The aspects of aetiology and peripheral pathogenetic mechanism of trigeminal … medica...

Ricardas Kubilius*, Gintautas Sabalys, Rimvydas Stropus70

The article presents the results of a study of 2963 patients with trigeminalneuralgia. Morphological investigation has shown that the peripheral pat-hogenetic mechanism of neuralgia includes a progressive dystrophy of theperipheral branches of the trigeminal nerve which determines a long-lasting continuous afferent impulse transmitting and forming a centralpathogenetic mechanism – a pathologic paroxysmal excitation focus inthe central nervous system. One of the causes of such process is compres-sion of branches of the trigeminal nerve. In one third of the studiedpatients, this process was revealed in the narrowed infraorbital canal(causing compression of the 2nd branch of the trigeminal nerve) and inthe mandibular canal (resulting in compression of the 3rd branch of thetrigeminal nerve). The blood flow velocity in the arteries located in thenarrowed canals was less than half the velocity determined in the contra-lateral arteries located in the unnarrowed canals.

The next cause of the progressive dystrophy is immune response ta-king place in them, during which degranulation of mast cells occurs andhistamine is released. The narrowing of the canals and local inflamma-tion are caused by inflammatory disorders in the ear, nose and larynx,and other maxillofacial regions.

Key words: trigeminal neuralgia – aetiology and pathogenesis

Ricardas Kubilius*,

Gintautas Sabalys,

Rimvydas Stropus

Department of MaxillofacialSurgery, Kaunas University ofMedicine, Eiveniø 2,LT-50009 Kaunas, Lithuania

The aspects of aetiology and peripheral pathogeneticmechanism of trigeminal neuralgia

ACTA MEDICA LITUANICA. 2005. VOLUME 12 No. 4. P. 70–76© Lietuvos mokslø akademija, 2005© Lietuvos mokslø akademijos leidykla, 2005

INTRODUCTION

Trigeminal neuralgia as a single disorder was descri-bed by N. André in 1756 (13). Since that time it hasbeen investigated by various researchers, such as den-tal medicine specialists, neurologists, neurosurgeons,otorhinolaryngologists, in several countries. However,some problems concerning the disorder still remainunsolved. Discussions are being carried out on themain aspects of aetiology, pathogenesis, diagnosis andtreatment of this neuralgia (2–9, 13, 14, 17).

The aim of this study was to investigate the mor-phological state of peripheral branches of the trige-minal nerve in different stages of neuralgia and to

* Corresponding author: Rimvydas Stropus, Laboratoryof Neuromorphology, Institute of Human Anatomy, Kau-nas University of Medicine, Mickevièiaus 9, LT-44307 Kau-nas, Lithuania. Fax.: +370 37 333514. E-mail: [email protected]

determine the causal agents influencing the develop-ment of this disorder, and basing on the obtaineddata to construct an aetiological and pathogeneticconception of trigeminal neuralgia.

MATERIAL AND METHODS

During the period 1973–2003 we treated 2963 pa-tients in the Department of Maxillofacial Surgery ofKaunas University of Medicine. Most of the patientswere women and individuals over 45 years of age(Table 1). Most of them suffered from the second-branch (37.7%) or third-branch (29.2%) trigeminalneuralgia. The duration of the disorder ranged fromseveral days up to 20 and more years. In 43.2% ofcases the patients had suffered for more than 3 years.

All patients had paroxysms of acute pain duringthe periods of recrudescence of neuralgia in the di-stribution of sensory divisions of the trigeminal ner-ve, correspondingly radiating to the skin of the face

The aspects of aetiology and peripheral pathogenetic mechanism of trigeminal neuralgia 71

Table 1. Distribution of patients according to sex and age

Patients Sex Age (years) Total

Men Women Under 45 45–59 60–75 >75

Number 1 235 1 728 136 1 081 1 428 318 2 963% 41.7 58.3 4.6 36.5 48.2 10.7 100.0

Table 2. Maxillofacial and otorhinolaryngological disor-ders in trigeminal neuralgia patients

Name of the disorder Patients

n %

Dental and periodontal disorders 2889 97.5Odontogenic sinusitis 827 27.9Rhinogenic sinusitis 184 6.2Sialadenitis 124 4.2Stomatitis 124 4.2Trauma to the face and jaws 121 4.1Embedded teeth 113 3.8Chronic tonsillitis 38 1.3

and the oral mucous membrane, and set off by tou-ching trigger points or activity (e.g., chewing). Thedental, maxillofacial and otorhinolaryngological disor-ders supposed to directly cause trigeminal neuralgiaare listed in Table 2. The following were commondiseases that could influence the development of tri-geminal neuralgia in the studied patients: atheroscle-rosis (in 28.3% of patients), arterial hypertension andatherosclerosis (in 12.8%), multiple sclerosis (0.2%).

In order to diagnose trigeminal neuralgia, revealthe cause of its development, evaluate the course ofthe illness and apply a purposeful management, weperformed, besides routine clinical tests, also the fol-lowing special investigations: X-ray examination of

Fig. 1. Morphologic state of the coverings of an affectedbranch of the compromised nerve in an acute period oftrigeminal neuralgia; van Gieson’s staining; magnification×320

Fig. 2. Fluorescent photomicrograph of an affected peri-pheral branch of the compromised nerve in an acute stageof trigeminal neuralgia. Mast cell degranulation. Magnifi-cation ×300

Fig. 3. Fluorescent photomicrograph of an affected peri-pheral branch of the compromised nerve in the remissionperiod of trigeminal neuralgia. Granules of mast cells. Mag-nification ×300

Fig. 4. Immunofluorescent photomicrograph of an affectedperipheral branch of the compromised nerve in the remis-sion period of trigeminal neuralgia. Small immune com-plexes. Magnification ×300


the infraorbital and mandibular canals, blood flowvelocity assessment in the infraorbital and inferioralveolar arteries by Doppler ultrasonography, deter-mining the levels of histamine in venous blood andsaliva. The resected trigeminal nerve branches werestudied by the neuromorphological, neurohistoche-mical and immunofluorescent methods.

RESULTS

We have detected by morphological methods certaininflammatory or dystrophic structural alterations in thesheaths of the peripheral branches of the trigeminalnerves taken from the patients who had not beentreated by destructive methods (injections of alcohol)prior to the surgical operation. During the acute pe-riod of neuralgia, the sheaths of peripheral branchesof the trigeminal nerve showed signs of acute inflam-matory alterations: swollen, hyperaemic epineurium,infiltrated with blood elements and homogenized col-lagen fibres with widened interspaces (Fig. 1). In theremission period, proliferative-reparative processes pre-dominated in the connective tissue of the nerve trunks.Macrophages and newly developed connective tissuewere found in the inflammatory focus. Examinationunder a fluorescence microscope of the nerve trunksresected during the acute period of neuralgia revea-led many yellowish green fluorescenting mast cells andtheir granules (Fig. 2). During remission, mast cellswere absent in the resected nerve trunks. Many disor-derly scattered granules of different size and their ac-cumulations were found in the internal and externalepineurium of the trunks (Fig. 3). For elucidation ofthe nature of inflammation, histologic specimens tre-ated with a fluorescein-labelled antiserum (Anti-Hu-man-C3 fluorescein-konjugiert-Magdeburg) were exa-mined under a fluorescence microscope. In the nervetrunks with many degranulating mast cells we obser-ved conglomerates of immune complexes of varioussize, whereas in the trunks with only mast cell granu-les there was a large number of small immune com-plexes (Fig. 4).

The morphologic alterations in the fibres of pe-ripheral branches of the trigeminal nerve dependedon the duration and stage of the illness. There wereonly some morphologic signs of early lesion in theaxis cylinders of the thick and middle-thick nervefibres. These fibres had some nodullary thickenedparts or were evenly swollen. Their myelin sheathwas swollen, and Schmidt–Lantermann incisures we-re widened. These morphologic alterations in the ner-ve fibres are characteristic of second-stage dystrop-hy. Almost all the nerve trunks contained some thin,even, slightly silver-stained regenerating nerve fibressurrounded by proliferating and hypertrophiedSchwann cells (Fig. 5).

During the acute period of neuralgia, the nervefibres were damaged more severely. Most of them

were unevenly swollen, vacuolated, disintegrated intofragments (Fig. 6). Some of the fibres were demye-linated or their myelin sheath was swollen, Schmidt-Lantermann incisures were widened (Fig. 7). The lat-ter alterations were characteristic of the third-stagedystrophy. During the acute stage of the illness, themorphologically detectable regenerating fibres wereabsent. During the acute stage of a long-term (ofmore than three-year duration) illness, fibres withsigns of third-stage dystrophy predominated in thenerve trunks. During transition of the illness to re-mission, the number of fibres with signs of dystrop-hy decreased while the number of regenerating fib-res increased. However, not all the damaged fibresrecovered. Part of the disintegrated cells was resor-bed and replaced by proliferating connective tissue.The longer duration of the illness, the more regene-rating nerve fibres with various size thickened ends,called the growth cones (Fig. 8), were found in thenerve trunks. The regeneration of the nerve fibresmay be interfered by proliferating connective tissuereplacing the disintegrated and resorbed nerve trunkfibres. With every exacerbation of neuralgia, dyst-rophic alterations in the peripheral branches of thetrigeminal nerve progressed, the amount of connec-tive tissue in them increased, and thus the condi-tions for regeneration of the nerve fibres worsened.In patients with long-term neuralgia, the number ofnerve fibres in the peripheral branches of the trige-minal nerve was smaller than in the analogous struc-tures of patients with a short duration of the illness,and interfibral spaces were wider in them (Fig. 9).These alterations indicate that part of the nerve fib-res were resorbed.

On analysing the X-ray films of the maxillary andmandibular canals, we determined that 29.2% of pa-tients with trigeminal neuralgia had a narrowed in-fraorbital canal transmitting the branches of the tri-

Fig. 5. Part of thick nerve fibres with nodular thickeningsin an affected peripheral branch of the compromised ner-ve taken during an acute period of trigeminal neuralgiafrom a patient with a more than three-year-long history ofthe disorder. Bielschowsky–Gross silver impregnation; mag-nification ×240


Fig. 6. Vacuolisation and disintegration of nerve fibres inan affected peripheral branch of the compromised nervetaken during an acute period of trigeminal neuralgia froma patient with a more than three-year-long history of thedisorder. Bielschowsky–Gross silver impregnation; magnifi-cation ×240

Fig. 7. Demyelinisation of nerve fibres in an affected pe-ripheral branch of the compromised nerve taken duringan acute period of trigeminal neuralgia. Marchi’s staining;magnification ×142

Fig. 8. Pathologic regeneration shown in a specimen of anaffected peripheral branch of the compromised nerve ta-ken during a remission period of trigeminal neuralgia.Bielschowsky–Gross silver impregnation; magnification ×150

Fig. 9. Increased amount of connective tissue and decre-ased number of nerve fibres in an affected peripheralbranch of the compromised nerve taken from a patientwith a more than ten-year-long history of trigeminal neu-ralgia. Silver impregnation; magnification ×75

Fig. 10. Orthopantomograph of patient with infraorbital neural-gia. A narrowed left infraorbital canal

Fig. 11. Orthopantomograph of patient with third-branch trigeminal neuralgia. A narrowed left man-dibular canal in the region of a molar tooth

geminal nerve. The infraorbital canal of patients withthe second-branch neuralgia was significantly narro-wer in the affected side of the face than the canalin the intact side. Its lumen was narrowed by theevenly thickened walls of the canal (Fig. 10). In so-

me patients with the third-branch trigeminal nerveneuralgia, the mandibular canal was narrowed alongits whole length; in others, there was a local narro-wing of the canal, most often near the molar teeth,rarer at the mental foramen.


It was determined by Doppler ultrasound exami-nation that during remission of the second-branchtrigeminal neuralgia the mean blood flow velocity inthe unnarrowed infraorbital arteries on the affectedside was 0.37 ± 0.05 m/s, whereas in the analogouscontralateral arteries 0.35 ± 0.04 m/s; asymmetry co-efficient, 1.02. In the patients with a narrowed canalon the affected side, the mean blood flow velocity inthe infraorbital arteries was 0.17 ± 0.03 m/s, where-as in the contralateral arteries on the intact side itwas 0.38 ± 0.02 m/s; asymmetry coefficient, 2.23. Inthe patients with the third-branch trigeminal neural-gia whose mandibular canals were symmetrical, themean blood flow velocity in the inferior alveolar ar-tery on the affected side was 0.33 ± 0.04 m/s, whe-reas in the contralateral analogous arteries it rea-ched 0.34 ± 0.02 m/s; asymmetry coefficient, 1.03.In the patients with asymmetrical canals, the meanblood flow velocity in the inferior alveolar artery onthe affected side (in the narrowed canal) was 0.15± 0.04 m/s, whereas in the contralateral artery onthe intact side it was 0.35 ± 0.03 m/s; asymmetrycoefficient, 2.33.

We have determined an increase of histamine inthe blood and saliva during the acute period of tri-geminal neuralgia. In the healthy individuals (con-trol group), histamine level in the blood was 0.558± 0.063 µmol/l and in saliva 0.522 ± 0.001 µmol/l,whereas in patients during the acute period of neu-ralgia the levels of histamine in blood (3.879 ± 0.342µmol/l) and saliva (4.554 ± 0.513 µmol/l) were sta-tistically higher than in the analogous fluids of he-althy persons. Moreover, the concentration of hista-mine in the saliva of the neuralgia patients was sig-nificantly higher than in their blood.

DISCUSSION

Morphological investigation of the resected peripheralbranches of the trigeminal nerve removed from thetrigeminal neuralgia patients has convincingly shownthat their morphological state mainly depended on thestage and duration of the illness. During the acute pe-riod of the illness, disintegration and demyelinisationof the nerve fibres takes place, whereas during remis-sion, partial restoration of these structural elementsoccurs. One of the causes of progressive dystrophy ofthe peripheral branches of the trigeminal nerve maybe their compression due to the narrow bone canals.As early as 1925, Sicard, and later (in 1941) Sepp andKrol (13) proposed a hypothesis according to whichtrigeminal neuralgia may develop due to the narro-wing of the osseous canals transmitting the correspon-ding nerve branches. This assumption has been con-vincingly confirmed by the data of our X-ray examina-tions in approximately one third of the patients withthe second- or third-branch trigeminal neuralgia: theinfraorbital or mandibular canals were narrowed on

the affected side of the face. We suppose that the wallsof the canals thicken and the lumina becomes narro-wed due to secondary hyperostosis caused by local chro-nic inflammation. Most of the patients with a narrowinfraorbital canal suffered from chronic maxillary sinu-sitis; the rest, from other facial and maxillary inflam-matory illnesses such as periodontitis, periostitis, phleg-mon, etc. The narrowed mandibular canals most oftenare located near dental cysts, the periodontium is da-maged by the inflammatory process or in the place ofteeth extracted because of chronic periodontitis. A qu-estion arises whether the narrowed canals always re-sult in a compression of the neurovascular bundle. Areply to this question may be found in the data of ourDopplerographic examinations: we found that the blo-od flow velocity in the narrowed canals was half thevelocity established in the normal lumen canals. Re-cently, the role of the compression factor in the deve-lopment of trigeminal neuralgia has been also confir-med by many other investigators who point out thatneuralgia develops due to compression exerted uponthe intracranial part of the trigeminal nerve by anoma-lous brain vessels, their aneurysms, brain tumours, etc.(1, 3, 4, 11, 12, 16). Joffroy et al. (6) call it “a neuro-vascular conflict” when an artery has an offending con-tact with the trigeminal nerve root, which results inlocal demyelination and ectopic triggering of neuraldischarges.

Another frequent cause of progressive dystrophyin the peripheral branches of the trigeminal nerve isallergic inflammatory reaction manifesting itself in themast cell degranulation when antibodies, most oftenof the immunoglobulin E class, attach to the specificreceptors on the surface of mast cells (5). Cells synt-hesizing IgE are present in the lymphoid tissue, inthe mucous membranes of the eye, nose, oral cavity,upper respiratory tract (10). In some disorders, theconcentration of IgE may increase greatly: in inflam-matory diseases of the otorhinolaryngological organs,trebly; in nasal polyps, five to six times (3, 5).

Thus, under the influence of various damaging fac-tors, such as cooling injury to the face, tonsillitis, chro-nic rhinitis, paranasal sinusitides, and chronic inflam-mation of other organs in the region of face and jaws,the amount of IgE and antibody complexes that mayattach to the mast cell and result in local immuneresponse during which degranulation of the cells isincreased. The degranulating mast cells release biolo-gically active substances as histamine, serotonin andothers into the intercellular space. This process is con-firmed also by the data of our morphologic and his-tamine investigations. The fact that we have determi-ned a significantly higher concentration of histaminein saliva than in blood shows the existence of a localhistamine source, which is conditioned by the localimmune reaction in the peripheral trigeminal nervebranches. Histamine actively participates in the regu-lation of functional activity of various neural structu-


res as a mediator of pain reactions (15). Therefore,undoubtedly, histamine which is released during a lo-cal allergic reaction and is accumulated in the trige-minal nerve plays an important role in the pathoge-nesis of neuralgia.

Due to inflammatory swelling of the trigeminal ner-ve branches, the canals transmitting them become re-latively too narrow, and in this way the mechanism ofthe nerve branch compression becomes involved inthe pathogenetic chain of trigeminal neuralgia.

The presented examples show that the essence ofthe peripheral mechanism of neuralgia is progressi-ve dystrophy of the trigeminal nerve which predeter-mines a long-lasting preliminal afferent pathologicalimpulsation. The trigeminal nerve system conjunc-ting the central structures capable to exert inhibito-ry action upon the segmental and suprasegmentalformations is able to form a stable irritation focusof paroxysmal type in the CNS, whilst a chronic ir-ritation focus exists in the periphery (8). Thus, pro-gressive dystrophy in the trigeminal nerve system sti-mulates the central pathogenetic mechanism of neu-ralgia. Undoubtedly, there should be appropriate con-ditions in the body for these pathogenetic mecha-nisms to manifest. Atherosclerosis and other age-related alterations weaken the state of the neurohu-moral barrier complex, on which the reliability ofadaptive and compensatory reactions depends. The-refore, more favourable conditions develop for theformation of the pathogenetic mechanisms of trige-minal neuralgia in the elderly and in old individualsaffected by an aetiologic factor.

CONCLUSIONS

1. The peripheral pathogenetic mechanism of trige-minal neuralgia is induced by progressive dystrophyin the peripheral branches of the trigeminal nervewhich predetermines long-lasting afferent impulsationand the formation of a central pathogenetic mecha-nism (a stable pathologic paroxysmal type irritationfocus in the CNS).

2. The dystrophy in peripheral branches of thetrigeminal nerve results in their compression in thenarrowed bone canals transmitting them and their in-flammatory processes manifesting by mast cell degra-nulation.

3. The narrowing of the bone canals transmittingthe peripheral trigeminal nerve branches and the in-flammatory processes can result in dental, otorhino-laryngological disorders and other illnesses of the fa-cial and maxillary region, which can be considered tobe the direct causes of trigeminal neuralgia, whereasatherosclerosis and arterial hypertension are the pre-disposing factors.

Received 4 July 2005Accepted 2 November 2005

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Rièardas Kubilius, Gintaras Sabalys, Rimvydas Stropus

TRIÐAKIO NERVO NEURALGIJOS ETIOLOGIJOSIR PERIFERINIØ PATOGENETINIØ MECHANIZMØASPEKTAI

S a n t r a u k aÐiame straipsnyje pateikiami 2 963 pacientø, serganèiø tri-ðakio nervo neuralgija, tyrimo rezultatai. Mûsø atlikti mor-fologiniai tyrimai rodo, kad periferinis patogenezës mecha-nizmas apima progresuojanèià periferiniø triðakio nervo ða-kø distrofijà. Ðis centrinis patogenezës mechanizmas apibrë-


þiamas kaip ilgai trunkantis ácentrinis impulsas, kuris pato-loginio paroksizminio tipo þidiná formuoja centrinëje nervøsistemoje. Viena ið ðio proceso prieþasèiø yra triðakio ner-vo ðakø kompresija. Vienam treèdaliui mûsø tirtø pacientøðis procesas pasireiðkë susiaurëjusiame paakiduobiniame ka-nale (sukeldamas II triðakio nervo ðakos kompresijà) ir apa-tinio þandikaulio kanale (sukeldamas III triðakio nervo ða-kos kompresijà).

Kraujo tekëjimo greitis arterijose, esanèiose ðalia susiau-rëjusiø kanalø, buvo perpus maþesnis negu kolateralinësearterijose, iðsidësèiusiose platesniuose kanaluose.

Kita ðios progresuojanèios distrofijos prieþastis yra ner-vø imuninis atsakas, kai vyksta kamieniniø làsteliø degranu-liacija ir iðsiskiria histaminas. Kanalø susiaurëjimà ir vieti-ná uþdegimà sukelia uþdegiminiai reiðkiniai ausyse, nosyje,gerklose ir kitose veido þandikauliø srityse.

Raktaþodþiai: triðakio nervo neuralgija, etiologija, pato-genezë

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