by pineal cavernoma with pain symptoms in the orofacial region and pronounced bruxism.
Discussion
The main aim of this study was to electrophysiologically document hyperexcitability of the trigeminal nervous system in a patient affected by pineal cavernoma with pronounced symptoms of OP and bruxism, and who was resistant to any pharmacological or odontological treatment.
We found evidence of activation and peripheral sensitization of the nociceptive fibers, the primary and secondary nociceptive neurons in the CNS, and the endogenous pain control systems, including both the inhibitory and facilitatory processes in our subject.
The concentration of extracellular glutamate in 13 patients affected by cavernous angioma [
12] was reported to be increased in comparison with physiological concentrations. High levels of glutamate can cause negative effects on the brain through excitotoxic mechanisms, including degeneration of the superficial layer of the retina in a mouse after repeated administration of glutamate, termed “glutamate excitotoxicity” [
13], resulting from NMDA receptor hyperactivation [
14]. In a study in which the trigeminal ganglion neurons were exposed to KCl, the calculated release of glutamate was 10 times greater than the basal level [
15]. Further, a significant reduction in the release of potassium-induced glutamate was observed with addition of ω-agatoxin TK, a powerful P/Q calcium channel blocker, while the N-type calcium channel blocker ω-Cgtx conotoxin had a similar effect [
16]. Nimodipine, an L-type calcium channel blocker, was also found to reduce the amount of potassium-induced glutamate release [
17]. These studies suggest that the P/Q-, N-, and L-type calcium channels each mediate a significant fraction of depolarization-associated glutamate release.
Glutamate release is obviously a much broader and more complex phenomenon. NMDA, kainate, and AMPA ionotrophic receptors, and the metabotropic glutamate receptors, have been found in the superficial lamina of the trigeminal nucleus caudalis in mice [
18]. NMDA and AMPA receptor antagonists can block the transmission of the nociceptive trigeminal-vascular signals [
19,
20] and reduce the high level of c-
fos observed in the trigeminal nucleus caudalis following cisternal injection of capsaicin [
21]. Furthermore, micro-injections of ω-agatoxin into the ventrolateral area of the periaqueductal gray cause a facilitatory response of nociceptive activity in the trigeminal nucleus caudalis (TNC) activated by tonic electrical stimulation of the supratentorial parietal dura, adjacent to the middle meningeal artery [
22]. This response can occur through antinociceptive and/or pronociceptive effects, because the presence of P/Q-type calcium channels is required at the synaptic level for the presynaptic action potentials to couple with the neurotransmitter release processes [
23]. Of note, the pre-synaptic afferents in the PAG are positioned on GABAergic inhibitory interneurons and on descending projection neurons. Therefore, the facilitatory effect may be explained by an increased release of GABA, which would indirectly disinhibit the dorsal horn neurons, or by a direct pronociceptive mechanism [
24]. These experimental results provide further understanding of the clinical manifestations of pain and central nervous system hyperexcitability found in cases of cerebral cavernous malformations.
Indeed, a blink reflex study on a 38-year-old patient with right hemicranial symptoms associated with a pontine cavernoma affecting the nucleus raphes magnus area revealed a reduction of the pain threshold and a persistent facilitation of the R2 response, with an onset latency difference of 4.4 ms less in the side displaying the symptoms [
8]. This confirms a regulatory role for release of neurotransmitters by the nucleus raphes magnus, which exhibits a descending inhibitory control on the TNC [
25] and on the entire antinociceptive mesencephalic complex [
26]. Our results suggest a hyperexcitability of the trigeminal nervous system in our subject, as follows. First, we evoked a direct response of the trigeminal motor system (
bR-MEPs) to provide a value for reference and for amplitude symmetry, as the direct response of the trigeminal motor branch was not affected by any conditioning. A comparison between the jaw jerk responses versus the ipsilateral responses of the R-MEPs showed a much higher amplitude ratio than in normal subjects [
11] (Table
1). Therefore, these data indicate the presence of hyperexcitability of the trigeminal system.
The facilitatory effect on the masseter reflex could be indirect. The highest concentration of premotoneurons in the orofacial motor nuclei is found in the bulbar and pontine reticular formations adjacent to the motor nuclei themselves, where these are GABAergic, glycinergic, and glutamatergic-type premotoneurons [
27]. In addition, the significant increase of the SP2 recovery cycle from S2 compared with the response from S1 (Table
2) corroborates the hypothesis of hyperexcitability of the trigeminal system. In an
in vitro study performed on encephalic slices [
28], intracellular recording of interneurons of the peritrigeminal area (PeriV) surrounding the trigeminal motor nucleus (NVmt) and of the parvocellular reticular formation (PCRt) demonstrated that electrical stimulation of the adjacent areas could evoke both excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs). All the EPSPs induced by stimulation of the PeriV, PCRt, and NVmt were shown to be sensitive to ionotropic glutamate receptor antagonists (DNQX and APV), while the IPSPs were sensitive to the GABA and glycine receptor antagonists, bicuculline and strychnine. The cells of this sample showed a long after-hyperpolarization (AHP).
In an electrophysiological study that analyzed a population of neurons and interneurons in the NVmt [
29], three types of AHP were seen: fast, slow, and biphasic. The majority of the motoneurons had a fast AHP (fAHP), whereas most of the interneurons had a slow AHP. The basic properties of these interneurons are similar to the previously described “last-order pre-motoneurons” in the PeriV [
30], suggesting that the interneurons in the NVmt are part of an interneuronal matrix surrounding the NVmt in which the motoneurons are inserted. In this last study, the authors describe the possibility, although rare, of interneurons also having an fAHP.
In our study, the increased duration of the SP2 from S2 invades the IA rather than expanding into the EMG reactivation after the silent period. The afferents for the SP2 descend their intra-axial process along the trigeminal spinal tract and connect with a polysynaptic chain of excitatory interneurons located in the reticular formation at the level of the pontocerebellar junction. The last interneuron in the chain is inhibitory, and sends ipsilateral and controlateral collaterals that ascend medially to the right and left spinal trigeminal complex to reach the trigeminal motoneurons [
31]. The interneural sensitization in the
rcMIR may be linked to a combination of the excitatory effect of glutamate, with a contribution from the intraneuronal fAHP, and to the disinhibition of the inhibitory processes due to the effect of glycine and GABA.
Overall, our data suggest that certain types of OP, at least those of a central origin, and bruxism are caused by a disruption and homeostatic imbalance of cerebral neurobiochemistry, particularly of the excitatory and inhibitory neurotransmitters in the trigeminal nervous system.
This gives rise to the following questions: Is there a correlation between OP and bruxism, and can bruxism be considered a clinical form of orofacial dystonia?
With respect to the correlation, a distinction should be made between central and peripheral OP on the basis of case history and clinical examination. The muscle discomfort of bruxism is mainly a peripheral phenomenon, resulting from muscle hyperfunction leading to destruction of the myofibrils and release of algogenic substances including myoglobin into bloodstream. By contrast, OP radiating to one or more areas of the face correlated with a clear manifestation of nocturnal or diurnal bruxism could be considered a central type disorder. In these cases, trigeminal electrophysical examinations are highly informative, particularly the rcMIR, blink reflex, JJr, and bR-MEPs, for a differential diagnosis between organic-type lesions of the CNS and functional-type diseases such as TMDs.
Thus, although bruxism and central OP can coexist, they are two independent symptoms, which is why many experimental and clinical studies fail to reach unequivocal conclusions [
32].
It is also possible that bruxism may be a clinical form of dystonia. Our data indicate that bruxism may be a clinical manifestation linked to a CNS neurotransmitter imbalance, and therefore should be considered a subclinical condition of orofacial dystonia or dystonic syndrome. Nevertheless, this phenomenon also appears in a transitory form in children and is resolved with the eruption of mixed dentition [
33,
34].
Many studies and diagnostic research protocols, including the Research Diagnostic Criteria (RDC), continue to appear in the field of OP and TMDs, although clear consensus has not yet been reached among the international scientific community [
35]. The RDC should consider the patient as affected by a painful syndrome, and should tend towards the definition of a differential diagnosis between organic and/or functional pathologies [
36].
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
GF and FF drafted the first manuscript and contributed to data acquisition and interpretation. GF, FF, GFS and EMS supervised the study, participated in its design and coordination, and revised the manuscript that led to the final approval of the current submission. CI is a treating neurologist of the patient, and made a contribution to data acquisition and interpretation. GC, CL, PE, DS, and AL contributed to acquisition and interpretation of data literature search. All authors read and approved the final manuscript.