The aim of present paper was to discuss issues related to trigeminal
neuralgia with strong emphasis on the aetiology and pathogenesis of this
problem.
Material and Methods
An electronic search of 5 databases (1965 - Oct 2012) and a hand search of
peer-reviewed journals for relevant articles were performed. In addition,
experience acquired from treating 3263 patients in the Department of
Maxillofacial Surgery, Lithuanian University of Health Sciences, were also
summarized.
Results
Generally, aetiological factors can be classified into 3 most popular
theories that were based on: 1) Related to other disease, 2) Direct injury
to the trigeminal nerve, and 3) Propagates the polyetiologic origin of the
disease. In addition, two pathogenesis mechanisms of trigeminal neuralgia
were proposed. First: the peripheral pathogenetic mechanism that is often
induced by progressive dystrophy around the peripheral branches of the
trigeminal nerve. Second, central pathogenetic mechanism which often
triggered by peripheral pathogen that causes long-lasting afferent
impulsation and the formation of a stable pathologic paroxysmal type
irritation focus on the central nerve system (CNS).
Conclusions
Patients with susceptive trigeminal neuralgia should be examined carefully by
specialists who have expertise in assessing and diagnosing of possible
pathological processes and be able to eliminate the contributing factors so
the trigeminal neuralgia can be properly managed.
Trigeminal neuralgia (TN) is one of the most common diseases of cranial nerves.
Furthermore, it is the most frequently diagnosed form of facial pain with a
prevalence of 4 per 100,000 in the general population [1]. This condition has been known since ancient times, having
been described by Arateus in the first century A.D. [2]. John Locke, in 1677 identified the major clinical features of TN
[3]. French physician Nicolaus Andre in
1756 gave the name "tic douloureux" because of the facial spasms that would
accompany the attacks [4]. English physician
John Fothergill in 1773 defined the major clinical features of TN [5]. Since that time TN has been investigated
extensively by scientists and clinicians from different fields: pathophysiologists,
neuromorphologists, dentists, neurologists, neurosurgeons, oculists, and
psychiatrists. Unfortunately many problems associated with TN remain unresolved.
MATERIAL AND METHODS
This article reviewed the literature related to the etiologies and pathogenesis of
TN. Due to enormous literature available it is impossible to review and cite all
papers, hence we cited literature when appropriate. In addition, we have added our
experience/views acquired from treating 3263 patients in the Department of
Maxillofacial Surgery, Lithuanian University of Health Sciences.
Aetiology of trigeminal neuralgia (TN)
There are many different opinions concerning TN aetiology, however some of them are
controversial and suffer from a lack of objective evidence. Such are aetiologic
theories as endogenous and exogenous intoxication [6], temporomandibular joint pathology [7,9] and high position of the
petrous pyramid apex of the temporal bone [10].
Currently, there are three most popular TN aetiologic theories. First theory is based
on diseases-related, second is direct trauma to the nerve and the third theory
propagates the polyetiologic origin of the disease (Table 1). In reality, for most patients with TN, there is no
identifiable cause [11].
Three most popular theories of trigeminal neuralgia aetiology
Diseases related
Direct injury to the trigeminal nerve
Polyetiologic origin
Peripheral part of TNS
Central part of TNS
Vascular diseases, multiple sclerosis, diabetes
mellitus, rheumatism and others.
"Allergic hypothesis" due to odontogenic inflammatory diseases,
otolaryngological pathology, getting cold and others.
"Neurovascular compression hypothesis" at the root
entry zone due to arteriovenous malformation, vestibular
schwannomas, meningiomas, epidermoid cysts, tuberculomas, various
other cysts and tumours, aneurysm, vessels aggregation and occlusion
due to arachnoiditis and others.
All possible aetiological factors that can affect TNS
and evoke demyelination and dystrophy.
"Compression syndrome hypothesis" due to the narrowing of the
osseous canals, trauma.
TNS = trigeminal nerve system.
Because patients suffering from TN often have vascular diseases such as
atherosclerosis, arterial hypertonia, some authors suggested vascular theory of TN
aetiology. They found morphological and functional disturbance in blood vessels
supplying the peripheral [12] and central
[13,14] part of trigeminal nerve system (TNS). However, there is no evidence
that supports direct relation of blood vessels pathology to TN. Smoliar [15] investigated blood vessels supplying
trigeminal nerve for a large number of cadavers who died because of cardiovascular
disease. Although, clear morphological changes were noted in the blood vessels but
no TN was diagnosed. That's why we prefer to support the concept [16,17]
that organic or functional changes of blood vessels supplying TNS can not be the
primary cause of TN, however, they can make influence on pathogenesis of the
disease.
Some authors have suggested the importance of multiple sclerosis in TN aetiology
[17,26]. However, others have disputed this link because TN is reported to
occur only in 0.9% to 4.5% of patients that had multiple sclerosis [27,29].
Conversely, 1.7% to 15% of patients diagnosed with TN had developed of multiple
sclerosis [1,27,28,30,31]. This is further
supported by Rusthon and Olfason [27], who
examined 3880 patients with multiple sclerosis and 1735 patients with TN and found
only 35 patients had both diseases. In patients with both TN and multiple sclerosis,
TN is the first symptom of multiple sclerosis in 9% - 14% patients [29,30].
After treatment of 3263 patients with diagnosed TN in our department, we found that
46 (1.4%) of patients suffered from rheumatism, only 7 (0.23%) from multiple
sclerosis and 7 (0.23%) from malaria. Therefore, there is insufficient evidence to
support that multiple sclerosis can be a primary cause of TN.
Urban et al. [32] investigated the frequency
of subclinical trigeminal and facial nerve involvement in 40 patients with diabetes
mellitus (DM) and without clinical signs of cranial nerve lesions. Sixty percent of
the patients had distal symmetric sensory polyneuropathy that was confirmed by nerve
conduction studies. An electrophysiological study indicated that DM could often
affect trigeminal nerve function. Finestone et al. [33] reported that among a series of 40 patients with TN, 19 patients
(48%) had DM. Collis et al. [34] reviewed 30
patients with typical TN and found elevated blood sugar (using glucose tolerance
tests) in 10 patients. Consequently, DM can be a causative factor for TN.
One of the local aetiological TN factors discussed in the literature is the history
of odontogenic inflammatory diseases. Some authors declare that a variety of
odontogenic inflammatory diseases can be a cause of TN development [35-39].
In contrast, Kerr [16] deny the odontogenic
origin of TN.
There seem to be a consensus between different authors concerning the importance of
the otolaryngological pathology in TN aetiology. Chronic inflammation of maxillary
sinuses and other ear, nose and throat (ENT) inflammatory disorders can be a direct
cause of TN development [40,43]. Consequently, 89.5% of our treated
patients suffered from inflammatory diseases in the maxillofacial region or had
history of inflammatory disorders of ear, nose and throat region. Most of them
suffered from chronic maxillary sinusitis, periodontitis, periostitis, phlegmone,
and dental cysts.
Some authors suggest that the cause of the TN can be related to the compression
syndrome, and the most popular is neurovascular compression hypothesis [44-56].
Neurovascular compression at the root entry zone can be evoked by an arteriovenous
malformation [57-60]. A wide range of other compressive lesions can also cause
TN. These include vestibular schwannomas [61,62], meningiomas [63-66],
epidermoid cysts [67,70], tuberculomas [71,72] and various other cysts
and tumours [66,67,70,73-77].
TN can be evoked also by presence of aneurysm [78,79], vessels aggregation and
occlusion due to arachnoiditis [80].
Compression of the trigeminal nerve root may be mediated by the tumour itself, by an
interposed blood vessel or by distortion of the contents of the posterior fossa with
displacement of the nerve root against a blood vessel or the skull base.
On the other hand, many patients with TN do not have a culprit vessel [81]. In several reported cases, the neuralgia
was contralateral to the side of the mass lesion [63,74,75]. Furthermore, there is some evidence contrary to the
neurovascular compression hypothesis. For example, in two studies on cadavers
without TN, neurovascular contact was observed in 13 - 32% of cadavers with
neurovascular compression ranging from 8 to 10% [45,82]. Similarly, in one MRI
study that examined 170 trigeminal nerves in 85 non-TN patients, 79 nerves (46%) had
some point of contact with a vascular structure, 24 (14%) had cisternae contact, 52
(30%) had contact at the root entry zone, and remaining 3 (2%) had an actual
deformity of the root entry zone [84]. On the
contrary, in non-TN patients, vascular contact with trigeminal nerve occurred only
in 7% [84] and 8% [85] of cases. Although the vascular compression theory is
popular, it cannot account for all phenomena associated with the TN [86].
As early as 1925, Sicard [87] proposed a
hypothesis according to which TN may develop due to the narrowing of the osseous
canals transmitting the corresponding nerve branches. We analyzed the maxillary (n =
359) and mandibular (n = 239) canals using the orthopantomograms in patients
suffering from TN. The analysis revealed that 29.2% of patients had a narrowed
infraorbital canal (Figure 1) and 31.4% mandibular canal (Figure 2) transmitting the
branches of the affected side of trigeminal nerve. Doppler ultrasound examination
indicated reduced blood flow velocity in the infraorbital (asymmetry coefficient =
2.23) and inferior alveolar (asymmetry coefficient = 2.33) arteries on the affected
side in comparison with intact side arteries, confirmed radiological findings and
presence of compression mechanism.
An orthopantomograph of a patient with infraorbital neuralgia: a narrowed
left infraorbital canal (arrow).
An orthopantomograph of a patient with a third-branch trigeminal neuralgia:
a narrowed left mandibular canal in the region of a second molar.
"Allergic hypothesis" of TN aetiology has also been proposed [88-91]. However, there
is only indirect evidence that supports allergy might cause TN. This is often due to
unexpected and irregular rise of the clinical symptoms, remissions and recurrences,
sensitive to the provocative endogenous and exogenous factors, and finally the
increased serum levels of histamine. We noted that under the influence of various
damaging factors, such as getting cold, tonsillitis, chronic rhinitis, maxillary
sinusitis, and chronic inflammation existed in the maxillofacial region can trigger
local immune response. As a result, the amount of IgE secretion increases. The
degranulating mast cells release biologically active substances, such as histamine,
serotonin and others, into the intercellular space. Hence, histamine release and
accumulation in the trigeminal nerve during a local allergic reaction plays an
important role in the pathogenesis of neuralgia [92]. Furthermore, this process is confirmed by the data of our
morphologic trigeminal nerve examination and histamine levels in peripheral blood
and saliva investigations [92]. Thus,
microscopic immuno luminescent investigation of peripheral part of trigeminal nerve
rhizotomy specimens from the TN patients revealed many degranulating mast cells and
conglomerates of immune complexes of various sizes (Figure 3A). During remission,
mast cells were absent in the resected nerve trunks. Many disorderly scattered
granules of different size and their accumulations were found in the internal and
external epineurium of the trunks (Figure 3B). At the same time we have determined
an increase of histamine level in the blood and saliva during the acute period of
TN. Consequently the levels of histamine in blood were: 3.879 ± 0.342 μmol/l
(mean ± standard deviation) and saliva 4.554 ± 0.513 μmol/l were statistically
significantly higher (P < 0.05) when compared to the healthy individuals where
the histamine level in the blood was 0.558 ± 0.063 μmol/l and in saliva 0.522 ±
0.001 μmol/l. Moreover, the concentration of histamine level in the saliva of
the TN patients was significantly higher (P < 0.001) than in their blood. This
fact indicates that histamine is released locally for those patients.
Fluorescent photomicrograph of an affected peripheral branch of the
compromised nerve:
A = Acute stage of TN. Mast cell degranulation. Magnification
x300.
B = Remission period of TN. Granules of mast cells. Magnification x300.
Jia and Li [93], explored the non-invasive
methods to treat TN and as a result they also proposed a new hypothesis on the
pathogenesis of TN - bioresonance. The bioresonance hypothesis states when the
vibration frequency of a structure surrounding the trigeminal nerve becomes close to
its natural frequency, the resonance of the trigeminal nerve occurs. The
bioresonance can damage trigeminal nerve fibers and lead to the abnormal
transmission of the impulse, which may finally result in facial pain.
Devor et al. [94] raised the ignition
hypothesis of TN that is based on recent advances in the understanding of abnormal
electrical behavior in injured sensory neurons and the findings from histopathologic
observations obtained from patients with TN, who are undergoing microvascular
decompression surgery. According to this hypothesis, TN results from specific
abnormalities of trigeminal afferent neurons in the trigeminal root or ganglion.
Injury renders axons and axotomized somata hyperexcitable. The hyperexcitable
afferents, in turn, give rise to pain paroxysms as a result of synchronized after
discharge activity. Nonetheless, more evidences are needed to further verify this
hypothesis.
Pathogenesis and pathomorphology
Pathogenesis of TN is one of the most complicated, unclear and extensively debated
topics in medicine. Many theories and hypotheses concerning peripheral and central
pathogenetic mechanisms existed today. At the beginning TN was characterized as
functional disease because there was no evidence of organic (morphologic) changes in
trigeminal nerve. However, more than 40 years ago, Kerr [16] examined histologically the rhizotomy specimens from the TN
patients and found morphological nerve changes existed typical for interstitial
neuritis, neural fibers demyelization, and perineural and endoneural sclerosis. For
many years, the most popular theory of peripherial mechanism of the disease was
"short connection" theory proposed by Dott in 1951 [103]. According to this theory, TN attack starts from demyelinated axons
interconnection, spontaneous activity and ectopic impulses generation. Later
published data addressing morphological changes occurred not only in peripheral
branches but also in central structures of trigeminal nerve [95,98]. Central
mechanisms theory assumes that TN starts due to thalamus [99], nuclei of trigeminal nerve [100], encephalic trunk or cerebral cortex injury [101,102]. However, there is a lack of objective evidence supporting the
theories of central and peripheral TN pathogenic mechanism. Furthermore, such
theories are not clarifying symptoms and clinical course of the disease. More works
in this area are needed.
Williams [104] was first to describe TN
attack as multineuronal reflex, which involves the following structures: trigeminal
and facial nerves systems, formation reticularis, diencephalon nucleus and cortex of
the brain. Some researchers [101,105] have indicated that afferent physiologic
stimulation of trigeminal nerve receptors can induce paroxysmal excitation focus on
central structures that generates efferent impulses to the peripheries. However two
main questions remain unanswered: what structures are generating long prethreshold
impulses from peripheries? And what central structures of the trigeminal nerve are
responding by paroxysmal type discharge?
The morphological data obtained from rhizotomy specimens collected from the 212 TN
patients [89] was designed to answer the
first question and to explain the peripheral pathology mechanism of the TN. The
dystrophy of neural fibers is prevalent in the acute period of neuralgia. In
contrast, proliferation and reparation is starting in subacute period: number of
neural fibers with signs of dystrophy is decreasing and fibers with signs of
regeneration increasing (Figure 4A). Connective tissue is replacing destroyed neural
fibers. Consequently the conditions for nerve regeneration are worsening after each
exacerbation of the disease (Figure 4B). These include but not limited to sclerotic
changes of the nerve, hypoxia due to insufficient blood supply is developing and
metabolic products are accumulating. Peripheral nerve branches are first affected by
dystrophic changes. Nerve dystrophy is developing retrogradially and finally all
peripheral branches of trigeminal nerve system are involved. This is often referred
to "vicious cycle". Because the functional and anatomical connectivity between
neural fibers of main trigeminal nerve branches and their surrounding sheaths and
blood vessels, when one get affected, it affects the others too and vise versa. With
progressing of the disease, the dystrophy is developing not only in peripheral
branch of trigeminal nerve but also in intracranial nerve part. Injury of "vicious
circle" and dystrophy of the TNS can be evoked by mentioned above different
aetiological factors.
Illustrated an affected peripheral branch of the compromised trigeminal
nerve. This sample was taken during an acute period of trigeminal neuralgia from a
patient with at least three-year-long history of the TN (Bielschowsky-Gross silver
impregnation; magnification x240): A = Part of thick nerve fibers with nodular
thickenings; B = Vacuolisation and disintegration of nerve fibers.
It was demonstrated that allergic-immune reaction of trigeminal nerve peripheral
branches with expressed mast cells degranulation could be other cause of the TNS
dystrophy. Biologically active agents like histamine, serotonin, heparin,
bradikinine, and others are migrating into intracellular spaces during mast cells
degranulation [106,107]. Mast cells degranulation evokes local immediate
hyperergic reaction [108,109]. This reaction starts when
immunoglobulines, mainly IgE, are fixing to specific receptors of mast cells [110,111]. Cells producing IgE are localized in lymphoid tissue, ears, nose,
oral cavity and upper respiratory tract mucous membrane [112]. In presence of some diseases, concentration of IgE is
increasing considerably, for example in case of ear, nose and throat inflammatory
disease it increases 3 times and in nasal polyps 5 - 6 times [113]. Therefore, the amount of IgE-antibodies is increasing
when individual is suffering from inflammatory diseases noted in the maxillofacial
region (e.g., face, nose, maxillary sinus, tonsil etc) as it was shown in case of TN
(Figures 5and6).
Pathologic regeneration shown in a specimen of an affected peripheral
branch of the compromised nerve taken during a remission period of TN
(Bielschowsky-Gross silver impregnation; magnification x150).
Increased amount of connective tissue and decreased number of nerve fibers
in an affected peripheral branch of the compromised nerve. The samle was taken from
a patient with a more than ten-year-long history of TN (Silver impregnation;
magnification x75).
Furthermore, histamine level increases significantly (P < 0.05) in acute TN period
[114]. Histamine is an active regulator
of neural structures functional activity including pain reaction mediation [115]. It has been shown that TNS is
chemoreceptor trigger zone of histamine [89].
This may explain why histamine released during immediate local immune reaction and
accumulated in trigeminal nerve during TN pathogenesis. Neurovascular bundles of
trigeminal nerve are localized in osseous canals. Hence, edema of peripheral nerves
evoked by immune inflammation often results in manifestation of "tunnel syndrome".
It means that the osseous canals will become narrower to compress the nerve that can
lead to TN.
What we have discussed here are examples to illustrate that peripheral mechanism of
TN pathogenesis. This theory is based on dystrophy of progressing TNS, which evokes
long-lasting prethreshold afferent pathologic impulsion. Studies have shown that
ectopic impulses can arise from demyelinated axons [116,117]. However, this
hypothesis is not in coincidence with clinical signs of short paroxysms. Maybe,
there are other pathologic mechanisms of TN, which might evoke pain paroxysms.
Karlov [118] proposed the "Central
pathogenesis theory" since TNS conjunction to the central structure is capable to
exert inhibitory action upon the segmental and suprasegmental formations. This
inhibitory action is capable to form a stable irritation focus of paroxysmal type
located in the CNS. This central pathogenesis theory was confirmed further by Smith
and McDonald [117]. They proved
experimentally that demyelination could be the source of ectopic impulses that
evokes functional disturbances and pain dominant focus formation in the segmental
apparatus of brain stem and in suprasegmental brain centers. Thus, progressive
dystrophy in the TNS stimulates the central pathogenesis mechanism of neuralgia.
Undoubtedly, there should be appropriate conditions in the body for these
pathogenetic mechanisms to manifest. Atherosclerosis and other age related
alterations weaken the state of the neurohumoral barrier complex, on which the
reliability of adaptive and compensatory reactions depends. Therefore, more
favorable conditions develop for the formation of the pathogenetic mechanisms of TN
in the elderly and in older individuals affected by the local aetiologic
factors.
We support mechanism of TN where a long-lasting afferent pathologic impulsation from
periphery is forming "focus" or "generator" in CNS which is independent of afferent
impulsation. Impulses from trigger zones are passing to the main neurons of
"generator" and activating them. "Generator" is activating reticulate, mesencephalon
structures, limbo nuclei, limbic system, and brain cortex and finally pathologic
algogenic system is forming. Figure 7 describes the two most common mechanisms of
TN.
Pathogenetic scheme of TN.
CONCLUSIONS
The peripheral pathogenetic mechanism of trigeminal neuralgia is induced by
progressive dystrophy in the peripheral branches of the trigeminal nerve which can
be evoked by the compression syndrome (neurovascular compression due to neoplasms,
narrowed bone canals and others) or allergic-immune reaction (mast cell
degranulation and histamine release). This predetermines long-lasting afferent
impulsation and the formation of a central pathogenetic mechanism (a stable
pathologic paroxysmal type irritation focus in the central nerve system). Patients
with suspective trigeminal neuralgia should be examined carefully by specialists who
have expertise in assessing and diagnosing of possible pathological processes and be
able to eliminate the contributing factors so the trigeminal neuralgia can be
properly managed.
ACKNOWLEDGMENTS AND DISCLOSURE STATEMENTS
The authors report no conflicts of interest related to this study.