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Pathophysiology of Blepharospasm and Hemifacial Spasm
Mark Hallett, M.D.
Human Motor Control Section
Blepharospasm is a focal dystonia characterized by excessive involuntary closure of the eyelids. Typically, this is due to spasm of the orbicularis oculi muscles. Involuntary closure of the eyelids can also be caused by failure of levator contraction, a condition known as apraxia of lid opening or motor persistence of the orbicularis oculi muscles.(Aramideh et al., 2001; Tozlovanu et al., 2001) These two conditions may co-exist. The focal dystonia can spread to the rest of the face and then it is called Meige syndrome. Involvement of the perioral muscles and jaw would be called oromandibular dystonia. Patients may also be affected by other focal dystonias such as cervical dystonia (spasmodic torticollis), spasmodic dysphonia or focal hand dystonia (writer’s cramp). Most epidemiological studies suggest that BEB is an autosomal dominant disorder with reduced penetrance of about 5%.(Hallett and Daroff, 1996) It does not seem to be a forme fruste of the generalized dystonia resulting from a gene defect at the DYT1 site.
The orbicularis oculi (OO) muscle is innervated unilaterally from the facial nucleus and the levator palpebrae (LP) muscle is innervated bilaterally from the central caudal subdivision of the oculomotor nucleus. The synaptic circuitry of the input to these brainstem nuclei is being worked out.(May et al., 2002; May and Porter, 1998) Primary sensory afferents from the cornea and eyelid terminate most densely in the medullary spinal trigeminal nucleus. The pars caudalis of the spinal trigeminal nucleus sends excitatory projections to the OO motoneurons, ipsilaterally. The principal trigeminal nucleus sends excitatory projections to the OO motoneurons and inhibitory projections to the LP motoneurons, bilaterally. This is the appropriate circuitry for the trigeminal blink reflex, which should occur with orbicularis oculi contraction and levator inhibition.
There has been a new breakthrough in understanding of the cortical innervation of the eyelids. While there has been the clinical notion that there is bilateral innervation from the primary motor cortex, anatomical studies have failed to show either contralateral or ipsilateral innervation.(Jenny and Saper, 1987) In a study of rhesus monkeys, first the musculotopic organization of the facial nucleus was defined by injecting fluorescent retrograde tracers into individual muscles of the upper and lower face.(Morecraft et al., 2001) Then anterograde tracers were placed in different motor regions of the cortex to see the innervation of these defined regions of the facial nucleus. The orbicularis oculi region was innervated mostly by the rostral cingulate motor region (called M3). Such a pattern explains the upper face sparing in typical middle cerebral artery stroke since the descending axons from the rostral cingulate motor cortex would likely be spared.
The physiology of spontaneous blinking and voluntary blinking is not well known. There have been detailed investigations, however, of the blink reflex. Most commonly, the reflex is elicited with electrical stimulation of the supraorbital nerve. The OO blink reflex consists of two components: an early, first response (R1) and a late, second response (R2). R1 is a brief unilateral response, ipsilaterally to the stimulated side, with a latency of about 10 ms. R2 has a latency of about 30 ms, is longer in duration and appears bilaterally. The common afferent limb of OO R1 and R2 is the ophthalmic (first) trigeminal division, while the common efferent limb is the facial (seventh) nerve and its intermediate subnucleus of the facial nucleus.
In close connection with the excitatory OO responses the LP acts antagonistically with an inhibitory response. To record from LP, a bipolar needle electrode can be inserted through the skin in the middle portion of the upper eyelid and directed toward the LP while the subject looks downward and keeps the eyelids gently closed. The subject is then asked to open the eye. This maneuver results in tonic EMG activity of LP. The inhibitory LP response can be examined together with OO responses and consists of two silent periods (SPs): an early, brief, first bilateral (SP1) and a late, longer, bilateral second SP (SP2). Ipsilateral to the stimulation, R1 of the OO response occurs during SP1, while the contralateral SP1 has no R1 counterpart. SP2 appears bilaterally and concurrently with the bilateral R2.
Based on analysis of human lesions, the central pathways through which OO responses are mediated are relatively well known, while the pathways for the LP responses are not. Impulses for R1 and R2 enter through the first trigeminal division into the pons. For R1 they are conducted through the pons and are relayed via an oligosynaptic arc consisting of one or two interneurons located in the vicinity to the main sensory trigeminal nucleus. From there, fibers impinge upon motoneurons within the intermediate subnucleus of the motor facial nucleus. For R2, afferent impulses are conducted through the descending trigeminal spinal tract in the pons and dorsolateral medulla oblongata before they reach the caudal spinal nucleus. From there, impulses are relayed via a medullary ascending pathway ipsilateral to the stimulated side and an ascending route that crosses the midline before it ascends contralaterally. Both routes connect with the facial nerve nucleus in the pons on the two sides. The trigemino-facial connections are thought to pass through the lateral tegmental field medial to the spinal trigeminal nucleus. The ascending pathways originate at the level of the lower medulla oblongata and the crossing of the contralateral path takes place at the level of the lower third of the medulla oblongata. The OO reflex can be influenced by suprasegmental structures, including the cortex and basal ganglia.
For the inhibitory LP reflex, preliminary data derived from patients with vascular brainstem lesions suggest that impulses mediating SP1 travel through the mid-pons and those for SP2 through the medullary spinal trigeminal tract (Ongerboer de Visser and Aramideh, unpublished data). A midbrain lesion may impair impulses ascending to the LP motoneuron nucleus. With such a lesion, antagonistic actions between LP inhibition and OO excitation are disturbed. Cerebral infarction may reduce or even remove SP2 inhibition similar to the effects on R2.
While the etiology of dystonia is still unknown, one theme of considerable interest currently is the concept that dystonia arises from aberrant brain plasticity (Berardelli et al., 1998; Hallett, 1998; Hallett, 2001). The brain is capable of changing by processes such as altering synaptic strength and rewiring synaptic connections. Changes ordinarily occur for a number of reasons, for example, the learning of a new motor skill or repetitive use of a body part. It would then be possible for some plastic changes to be aberrant. For example, writing for 5 hours per day might lead to deranged organization of the motor system and dystonic hand movements. Plastic changes are facilitated by reduction in the amount of inhibition in brain circuits, so that if inhibition were for any reason diminished, there might be a propensity for increased change and possibly aberrant change.
A possible animal model of dystonia was created in nonhuman primates with synchronous, widespread sensory stimulation to the hand during a repetitive motor task.(Byl et al., 1996; Byl et al., 1997) Over a period of months, the animals’ motor performance deteriorated. After development of the movement disorder, the primary somatosensory cortex was mapped, and each cell was analyzed for the region of the body that activated the cell, its “receptive field.” Receptive fields in area 3b were increased ten- to twenty-fold, often extending across the surface of two or more digits. The investigators suggested that synchronous sensory input over a large area of the hand can lead to remapping of the receptive fields and subsequently to a movement disorder. However, these tasks also involve repetitive movements, which can lead to remapping of the motor system directly.
Some trigger appears to initiate BEB in individuals genetically and/or environmentally predisposed to dystonia. Animal models of blepharospasm mimic this pattern by artificially creating a “predisposing neuronal environment” and then testing various triggers. The predisposing condition in a rat model of blepharospasm(Schicatano et al., 1997) is an approximately 30% unilateral loss of dopamine-containing neurons in the substantia nigra pars compacta. In the presence of the reduced inhibition within the trigeminal blink circuits created by this dopamine loss,(Basso et al., 1996) weakening the orbicularis oculi muscle triggers spasms of lid closure and other symptoms characteristic of blepharospasm in humans. Recent studies have examined how orbicularis oculi weakening might be a trigger for blepharospasm.
Weakening the orbicularis oculi creates two difficulties that initiate compensatory motor learning by blink neural circuits. First, the difference between the planned and the actual eyelid movement caused by orbicularis oculi weakness increases the drive on reflex blink circuits to compensate for muscle weakness. In other words, the nervous system learns a new relationship between blink-evoking stimulus magnitude and the motor drive required to generate the correct size blink. Second, muscle weakness decreases tear film distribution across the cornea, which leads to corneal irritation. Corneal irritation and dry eye profoundly alter trigeminal reflex blink circuits. Normally, a single trigeminal stimulus elicits a single reflex blink. With dry eye, however, this same trigeminal stimulus elicits a reflex blink and a series of additional blinks that occur with a constant interblink interval, blink oscillations (Evinger, unpublished data). Dry eye might be a model for the eye irritation that appears to trigger blepharospasm. The blink oscillations created by the trigeminal complex in response to eye irritation may be a slower version of the repetitive OO contractions that characterize spasms of lid closure in some patients with blepharospasm. Eye irritation may also be responsible for photophobic responses.
A human correlate to the rat model (Schicatano et al., 1997) is the observation of patients with facial palsy who developed blepharospasm.(Baker et al., 1997; Chuke et al., 1996) If this is a good model, then facial weakness should cause an increase in the excitability of reflex blinking. The size of the R2 response on the normal side in 30 normal volunteers and 68 patients with idiopathic or herpetic peripheral facial palsy was investigated.(Manca et al., 2001) In patients, the reflex R2 responses were larger when the stimuli were applied to the contralateral trigeminal nerve than when the stimuli were applied to the ipsilateral trigeminal nerve. This was significantly different from what was observed in control subjects, who showed larger responses to ipsilateral than to contralateral nerve stimulation. A second study reported the blink reflex recovery curve in normal subjects and patients with Bell's palsy who either recovered facial strength or who had persistent weakness.(Syed et al., 1999) Blink reflex recovery was enhanced in patients with residual weakness but not in patients who recovered facial strength. Facial muscles on both the weak and unaffected sides showed enhancement. In patients with residual weakness, earlier blink reflex recovery occurred when stimulating the supraorbital nerve on the weak side. Sensory thresholds were symmetric. The authors concluded that enhancement of blink reflex recovery is dependent on ongoing facial weakness. Faster recovery when stimulating the supraorbital nerve on the paretic side, similar to the results of the other study,(Manca et al., 2001) suggests that sensitization may be lateralized, and suggests a role for abnormal afferent input in maintaining sensitization. Interneurons in the blink reflex pathway are the best candidates for the locus of this plasticity.
The observations in animals and humans, that orbicularis oculi weakness may predispose to BEB, raises a point of concern about the use of botulinum toxin for therapy. Might not induced weakness of the eyelids make the situation worse? From clinical experience, however, botulinum toxin certainly improves most patients and the improvement can be sustained for as long as the drug is given, in many patients more than a decade. The current conclusion is that while weakness might help trigger the development of BEB, further weakening does not appear to aggravate the condition.
Patients with BEB may have a sensory trick, such as touching the face, that improves their eyelid spasms. The physiology of these tricks is unknown. The R2 of the blink reflex is reduced, but the blink reflex recovery curve is not affected, during a sensory trick.(Gomez-Wong et al., 1998a) Patients who have a sensory trick are more likely to have a significant effect of pre-pulse inhibition with sensory stimulation of the hand.(Gomez-Wong et al., 1998b) This appears to indicate a greater influence of sensory input on eyelid control.
Neuroimaging studies support the general concept that there is pathology in the basal ganglia and its circuitry. PET studies have identified movement-free patterns of covariance in fluoro-deoxyglucose (FDG) uptake in the brains of people that are non-manifesting carriers of an autosomal dominant childhood onset torsion dystonia with defects in the DYT1 gene, as well as in manifesting carriers of DYT1.(Eidelberg et al., 1998) A similar covariance pattern, involving basal ganglia, was also seen in patients with essential blepharospasm.(Hutchinson et al., 2000) Both of these studies identified the abnormal covariance pattern in sleeping subjects, thereby eliminating the confound of the afferent effects of the movement on local brain metabolism. When blepharospasm is active during the scanning, then there are increases in glucose metabolism in pons and cerebellum suggesting that these regions either are important in generating the movements or are involved in afferent activity produced by the movements.(Hutchinson et al., 2000) In another study of BEB, increased glucose metabolism was found in the striatum and thalamus.(Esmaeli-Gutstein et al., 1999) An MRI study found approximately 10% enlargement of putamen in people with either hand or facial dystonia,(Black et al., 1998) and a magnetic resonance spectroscopy study showed a loss of N-acetylaspartate in basal ganglia.(Federico et al., 1998)
Several clues from neuroimaging studies implicate striatal dopamine dysfunction or changes in striatal-cortical pathways in dystonia. Relevant findings come from animal studies as well as from neuroimaging studies in humans. Nonhuman primates treated with intracarotid MPTP developed transient hemidystonia prior to chronic hemiparkinsonism.(Perlmutter et al., 1997b) This transient dystonic phase corresponds temporally with a decreased striatal dopamine content and a transient decrease in D2-like receptor number.(Todd and Perlmutter, 1998) The reduction in striatal dopamine receptors matches closely the reductions of in vivo striatal dopamine receptor binding found in humans with primary focal cranial or hand dystonia(Perlmutter et al., 1997a) and subsequently confirmed in cervical dystonia.(Naumann et al., 1998) These changes suggest dysfunction of the D2-like receptor mediated indirect pathway in the basal ganglia with a loss of ability to inhibit unwanted motor activity “surrounding” an intended movement.(Mink, 1996)
PET can be used to measure the brain responses to specific dopamine agonists. Early studies have demonstrated appropriate dose response and specificity of such techniques for specific D2 and D1 dopamine agonists.(Black et al., 1997; Black et al., 2000; Hershey et al., 2000) These pharmacologic activation methods may provide additional insights into the function of selected dopaminergic pathways in dystonia, as they have already in Parkinson disease.(Hershey et al., 1998)
There have been only few functional neuroimaging studies of sensorimotor processing in patients with focal dystonias, including blepharospasm. In these studies, several different groups of patients with dystonia have reduced vibration-induced blood flow responses in sensorimotor cortex and supplementary motor area.(Feiwell et al., 1999; Tempel and Perlmutter, 1993) Motor activation paradigms in focal or generalized dystonia also show abnormal activation in cortical regions,(Ceballos-Baumann et al., 1995; Ibanez et al., 1999) but there have not been studies with BEB patients. These studies do not tell a clear story yet.
Hemifacial spasm is characterized by synchronous spasms of one side of the face. The spasms are usually very brief, but can occur in runs and are occasionally tonic. The disorder typically begins around the eye and this often is the most symptomatic aspect to the disorder. The disorder can be bilateral, but then the two sides of the face do not spasm in synchrony. Cases do seem to be more common in persons of Asian origin (Poungvarin et al., 1995). Twitching can be brought out by facial muscle contraction. The disorder clearly involves the facial nerve, and the etiology appears to be most frequently (94%) a compression of the nerve by a blood vessel just as the nerve leaves the brainstem. About 4% of cases are due to a tumor compressing the nerve. Biopsy of the compressed nerve shows demyelination. Definitive treatment can be by surgery to decompress the nerve (Samii et al., 2002), although many patients prefer botulinum toxin treatment which can be highly effective (Defazio et al., 2002; Jost and Kohl, 2001; Poungvarin et al., 1995).
Although the etiology is relatively clear, the pathophysiology is still not certain. There are two main hypotheses and there are good data to support each.
Nerve origin hypothesis. This hypothesis proposes that the abnormal discharges producing the spasms comes from the region of demyelinated nerve under the compression (Nielsen, 1984a; Nielsen, 1984b; Nielsen and Jannetta, 1984). It is known that demyelinated nerve can produce spontaneous discharges, called ectopic discharges. In addition, there can be lateral transmission of activity between demyelinated nerve axons, called ephaptic transmission. Ephaptic transmission can be responsible for involvement of much of the face. It is also possible for activity in demyelinated axons with ephaptic transmission for there to be trains of activity produced following a single action potential. These phenomena could well explain many of the clinical features.
Additionally, there are physiological studies that are consistent. If a branch of the 7th nerve is stimulated, in these patients there will be late responses seen in muscles innervated by other branches at latencies consistent with ephaptic transmission at the site of demyelination. This phenomenon is not influenced with botulinum toxin treatment (Geller et al., 1989). Studies of the variability of transmission of this effect, using the technique of jitter, are consistent with only the neuromuscular junction and no intervening synapses (Sanders, 1989).
The final argument in favor of the nerve origin hypothesis is the fact that the disorder very rapidly ameliorates following decompression.
Facial nucleus hypothesis. By this theory, the peripheral lesion leads to hyperexcitability of the facial nucleus and the discharges arise there. There is a rat model where such a phenomenon has been demonstrated. Perhaps the most persuasive argument for this hypothesis is that there is hyperexcitability of the blink reflex in hemifacial spasm, and this must involve brainstem synaptic circuitry. By this theory, the late responses seen with stimulation of branches of the nerve are enhanced F-waves (Ishikawa et al., 1994; Roth et al., 1990). Lastly, while the calculations deal in differences of only a millisecond or two, the conduction times may be more consistent with transmission all the way to the brainstem and back, rather than just to the site of demyelination (Moller, 1987; Moller and Jannetta, 1984).
Conclusion The debate is still going on. I personally favor the nerve origin hypothesis noting that there will also be some increased excitability of the nucleus.
The blepharospasm part of this syllabus is modified from a review in Neurology that summarizes a workshop supported by the BEBRF (Hallett, 2002).
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