Histopathological Evaluation of Inferior Alveolar Neurovascular Bundle in Cases of Trigeminal Neuralgia

Abstract

Background

Trigeminal neuralgia is a painful disease that has been afflicting mankind since time immemorial. The etiology and pathophysiology have been widely studied but poorly understood. There are well-documented researches analyzing ultrastructural changes in trigeminal root specimens obtained following microvascular decompression surgery. However, there are no studies evaluating microscopic changes following peripheral neurectomy.

Purpose

The present study examined microscopic changes in inferior alveolar neurovascular bundle in trigeminal neuralgia patients of mandibular division with no underlying cause.

Materials and Methods

The biopsy specimens were obtained from peripheral neurectomy of 11 trigeminal neuralgia patients’ refractory to anti-neuralgic medications. The autopsy specimens from 10 cadavers were used as control. The specimens were subjected to histopathological examination by hematoxylin and eosin, Masson trichrome and Luxol fast blue stains.

Results

All biopsy specimens reported luminal occlusion of small vessels, medial degeneration and intense mononuclear inflammatory infiltrate. Focal myelin digestion chambers were observed in large and small axons. No pathological alterations of either blood vessel or nerve fibers were reported in autopsy specimens.

Conclusion

The demyelination of inferior alveolar nerve due to pathologic vascular changes in peripheral vasculature may have a role in initiation and precipitation of trigeminal neuralgia, and hence, peripheral neurectomy has a significant role in alleviating pain.

Introduction

Trigeminal neuralgia (TN) is one of the most excruciating pain syndromes afflicting the orofacial region. It is characterized by brief, episodic, lancinating pain in the distribution of one or more divisions of the trigeminal nerve, either spontaneously or in response to gentle tactile stimulation of a trigger point on the face or in the oral cavity. The pain is severe and typically lasts for seconds. Classical TN has an incidence of four to five people in 100,000 [1]. It occurs in bouts lasting weeks or months, with periods of remission of months or years.

The etiology of TN is the most controversial aspect of the disease, and apart from vascular compression of trigeminal ganglion, several other causative factors are trauma, viral infection, demyelinating diseases, vascular diseases and granulomatous inflammation. Genetic disorder has also been attributed toward its onset as there are reports of familial TN. However, in most of the patients, no definitive causative agent can be identified [2]. The pathophysiology of TN is not clear, and the debate of central versus peripheral pathogenetic mechanisms still rages on. Proponents of peripheral mechanism consider cross-connection among demyelinated and degenerated axons that generate long-lasting prethreshold ectopic afferent impulses resulting in pain paroxysm. Central mechanism theory assumes that TN starts due to trauma to thalamus, nuclei of trigeminal nerve, encephalic trunk or cerebral cortex. However, there is a lack of objective evidence supporting the theories of central and peripheral TN pathogenetic mechanism [3].

The management of TN is focused to alleviate the pain, thereby improving the quality of life. When the patient does not respond to pharmacotherapy, other modalities like peripheral injections, peripheral neurectomy, cryotherapy, microvascular decompression, radiofrequency thermocoagulation and gamma knife radiosurgery are contemplated [4]. An ideal treatment is one that causes minimal morbidity and preserves the normal sensation of the face. However, such an ideal treatment does not yet exist. Keeping in view the age of patient and associated systemic conditions, aggressive surgical intervention may not often be indicated. Peripheral neurectomy though considered to be obsolete, still is an effective, simple and safe procedure in such cases. Peripheral branches of trigeminal nerve like inferior alveolar, mental and infraorbital branches can be easily accessed and treated by neurectomy. The pain-free duration following neurectomy has been reported to be 2–5 years [5]. Some authors even recommended repeated neurectomy of the same branch [6]. Peripheral neurectomies though in practice for quite some time, histopathological changes in the nerve specimen have not been reported previously. In the present article, authors have reported microscopic alterations of inferior alveolar neurovascular bundle in cases of TN of mandibular division.

Materials and Methods

Patient Population

The prospective study was conducted in the Department of Maxillofacial Surgery from Oct 2014 to Sep 2015 after obtaining approval from the Institutional Ethics Committee. Eleven patients of both genders (seven females, four males) of 55 to 75 years of age diagnosed with trigeminal neuralgia and had persistent symptoms over the area of distribution of the inferior alveolar nerve for duration of more than 5 years in spite of being managed with two or more anti-neuralgic medications were included. Written informed consent was obtained from patients before their inclusion in the study, and Helsinki guidelines were followed. Patients with diabetes, hypertension, other systemic anomalies, history of previous trauma and who had undergone previous surgical management for trigeminal neuralgia and those unwilling to participate were excluded from the study. Magnetic resonance imaging (MRI) was done to exclude any underlying structural abnormalities such as tumors, multiple sclerosis, vascular abnormalities and other intracranial abnormalities. Orthopantomogram (OPG) was done for every patient to rule out any local pathology and narrowing of mandibular canal.

Surgical Technique

An intraoral vestibular incision was placed, and subperiosteal dissection was carried out to expose the mental nerve. The periosteum around the neurovascular bundle was sharply dissected, and the nerve was dissected free of its soft tissue attachments for a length of about 1.5 cm distally from the mental foramen where it was clamped, ligated and sharply sectioned. An incision of 2.5 cm extending from the retromolar trigone along the external oblique ridge to the anterior border of ramus of the mandible was placed, and subperiosteal dissection was carried out to reach the lingula and mandibular foramen exposing the neurovascular bundle. The neurovascular bundle was ligated 1 cm proximal to its entry into the mandibular canal with the help of mixter forceps and silk sutures and transected. The freed intracanal portion of the inferior alveolar nerve was gently teased out of the canal (Fig. 1) and placed in 2% paraformaldehyde. Postoperatively, anti-neuralgic medications were not prescribed. Patients were clinically evaluated at 1 week, 1 month and every 6 months’ interval thereafter.

Fig. 1.

Dissected inferior alveolar neurovascular bundle

Biopsy, Control Tissues (Autopsy) and Laboratory Procedure

The autopsy specimens from 10 cadavers (six females, four males) of approximately above 55 years of age having full component of mandibular teeth were used as control. The biopsy and autopsy specimens were preserved in 2% paraformaldehyde and were kept in it for 3–4 h for adequate fixation followed by an overnight wash in phosphate-buffered saline (pH 7.4) containing 6.8% sucrose at 4°C prior to dehydration in 100% acetone for 60 min. It was then placed in an infiltrating solution (Technovit 8100; M/s Heraeus Kulzer, Friedrichsdorf, Germany) for 7–8 h prior to embedding overnight. An ultramicrotome was used to cut serial semi-thin sections (2–3 µ) from the plastic-embedded tissue block. The sections were initially stained by routine hematoxylin and eosin (HE) to evaluate the overall histomorphology, followed by Masson trichrome (MT) to evaluate the quantum of fibrosis and Luxol fast blue (LFB) to assess the degree of demyelination of axons.

Results

The mean age of patients was 63.64 ± 6.15 years, and all patients were found to confirm to the diagnosis of trigeminal neuralgia of mandibular division as per international headache society criteria for the classification of headache disorders II [7]. The total duration of distress of these patients ranged from 6 to 20 years with an average of 10.55 ± 4.34 years. They had a history of extraction of multiple teeth subsequent to pain symptoms and were partially or completely edentulous in the mandibular arch. The patients responded initially to carbamazepine therapy but over a period of time had become refractory to combination of anti-neuralgic medications. Post-inferior alveolar neurectomy, they were free of symptoms from the first postoperative day to various durations of follow-up ranging from 2 to 3 years with an average of 2 years 6 months ± 3 months. All the patients had no remission of pain and were not prescribed any anti-neuralgic medications.

The histopathological examination of HE-stained sections at 40× magnification revealed fasiculi of nerve bundle with artery and vein. The principal vascular pathological finding at 100× magnification was thrombotic occlusion of small blood vessel adjacent to the fasiculi and was reported in nine HE-stained biopsy specimens. The thrombotic plaque formation of blood vessel wall was clearly identifiable at 400× magnification (Fig. 2). The severity of obstruction varied with stenosis ranging up to 30% in four samples, 31–50% in two specimens, 51–70% in two specimens and more than 70% in one specimen. In all biopsy specimens, degeneration of the tunica media of the blood vessel was observed. HE-stained specimen at 200× magnification and MT-stained section at 400× magnification clearly revealed focal smooth muscle disruption and fibrogenesis depicting medial degeneration of blood vessel (Fig. 3). The disorganization and fibrogenesis of the smooth muscle of tunica media were histologically graded as mild, moderate and severe. All autopsy specimens of cadavers revealed no pathological abnormalities of blood vessel wall (Fig. 4).

Fig. 2.

Hematoxylin and eosin-stained biopsy specimen (×400 magnification) depicting small vessel occlusion by thrombotic plaque (arrowhead)

Fig. 3.

Focal smooth muscle disruption of the blood vessel a Hematoxylin and eosin-stained biopsy specimen (×200 magnification) (arrowhead) and b Masson trichrome-stained biopsy specimen (×400 magnification) (arrowhead)

Fig. 4.

Hematoxylin and eosin-stained autopsy specimen (×200 magnification) depicting no pathological alterations of the blood vessel

Large and small diameter axons devoid of myelin sheath were observed adjacent to sites of medial degeneration of blood vessel in all biopsy specimens. Focal myelin digestion chambers representing demyelination were evident at 400× magnification using HE stain and LFB stain (Fig. 5). No areas of demyelination or focal myelin degeneration chambers were noted in neural fibers obtained from autopsy specimens. Patients’ characteristics and histopathological features are summarized in Table 1.

Fig. 5.

Focal myelin degeneration chambers a Hematoxylin and eosin-stained biopsy specimen (×400 magnification) (arrowhead) and b Luxol fast blue-stained biopsy specimen (×400 magnification)

Table 1.

Patients’ characteristics and histopathological findings of biopsy specimens

Case no.	Age (years), sex	Preoperative pain duration (years)	Postoperative pain relief (months)	Vascular pathological findings		Axonal pathological findings
				Thrombotic plaque formation	Tunica media degeneration	Myelin sheath degeneration
1	58, F	6	36	< 30% stenosis	Mild degeneration and fibrogenesis of smooth muscle	Vacuolization and focal myelin sheath degeneration
2	63, F	8	34	< 30% stenosis	Moderate degeneration and fibrogenesis of smooth muscle	Vacuolization and focal myelin sheath degeneration
3	55, M	6	34	51–70% stenosis	Severe fibrogenesis and thinning of tunica media	Vacuolization and focal myelin sheath degeneration
4	68, F	14	33	31–50% stenosis	Moderate degeneration and fibrogenesis of smooth muscle	Vacuolization and focal myelin sheath degeneration
5	72, M	15	31	No plaque formation	Mild degeneration and fibrogenesis of smooth muscle	Vacuolization and focal myelin sheath degeneration
6	66, M	11	30	< 30% stenosis	Mild degeneration and fibrogenesis of smooth muscle	Vacuolization and focal myelin sheath degeneration
7	75, F	20	29	> 70% stenosis	Severe fibrogenesis and thinning of tunica media	Vacuolization and focal myelin sheath degeneration
8	60, F	8	29	No plaque formation	Mild degeneration and fibrogenesis of smooth muscle	Vacuolization and focal myelin sheath degeneration
9	59, F	7	28	31–50% stenosis	Moderate degeneration and fibrogenesis of smooth muscle	Vacuolization and focal myelin sheath degeneration
10	60, M	10	26	< 30% stenosis	Mild degeneration and fibrogenesis of smooth muscle	Vacuolization and focal myelin sheath degeneration
11	64, F	11	25	51–70% stenosis	Moderate degeneration and fibrogenesis of smooth muscle	Vacuolization and focal myelin sheath degeneration

Discussion

Trigeminal neuralgia is the most common neuralgic cause of facial pain. The diagnosis of TN is based primarily on a history of characteristic paroxysmal unilateral pain attack evoked by facial and perioral triggers limited to one or more divisions of trigeminal nerve. It is common above 50 years of age occurring in both genders with a slight female predominance [2]. The dental practitioners are often the first to be consulted when patient experiences these pain attacks. A detailed maxillofacial and intraoral examination should be performed to rule out odontogenic and non-odontogenic sources of pain. Periapical, panoramic radiography and computed tomography or MRI scan should be done for evaluation of dento-alveolar and intracranial abnormalities. The present study reported female predominance with a mean age of 63.64 ± 6.15 years and ruled out diabetes mellitus, multiple sclerosis, vascular compression, tumors, previous trauma and odontogenic and non-odontogenic causes of pain.

The etiology and pathogenesis of TN are the most complicated and unclear topics in medicine. The most common TN etiological theories are diseases related, direct trauma to the nerve and multifactorial origin of the disease. The neurovascular compression as a cause of TN was proposed by some authors [8, 9]. On contrary, culprit vessel as a cause of TN was not observed in every study and it has been recognized that there are TN patients who present with a well-defined symptomatic history but no neurovascular compression [10, 11]. Some authors have suggested multiple sclerosis as a cause of TN [12]. However, others have disputed this link because TN is reported to occur only in 0.9% to 4.5% of patients those had multiple sclerosis [13]. Allergic hypothesis of TN etiology has also been proposed [14]. However, there is only indirect evidence that supports allergy might cause TN.

The present study reported occlusion of blood vessel by thrombotic plaque formation and degeneration of tunica media in biopsy specimens. The obstruction of lumen of vessel and impaired contractile abilities could have resulted in reduced local blood supply. Hypoxia due to insufficient blood flow led to the accumulation of metabolic products resulting in dystrophic alterations of nerve fibers. The myelin sheath is particularly sensitive and undergoes progressive alteration from demyelination to disintegration as pathological alterations in trigeminal vasculature become more severe. Marinković et al. [15] observed vascular pathologic alterations like apoptosis or degeneration of some endothelial and smooth muscle cells in the wall of the trigeminal arterioles. The occurrence of TN in older individuals is also enlightened by the fact that as the age advances, atherosclerosis weakens the state of the neurohumoral barrier complex, on which the reliability of adaptive and compensatory reactions depends. Thus, authors conclude that demyelination of peripheral fibers of trigeminal nerve adjacent to sites of morphological and functional disturbances in blood vessels can be an etiological factor in onset of TN.

The peripheral pathogenetic mechanism of TN is induced by progressive dystrophy in the peripheral branches of the trigeminal nerve. As the disease advances, neural degeneration progresses retrogradially involving all the peripheral branches and then anterogradially toward intracranial part of trigeminal nervous system. This is often referred to as vicious circle. The authors have observed groups of demyelinated axonal fibers in close approximation to each other in the biopsy specimens. Close membrane approximation is a pathological condition known to facilitate axon-to-axon cross-excitation [16–18]. This accounts for pain paroxysm often triggered by stimulation of facial or intraoral zone innervated by one or more members of these demyelinated axonal group leading to activation of entire group. The demyelinated nerve fibers can be the source of ectopic afferent impulses that evokes functional disturbances and pain-dominant focus formation in the segmental apparatus of brain stem and in suprasegmental brain centers [3]. Thus, progressive dystrophy of peripheral branches initiates peripheral pathogenetic mechanism which in turn triggers central pathogenetic pain mechanism.

The management of TN should aim to improve the quality of life. Anti-neuralgic medications such as carbamazepine, phenytoin, gabapentin and lamotrigine stabilize the hyperexcited nerve membranes, inhibit repetitive neuronal discharges and reduce synaptic propagation of excitatory impulses. This action occurs in the peripheral nervous system by blockage of voltage-gated sodium channels. They also exert central inhibitory actions by suppressing seizure activity in central nervous system [19–21]. As the disease progresses, ever-increasing doses of these drugs are required until side effects such as nausea and sedation become intolerable and surgical intervention is required. Peripheral neurectomy is a surgical procedure in which one section from the extracranial portion of a nerve is excised in order to interrupt the conductivity of the painful sensation from the area innervated by that nerve. It is performed occasionally on the cervical nerve, phrenic nerve and sciatic nerve for correction of spastic torticollis, collapse of the lung and relief of obstinate sciatica, respectively, but most frequently on the fifth cranial nerve for the management of TN [5, 6, 22–25]. Peripheral neurectomies have played a role in the past for the management of TN, but these procedures are not commonly performed presently because of a high incidence of pain recurrence. They have been superseded by more complex procedures like microvascular decompression and radiofrequency thermocoagulation [4]. In the present study, the authors reported their experience of 11 elderly TN patients who underwent inferior alveolar neurectomy. It is an effective, safe and simple procedure for elderly patients suffering from TN. These patients did not receive any anti-neuralgic medications following surgery and had good pain relief for a mean of 30 months postoperatively. There were no major complications reported except for postoperative edema. The authors conclude that peripheral pathogenetic mechanism may be accountable for signs and symptoms of TN and neurectomy of degenerated peripheral branches of trigeminal nervous system for its effectiveness.

In conclusion, TN is a neuropathic pain disorder that at times is medical refractory, thus requiring surgical management. An accurate preoperative diagnosis is of utmost importance as identification of correct etiological agent will dictate the surgical modality to be used in each individual case. The observations of current study pointed out the possibility of vascular pathologic alterations of peripheral neurovascular bundle as the primary factor in pathogenesis of TN in elderly patients with no underlying cause. The resulting peripheral neural dystrophy leads to axonal interconnection, spontaneous activity and ectopic impulse generation. The article also highlighted the importance of peripheral neurectomy as a choice of surgical procedure in these patients, thus obviating the need for more invasive surgical procedures. However, continued research will further establish the role of peripheral vascular alterations in pathogenesis of trigeminal neuralgia and peripheral neurectomy as a choice of surgical procedure.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Compliance with Ethical Standards

Conflict of interest

All authors have no conflict of interest to declare.

Ethical Approval

All procedures involved in the present study involving human participant were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. Institutional ethical committee approval was obtained from Armed Forces Medical College, Pune. Protocol No: OMFS/1/2014 version 1.

Informed Consent

Written informed consent was obtained from patients included in the study. However, article included only histopathological pictures and no clinical photographs.