Etiology, Epidemiology, and Pathophysiology of Post-Facial Paralysis Synkinesis

Etiology and Epidemiology

Faulty regeneration is the norm and not the exception following facial nerve injury of any cause. Facial synkinesis has been reported in a wide range of ages from infants to elderly patients and does not appear to be limited to a specific demographic. The most common causes of facial paralysis, such as Bell’s palsy, Ramsey Hunt syndrome, trauma, and postsurgical injury, have all been associated with synkinesis to varying degrees. In one study, synkinesis was clinically observed in 55% of patients. Using electrophysiologic criteria, synkinetic movement can be detected in nearly all patients with proximal facial nerve injury. In one of the largest studies evaluating the natural course of idiopathic peripheral facial nerve palsy, synkinesis was recorded in about 16% of patients. In a retrospective study of 102 patients with untreated Ramsay Hunt syndrome, all patients who initially developed complete paralysis also developed synkinesis, whereas synkinesis was recorded in 10% to 15% of those with incomplete paralysis. Pregnancy, advanced age, and diabetes have been studied as potential risk factors for Bell’s palsy but have not shown to be linked with severity of synkinesis. However, there is a clear relationship between the severity of facial palsy and the degree of synkinesis. This link is further supported by electrophysiologic studies showing that patients with a prognostic electroneurography (ENoG) value of less than 10% have higher risks of aberrant regeneration and moderate-to-severe synkinesis than those with an ENoG value of 10% to 20%.

The Facial Neuromuscular Network

The facial nerve is a mixed motor and sensory nerve composed of approximately 10,000 neurons. About 7000 of these neurons are motor and innervate the muscles of facial expression. The motor fibers originate from the motor face area of the frontal lobe and project via the corticobulbar tract and the internal capsule to the facial nucleus. These afferent motor fibers synapse with nuclei within the facial nucleus arranged into four major subgroups: dorsomedial, ventromedial, intermediate, and lateral. Each nuclei subgroup projects to a specific group of facial muscles and explains, in part, the intricate voluntary control of facial muscle movement. The degree of nuclei representation and projection to muscle groups are related to the functional and behavioral importance of each muscle. For example, the subnuclei representing the orbicularis oris and oculi are prominently represented compared to those of less important muscles such as the depressor septi nasi or auricularis muscles. Much of what is known about this facial nucleus sub-innervation in humans is extrapolated from tracer injection studies in primates. ^, The corticobulbar projections were defined by injecting anterograde tracers into the face representation of each motor cortex, and the musculotopic organization of the facial nucleus was defined by injecting fluorescent retrograde tracers into individual muscles of the upper and lower face. Following these injections, the facial nucleus was noted to received input from all face representations. Injections in all cortical face representations labeled terminals in all nuclear subdivisions (dorsal, intermediate, medial, and lateral). However, significant differences occurred in the proportion of labeled boutons found within each functionally characterized subdivision.

Once the facial nerve exits the brain stem, the discrete compartmentalization of motor neurons destined for specific muscle groups is lost. Consequently, the fibers to all facial muscles are distributed throughout the nerve at all levels before peripheral branching occurs in the parotid. Within the parotid gland, the facial nerve divides into a superior (temporofacial) and an inferior (cervicofacial) division, interconnected but containing fibers destined to specific muscle groups. The delicate musculotopic arrangement of the facial nucleus and facial nerve is disrupted following facial nerve injury and explains in part abnormal motor recovery.

When A Nerve Is Injured

The axons that make up a motor nerve are myelinated and arranged in a fascicular architecture that is both protective and suited for rapid nerve conduction. The myelin sheath is made and maintained by Schwann cell membranes wrapped compactly around the axon. Myelin is in turn coated by a basal lamina, outside of which lies the endoneurium, which contains fibroblasts, blood vessels, and a few macrophages, which is ultimately surrounded by a multilayered cellular tube, the perineurium. This assembly of axons, Schwann cells, and connective tissue makes up a nerve. Injury to the facial nerve may disrupt the nerve architecture to varying degrees depending on the extent of insult. Seddon and Sunderland classified the fundamental types of nerve injury based on the extent of disruption of the endoneurium and perineum as well as the integrity of the axon. The imperfect response of peripheral nerves to injury underlies the clinical manifestation of synkinesis.

In response to injury, both neurons and Schwann cells switch to a cell state suited for nerve repair and regeneration. In damaged neurons, the signal switch to repair mode is heralded by the activation of an extensive gene program that facilitates axonal regeneration, a response classically referred to as the cell body response. Similarly, Schwann cells change into a phenotype primed for repair to facilitate nerve regeneration. This transformation to a repair-sustaining Schwann cell phenotype is mediated by a complex cellular process that is time dependent. Early after nerve injury, the Schwann cells distal to the damaged area lose contact with axons as they degenerate. The loss of contact is by itself a trigger for Schwann cell transformation. Invading macrophages secrete bioactive factors which, together with the loss of axonal contact, influence the change in surrounding Schwann cells toward a repair type cell.

Within their original basal lamina tubes, these transformed repair type Schwann cells aid in clearing degenerated myelin by autophagy. The released cytokines call in macrophages for further myelin clearance. The Schwann cells elongate forming regeneration tracts, Bunger bands, which guide regenerating axons towards their target. Axons that successfully grow across the regeneration zone induce transformation of the repair Schwann cells back to the myelin phenotype and become ensheathed in a new myelin membrane. This remarkable, adaptive injury response of neurons and Schwann cells is clinically inadequate in severe and long-lasting injuries. There are several reasons for this inadequacy. ^, First, the early regeneration-enabling environment that enables nerve regeneration is unstable as the number Schwann cell dwindles. The number of cells that can be isolated from nerves after 6 months of chronic denervation is only 10% to 15% of that obtained at 4 weeks. Second, with prolonged denervation, the remaining Schwann cells become less effective with surviving cells gradually down-regulating their repair phenotype, followed by the death of cells that have by that time lost most of their regeneration-supportive properties. Clinically suboptimal reinnervation of the facial muscles manifest as hypotonus, hypertonia, myokymia, or synkinesis.