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Year : 2019  |  Volume : 67  |  Issue : 2  |  Page : 377--388

The neurovascular syndromes: A review of pathophysiology – Lessons learnt from Prof. Chandy's paper published in 1989

Harjinder S Bhatoe 
 Department of Neurosurgery, Fortis Hospital, Mohali, Punjab, India

Correspondence Address:
Dr. Harjinder S Bhatoe
Department of Neurosurgery, Fortis Hospital, Mohali - 160 062, Punjab

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Bhatoe HS. The neurovascular syndromes: A review of pathophysiology – Lessons learnt from Prof. Chandy's paper published in 1989.Neurol India 2019;67:377-388

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Bhatoe HS. The neurovascular syndromes: A review of pathophysiology – Lessons learnt from Prof. Chandy's paper published in 1989. Neurol India [serial online] 2019 [cited 2019 Jun 19 ];67:377-388
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The sensory root is frequently indented, lifted up or bent at an angle by the artery …. This I believe is the cause of tic douloureux.

Walter E. Dandy[1]

Pulsatile propulsion of blood through blood vessels is responsible for its circulation and transport of oxygen and nutrients. The pulsatile impulse generated by the heart in the cardiac cycle propagates the pressure-related events right till the capillaries. The venous flow too has a waveform pattern, related partly to thoracic excursions leading to cyclical variations in intrathoracic pressure, thus regulating the venous return. Intracranially, the major trunks of the arteries and veins and the trunks of major cranial nerves course the cerebrospinal fluid–filled subarachnoid space. Since Walter Dandy[1] first described contact of a vessel loop with the trigeminal root in patients with trigeminal neuralgia, the theory of neurovascular compression has been widely accepted. It is believed that a close contact between a major artery and a nerve trunk over a prolonged period of time may cause changes in the nerve trunk, in the form of localized demyelination and initiates the phenomenon of ephaptic transmission [Figure 1].{Figure 1}

While the theory of neurovascular compression and consequent ephapsis and its clinical consequences is widely accepted, a number of studies, hypotheses, clinical, and radiological observations have attempted to prove the connect. This article reviews the data on the observations, likely pathological changes, and the pathophysiological mechanisms. A PubMed database search was performed for articles on pathophysiology and observations, using the key words trigeminal neuralgia, hemifacial spasm (HFS), glossopharyngeal neuralgia, vertigo, ephaptic transmission, and neurovascular compression. A total of 60 articles and book chapters were selected based on direct relevance and quality of information provided that enhanced the current understanding of pathophysiology of neurovascular compression. The articles and book chapters were reviewed, and the pathophysiology of neurovascular compression causing specific syndromes was analyzed.

Such ephaptic transmission can lead to abnormal volley of impulses to the target musculature or sensory receptors. Subsequently, there can be a rekindling phenomenon at the brainstem nuclei of the nerves concerned, leading to constant electric discharge and impulse transmission. As the cranial nerves enter/exit the brainstem in the posterior fossa, there is a change in the myelin sheath characteristics, central on the brainstem side and peripheral on the distal side. This change occurs close to the entry/exit zone, over a variable segment of the nerve, referred to as Obersteiner–Redlich zone. Extraneous contact with a vessel over this zone or close to the brainstem results in hyperactive dysfunctional syndromes.

In the case of trigeminal nerve, the response takes the form of trigeminal neuralgia in the region of distribution of one or more branches. In the case of facial nerve, there are intermittent tonic–clonic facial movements of one half of the face, commonly known as hemifacial spasm. Such disorders of ephaptic transmission can also be seen in space-occupying lesions (most of the times in the posterior fossa) [Figure 2], which probably act by causing or accentuating existing anatomical conflict between an artery and the corresponding nerve. Demyelination, as in multiple sclerosis, can also cause ephaptic transmission possibly by short-circuiting the impulse volleys. However, a contrarian observation involves the fact that proximal part of the superior cerebellar artery (SCA) passes below and is separated from the posterior cerebral artery by the oculomotor nerve. Nearly two-thirds of the SCA has a point of contact with the oculomotor nerve on the inferior surface of the nerve. The SCA passes near and frequently has points of contact with the oculomotor, trochlear, or trigeminal nerves. Oculomotor nerve may occasionally be constricted between the posterior cerebral artery (PCA) and SCA.[2] Yet, the only manifestation of oculomotor nerve compression by a vessel or a posterior communicating artery aneurysm is nerve dysfunction in the form of oculomotor nerve palsy, and an optic nerve compressed by ophthalmic segment aneurysm manifests as optic atrophy. Is the response to pulsatile impulse different for different cranial nerves?{Figure 2}

 The Transitional Zone

Obersteiner and Redlich[3] studied spinal nerves as they entered the spinal cord and described the transition zone of myelin depletion. They interpreted this finding as lack of myelin sheath for about 50 μm. It is now apparent that this depletion of myelin was due to preservation artifact, and the myelin sheath of the central portion is thinner[4] and more susceptible to injury.[5] The transition zone from central myelin to peripheral myelin still carries the label of being Obersteiner–Redlich zone.

There are three types of fibrocollagenous supporting tissue associated with each nerve:

Endoneurium: a delicate, collagen-rich tissue surrounding each nerve fiberPerineurium: a thin sheath with aggregation of funiculiEpineurium: the fibroareolar tissue that surrounds the funiculi and forms the nerve trunk.

In the central nervous system (CNS), there is lack of endoneurium, perineurium, and epineurium, and the axons are ensheathed in oligodendrocytes and follow a parallel course. The transition from central myelin (from oligodendrocytes) to peripheral myelin (elaborated by Schwann cells) takes place at a variable distance after the nerve exits the brainstem, much like handing over the baton in a relay race.[6] The sensory component of any nerve has a longer segment of central myelin than that of the motor root.[6] Guclu et al.,[7] studied the relationship between the length and the volume of the central myelin portion of these nerves with the incidences of corresponding syndromes of the cranial nerves. The central myelin is longer in case of facial nerve,[7] while it is wider in case of trigeminal nerve. It is very short in glossopharyngeal and vagus nerves, and these two nerves exit the brainstem as multiple rootlets, unlike the facial nerve which exits as a single nerve.

In its course to the brainstem, the cranial nerve splits into thinner rootlets which further subdivide into smaller rootlets. The trigger zone (TZ) occurs within each of these mini-rootlets, and centrally, the nerve bundles enter the brainstem as a mass of compact white matter.[8] The CNS portion of the mini-rootlets is convex in shape. Thus, the transition zone is arched, and there are two compartments within the mini-rootlets: a peripheral zone consisting of axons ensheathed in endoneurium; and, a central compact track of white matter. There is deficiency of central myelin in the area that is deficient of endoneurium, and myelin in this region is thin when compared with that within the brainstem.[4] The transition zone is also the region where the endoneurial microvasculature exits to anastomose with extraneural plexus, thus making the transition zone relatively poorly vascularized, creating a locus minoris resistentiae (Achilles heel).[8]


The current understanding of neurovascular compression is that a vessel is in close contact with a cranial nerve in the posterior fossa [Figure 3], [Figure 4], [Figure 5]. Furthermore, Jannetta[9] observed that these vessels cross the nerve at a right angle, and a vessel running parallel to the nerve does not cause clinical manifestations.{Figure 3}{Figure 4}{Figure 5}

Mechanical ectopic excitation: There is probably focal compression and demyelination in the course of adjacent axons, leading to a false synapse (ephapse).[10] Nielsen further stated that there is bidirectional cross-transmission between fibers, decreased conduction velocity in “pre-ephaptic” motor fibers, focal slowing of conduction over the suspected site of compression, suggested by increased latency of the R1 component of the blink reflex, lateral spread of orthrodromic impulses leading to increased amplitude of the blink reflex and occurrence of synkinetic responses in other facial muscles. There is also autoexcitation, related to the passage of a single anti- or orthrodromic impulse. With the lateral spread of current, often resulting in a “cascade effect”, clinically evident clonic–tonic spasms occur.[11] Ectopic excitation induced by hyperventilation, presumably due to reduction in the concentration of extracellular calcium caused by respiratory alkalosis, can precipitate the tonic–clonic event. All these observations fulfill the predictions made by a hypothesis that HFS is caused by abnormal conduction of impulses through the peripheral portion of the facial nerve. Rasminsky[12] summarized these four events as follows:

mechanically induced or ectopic excitationreflection of impulses: orthodromic and/or antidromic conductionephaptic excitation or “cross-talk” between axonsafter discharge or autoexcitation

It is possible that a demyelinated axon stimulates a myelinated one, instead of two demyelinated axons transmitting impulses.[13] Due to resistance (resulting from vascular compression) offered by the demyelinated axon, the impulse is directed and transmitted to an adjacent myelinated axon, stimulating muscles innervated by different axons. This phenomenon also explains the synkinesis.

Neuroplasticity or reorganization of the system explains some of the features of neurovascular compression. Extrapolating the observations from limb or digital amputees, it is observed that the topographic representation is altered after amputation. The deprived area of somatosensory cortex then becomes responsive to adjacent skin areas. Chronic stimulation of facial, trigeminal, cochleovestibular, and glossopharyngeal nerve results in reorganization of nuclei of these nerves; and, in abnormal discharges, perceived as pain in trigeminal distribution, and facial spasm in facial nerve motor distribution[14]Kindling: The kindling theory states that a vascular loop compresses the nerve, causing demyelination and creating a focus of ectopic excitation.[15],[16] Chronic stimulation causes reorganization in facial nerve nucleus in patients with HFS.[17] Another explanation hypothesized the presence of aberrant regeneration in the facial nerve distally from the point of compression in such a manner that some of the axons get misdirected to other targets.[18] In the trigeminal nerve, compression causes demyelination of inhibitory fibers. Tactile stimulation on the gum or alveolus causes increased activity of the trigeminal nucleus and increased discharge through the fibers, some of which may be demyelinated due to compression and there is amplification of impulse. The nuclear activity increases, and increased discharges are perceived as intense, intermittent lancinating pain, with a background dull ache over the same region.

Each of the three neurovascular complexes in the posterior fossa includes one of the three cerebellar arteries, one of the three parts of the brainstem, one of the three cerebellar peduncles, one of the three cerebellar surfaces, one of the three fissures between the brainstem and cerebellum, and one of the three groups of cranial nerves. There may be a combination of concurrent two neurovascular conflicts, causing tic convulsif (trigeminal neuralgia with HFS).[19],[20] The offending vessel in such cases is a tortuous vertebral artery, dissection of which should begin caudally and laterally. Tumors too are known to cause tic dolourouex or tic convulsif, probably by causing vessels to lie against the transition zone.[20],[21],[22] Rarely, supratentorial tumors can present with trigeminal neuralgia, presumably due to caudad displacement of the tentorium causing an abnormal neurovascular contact [Figure 6]. Such a contact might get reversed when the tumor is excised and the anatomy returns to normal.{Figure 6}

 Histopathological Changes

Devor et al.,[23] described structural and morphological changes seen in the trigeminal nerve as follows:

distortiondeviationgroove formationnerve atrophyaxonal loss and demyelinationmyelin abnormalities (dysmyelination)presence of excess collagennerve atrophy.[24]

The microscopic findings of compressed segments of the trigeminal, facial, and glossopharyngeal nerves are remarkably similar, despite the variations in the site of biopsy and nerves involved. Beaver et al.,[25] studied trigeminal nerve specimens from trigeminal nerve sections made for trigeminal neuralgia and demonstrated hypermyelination and demyelination. Demyelination of the point of contact was also reported in nerve specimens, obtained during microvascular decompression for HFS, on electron microscopy by Ruby and Jannetta.[26] The exact portion of the nerve compressed was biopsied, and the authors proposed that naked, demyelinated axons came in contact and affected ephaptic transmission. Hypertrophied myelin and Schwann cells were intermixed with axons. Brihaye et al.,[27] reported similar findings of demyelination in patients with glossopharyngeal neuralgia, who had nerve compression due to an atheromatous vertebral artery. Ishii[28] found demyelination and hypermyelination of the glossopharyngeal nerve in pharyngeal and cervical segments extracranially. In the case of vestibulocochlear nerve, however, there has been no demonstrable demyelination. On the contrary, there is endoneurial fibrosis,[29] which is a possible explanation for deafferentation.

According to another plausible theory proposed by Calvin et al.,[30] the mechanism of trigeminal neuralgia involves the presence of a slightly injured nerve due to constant pulsations of a vessel adherent to the nerve. Amplification of neural activity and cross-transmission at the site of contact also results from lack of input of A fibers to the caudal trigeminal nucleus, a mechanism which could result in disinhibition of pain circuits and thereby result in pain. Fromm and colleagues[31],[32] provided an explanation for trigeminal neuralgia (TN) with segmental inhibition, since the painful condition responds to baclofen, a drug that enhances segmental inhibition. Moreover, carbamazepine inhibits TN by acting centrally and is effective in HFS, indicating that it does not act at the site of vascular compression.

A combination of peripheral and CNS changes is involved in the etiology of trigeminal neuralgia. There is an apparent disconnect between nociception and cortical perception of pain. There is reduced tactile and temperature sensation indicating damage to small unmyelinated and large myelinated fibers, and abnormal temporal summation of pain suggests hyperexcitability.[33] With loss of inhibitory fibers, tactile stimuli on the face or gums cause increased activity in the trigeminal nucleus, resulting in increased discharge across the nerve till the effector organs. There is further amplification of impulses at the site of demyelination and reflection of these impulses back to the trigeminal nucleus. Summation of these impulses and response of the nucleus results in severe episodic, lancinating pain over the distribution of the nerve. In the facial skin, there is an abnormal neuronal activity, and a higher rate of firing of axons of small caliber fibers. Centrally, there is nociceptive modification of signal processing, N-methyl D-aspartate (NMDA) receptor activation with central hyperexcitability.[34]

Gardner[35] postulated that HFS occurs due to the reverberating circuit setup between afferent and efferent fibers at the point of facial nerve compression. He also advocated sectioning of nervus intermedius in cases of failed facial nerve decompression. The underlying cause of compression is invariably an ectatic or aberrant blood vessel that compresses the facial nerve at its exit from the brainstem.[36] The root entry/exit zone has some distinct features: the nerve fibres are ensheathed by the arachnoid membrane only, without the epineurium, and there are no connective tissue septae traversing the individual fascicles. This region is also the transitional zone between central (oligodendroglia) and peripheral (Schwann cells) myelination.[37] All these features result in increased vulnerability and therefore susceptibility to stimuli such as compression, which leads to lateral excitation of facial axons by ephaptic transmission[38] and hyperexcitability of facial motor neurons.[39] The site of compression plays an important role in the pathogenesis of HFS.[5] The cessation of antidromic stimulation when the conflicting nerve and vessel have been separated has been demonstrated by electromyographic monitoring, which returns to the pathological state if the vessel is replaced.[40] Nielsen[11] proposed the abnormal conduction of impulses through the peripheral portion of the nerve with ectopic excitation and ephaptic transmission due to focal demyelination. Nielsen[11] also observed electrophysiologically increased resistance in the para-axonal space, which is a prerequisite for ectopic/ephaptic excitation. Microvascular decompression (MVD) decreases this resistance and facilitates remyelination, thus explaining the delayed benefits of MVD in HFS, and the severity of compression has no statistically significant difference on the outcome after MVD.[41]

Not all cases of HFS have a neurovascular contact. Aoki and Nagao[42] described a case who had a 5-year history of HFS, in whom neurosurgical exploration was negative for any vascular contact or conflict. The authors merely dissected around the nerve complex, and symptoms were relieved after surgery. Conversely, Sunderland reported a neurovascular contact between a redundant loop of the anterior inferior cerebellar artery (AICA) and the facial nerve in more than 60% of his autopsy cases, thus proving that the incidence of neurovascular conflict is higher than the reported incidence of HFS in the general population.[43]

De Ridder et al., reviewed the neurovascular conflict of vestibulocochlear nerve in patients with tinnitus.[44] They hypothesized, based on electrophysiological studies by auditory brainstem responses, that the neurovascular conflict must occur in the intracranial portion of the nerve. Tinnitus may not be the result of demyelination, but rather due to the desynchronization of auditory impulses. The more synchronized the nerves fire, the higher will be the amplitude of the evoked potentials. Contact of a blood vessel with a nerve may alter neural conduction (resulting in deceased conduction velocity or inactivation of some fibers), decreasing the temporal coherence of the firing in the central segment of the auditory nerve, decreasing the amplitude of peak II, and clinically, this may result in frequency-specific tinnitus.[45] The desynchronized signal transmission within the auditory nerve from a vascular conflict may lead to reorganization of auditory nuclei in the auditory brainstem and auditory cortex by way of neuronal plasticity.[46],[47] Clinically, these patients suffer from recurrent vertigo, disequilibrium, ataxia, and unilateral high-frequency sensorineural hearing loss and spontaneous nystagmus on electronystagmography.[48] According to the explanation offered by Schwaber and Whetsell,[49] the onset follows an episode of vestibular neuronitis and adherence of vessel to the vestibulocochlear nerve. There is demyelination of the nerve at the point of contact and deafferentation, leading to reorganization of vestibular nuclei and abnormal discharges from these nuclei. It is likely that there are corresponding changes in the cortex also, and in the interaction between the vestibulospinal system, ocular motility, visual pathways, and the reticular system. Motion and visual cues can precipitate or accentuate the symptoms due to the presence of abnormal discharges.

Degrees of nerve contact: Anderson et al.,[50] and Cheng et al.,[51] described a variable degree of nerve and vessel contact in patients with neuralgia, ranging from no contact to severe deformation with or without nerve atrophy.

Patients with severe deformation tend to have a higher incidence of atrophy, which can be diagnosed preoperatively,[51] and the zone of atrophy consistently correlates with focal demyelination.

Brainstem surface conflicts

Can a contact between an ectatic and aberrant artery and brainstem trigger the features of a neurovascular conflict [Figure 7]a,[Figure 7]b,[Figure 7]c? Such neurovascular conflicts have been reported to cause ipsilateral sensorimotor symptoms, hypertension, intractable hiccups, painful HFS with spasm of masticatory, and ocular motor muscles.[52] Ipsilateral tongue wasting has been observed [Figure 8]. The hypothesis explaining multiple cranial nerve involvement again focuses on the neurovascular conflict between a vascular loop or an ectatic vessel and the neighboring brainstem nuclei. The reversal of clinical manifestations after MVD supports this hypothesis.[52] Intrinsic brainstem lesions like a diffuse glioma can be associated with HFS [Figure 9].{Figure 7}{Figure 8}{Figure 9}

Venous neurovascular conflicts

Veins also play part in neurovascular conflicts, which may be pure venous, or may be in combination with an arterial conflict. Far from being rare, there are reports of neurovascular conflicts due to pure venous compression [Figure 10] and [Figure 11], and a significant number of them had localized arachnoiditis.[53] The characterization of venous compression is difficult, and many of these may have atypical facial pain, with a background continuous pain and paroxysmal fits. The incidence range is wide, varying from 6.1% to 68%, with an average of 25.3%.[53] In another study, Dumot and Sindou[54] reported their experience with 326 consecutive patients who underwent MVD from 2005 to 2013. Of these, 124 (38%) patients had a venous conflict, either alone in 29 (8.9%) or in association with an artery in 95 (29.1%) patients. There may be an associated pathology like focal arachnoiditis and angulation of the nerve over the petrous apex.{Figure 10}{Figure 11}

The preoperative diagnosis of a neurovascular conflict is essentially clinical, based on the characteristic pain profile of trigeminal nerve root compression and appearances in hemifacial clonic contractions. The diagnosis of other cranial nerve involvement rests on the presence of intractable tinnitus and vertigo (vestibulocochlear nerve) and intermittent lancinating pain in the tonsillar fossa (glossopharyngeal neuralgia). Almost all cases of glossopharyngeal neuralgia are idiopathic,[55] although some cases have been described as occurring due to a calcified stylohyoid ligament,[56] nasopharyngeal and cerebellopontine angle tumors,[57] or compression by an artery.[27],[58] These symptoms have to be evaluated by an otologist. Rarely, there may be a conflict between the vertebral artery and the brainstem, or the hypoglossal nerve [Figure 7]a,[Figure 7]b,[Figure 7]c and [Figure 8]. Trigeminal neuralgia (after exclusion of atypical mimics) is graded by its severity (Barrows Neurological Institute grading) into five grades [Table 1].{Table 1}

 Neuroimaging and Operative Correlation

Detection of a neurovascular conflict

The T2-weighted magnetic resonance imaging (MRI) study of the posterior fossa, along with T1-weighted contrast administration, generally is sufficient to demonstrate the neurovascular conflict [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15]. Leal et al.,[59] carried out the three-dimensional (3D) time-of-flight magnetic resonance angiography and 3D T1-gadolinium-enhanced MRI to observe vessel related to the nerve in 100 patients with trigeminal neuralgia. Image analysis of these 100 patients showed that 88 had vessels in relation to the nerve, and 12 did not. All 88 patients had the neurovascular conflict observed at surgery, and thus, there were no false positives. Of the 12 patients who did not have the presence of a vessel in relation to the nerve, 9 did not have a neurovascular conflict at the time of surgery, leading to the conclusion that there were three false negative results. Thus, the sensitivity of MRI was 96.7% and specificity 100%, when correlated with surgical findings. Jani et al.[60] studied the images and operative findings around the trigeminal nerve in 27 patients undergoing surgery for HFS. In these patients with no symptoms of neuralgia, they found that 23 patients had an intraoperative evidence of neurovascular compression of the trigeminal nerve. 18 of these patients had MRI evidence of an aberrant artery in the root exit zone of trigeminal nerve. Furthermore, they observed that the remaining five patients, who did not have MRI evidence of a neurovascular conflict for trigeminal nerve, had an intraoperative neurovascular conflict.{Figure 12}{Figure 13}{Figure 14}{Figure 15}

Prediction of culpability of vessel in neurovascular conflict

In their study, the vessel was correctly predicted to be compressing the nerve in 91 of 100 patients, with an accurate prediction of SCA, anterior inferior cerebellar artery, and basilar artery compression; while the prediction was moderate in venous compression.

Prediction of the site of compression on the surface of the nerve

The image analysis correctly identified the surface of the circumference of the nerve as the site of compression, while also predicting the severity of compression.


After nearly five centuries of clinical description and more than a century of surgical management, the pathogenesis of neurovascular compression syndromes is by no means completely settled. While imaging studies confirm the presence of a neurovascular conflict in a majority of patients, the exact cellular and biochemical changes are unknown. Studies related to the transition zone and neuronal plasticity in response to ephapsis hold promise in unfolding the mystery of the changes that lead to clinical manifestations. Cochleovestibular manifestations and compression of the medulla by ectatic vessels too fall in the realm of the unknown. Microvascular decompression with its attendant universal, long-lasting, and permanent relief of symptoms does provide a fair evidence of the culpability of transition zone neurovascular conflict. The experience on microvascular decompression for trigeminal neuralgia shared in the article published in Neurology India in 1989 by Professor MJ Chandy and Dr. Shankar Prakash of the Department of Neurological Sciences, Christian Medical College and Hospital, Vellore, is a testimony to the pioneering advancements made in this field of neurosurgery in India in those earlier times.[61],[62]

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