The stimulus intensity modifies the blink reflex recovery cycle in healthy subjects and in blepharospasm

OBJECTIVE: The excitability of human brainstem interneurons is measured by the blink reflex recovery cycle and is abnormal in blepharospasm. We wondered whether the results of this paradigm depend on the stimulus intensity. METHODS: We investigated the blink reflex recovery cycle in 13 healthy control subjects and in 13 patients with blepharospasm (7 of them treated with botulinum toxin) using 4 levels of stimulus intensity (5, 12, 19 and 26 mA) and two interstimulus intervals (ISIs, 150 or 250 ms). RESULTS: In all groups the inhibition of the second R2 response was reduced with strong stimulus intensities: In controls, the inhibition of the second R2 decreased significantly (e.g. young controls, ISI 150 ms, from 89.6+/-15.6% at 5 mA to 21.9+/-49.7% at 26 mA, mean+/-standard deviation). In patients the R2 inhibition found at 5 mA was converted in an R2 facilitation at 26 mA, irrespective of the status of treatment. In addition, the patients' results at 5 mA did not differ significantly from the controls' results at 26 mA. CONCLUSIONS: The R2 inhibition and its sensitivity to detect abnormal interneuronal excitability depend on the stimulus intensity, which may act by modifying the excitability of the R2 interneurons.     

Blepharospasm associated with multiple system atrophy: a case report and review of the literature

Although blepharospasm has been occasionally associated with parkinsonism, it has rarely been reported in patients with multiple system atrophy (MSA). We report a 65-year-old woman with MSA who developed blepharospasm seven years after onset, rendering her functionally blind. Clinical course and the findings of magnetic resonance imaging indicated cerebellar type MSA. The blink reflex studies showed prolonged R2 response and enhanced recovery cycle, indicating an increased excitability of the brainstem interneurons. These results suggest that pathophysiology of blepharospasm in MSA is similar to that of essential blepharospasm. Recognition of blepharospasm in MSA patients is important, as blepharospasm is a treatable feature in this otherwise intractable disorder.     

Electrical activation of the orbicularis oculi muscle does not increase the effectiveness of botulinum toxin type A in patients with blepharospasm

Background: Our primary aim in this study was to determine whether electrically induced activation of the injected muscle increases effectiveness of botulinum type A toxin (BonT‐A) in patients with blepharospasm (BPS). The second aim was to assess the safety of BonT‐A by investigating whether BonT‐A injection alters the excitability of blink reflex circuits in the brainstem. Methods: Twenty‐three patients with BPS received BonT‐A (Botox) injected bilaterally into the orbicularis oculi muscle at a standard dose. In 18 patients, electrically induced muscle activation of the orbicularis oculi muscle on one side was performed for 60 min (4 Hz frequency) in a single session, immediately after BonT‐A injection and in five patients for 60 min once a day for five consecutive days. The severity of BPS was assessed clinically with the BPS score. Compound muscle action potential (cMAPs) from the orbicularis oculi muscles were measured bilaterally. The blink reflex recovery cycle was studied at interstimulus intervals of 250 and 500 ms. Participants underwent clinical and neurophysiological assessment before BonT‐A injection (T0) and 2 weeks thereafter (T1). Results: Compound muscle action potential amplitude significantly decreased at T1 but did not differ between stimulated and non‐stimulated orbicularis oculi in the two groups. BonT‐A injection left the blink reflex recovery cycle tested on the stimulated and non‐stimulated sides unchanged. Conclusions: In patients with BPS, the electrically induced muscle activation neither increases the effectiveness of BonT‐A nor produces larger electrophysiological peripheral effects. The lack of BonT‐A‐induced changes in the blink reflex recovery cycle provides evidence that BonT‐A therapy is safe in patients with BPS.     

Pretarsal blepharospasm: Clinical and electromyographic characteristics

ObjectiveTo describe the clinical and electromyographic characteristics of blepharospasm caused by selective involvement of the pars pretarsalis of the orbicularis oculi muscle.MethodsClinical assessment and simultaneous electromyographic recordings from levator palpebrae superioris and pars orbitaria and pretarsalis of orbicularis oculi muscles were performed in patients with blepharospasm and primary failure to botulinum toxin injections. Patients with selective abnormal electromyographic activity of the pars pretarsalis of the orbicularis oculi muscle were identified and treated with selective pretarsal injections of botulinum toxin.ResultsWe found 24 patients with pretarsal blepharospasm confirmed by the electromyographic assessment. All of them were functionally blind. Three clinical-electromyographic patterns were identified: (a) Impairment of eyelid opening; (b) Increased blinking; (c) Spasms of eye closure combined with varying degrees of excessive blinking and impairment of eye-opening. Pretarsal injections of botulinum toxin induced a significant improvement in all patients and 50 % regained normal or near-normal vision. The clinical improvement was sustained after repeated pretarsal injections.ConclusionsPretarsal blepharospasm can be suspected on clinical grounds and it can be confirmed by electromyographic recordings.SignificanceRecognition of this type of blepharospasm is important because of its excellent response to botulinum toxin injections applied into the pretarsal part of the orbicularis oculi muscle.     

Auditory startle response in cervical dystonia.

The excitability of brainstem neurons is abnormally enhanced in patients with cervical dystonia (CD), but the extend of such abnormality is not known. We examined whether patients with CD showed abnormalities in the auditory startle response (ASR), a brainstem reflex elicited by an unexpected loud stimulus. Thirteen patients with CD were investigated 3 months after botulinum toxin treatment. Thirteen healthy volunteers served as controls. ASRs were elicited by binaural high-intensity auditory stimuli. Reflex electromyographic (EMG) activity was recorded simultaneously with surface electrodes bilaterally from masseter, orbicularis oculi, sternocleidomastoid, and biceps brachii muscles. We found that ASR onset latencies were similar for patients and controls. CD patients had significantly lower ASR probabilities than controls (P = 0.007). ASR area under the curve was significantly smaller in CD patients (P = 0.017). Similar to controls, patients showed a significant habituation of ASR (P < 0.001, each); however, CD patients showed a prolonged tonic or phasic EMG activity after the initial ASR that was not observed in controls. Normal latencies and recruitment pattern indicate a preserved organization of intrinsic neural pathways mediating ASR in CD. Reduced ASR probability and magnitude as well as prolonged EMG activity after the proper startle response corroborate and extend previous findings on brainstem dysfunction in CD.     

Electromyography and recovery of the blink reflex in involuntary eyelid closure: a comparative study.

Electromyographic (EMG) activity of orbicularis oculi and levator palpebrae muscles was recorded to study the origin of involuntary eyelid closure in 33 patients. The evoked blink reflex in all patients and in 23 controls was also studied. To examine the excitability of facial motoneurons and bulbar interneurons in individual patients and to compare the results with EMG findings, R1 and R2 recovery indices were calculated in all subjects, as the average of recovery values at 0.5, 0.3, and 0.21 second interstimulus intervals. Based on EMG patterns, the patients were divided into three subclasses: EMG subclass 1, 10 patients with involuntary discharges solely in orbicularis oculi muscle; EMG subclass 2, 20 patients with involuntary discharges in orbicularis oculi and either involuntary levator palpebrae inhibition or a disturbed reciprocal innervation between orbicularis oculi and levator palpebrae; EMG subclass 3, three patients who did not have blepharospasm, but had involuntary levator palpebrae inhibition in association with a basal ganglia disease. The total patient group showed an enhanced recovery of both R1 and R2 components compared with controls. Although 30 out of 33 patients had blepharospasm (EMG subclasses 1 and 2), R1 recovery index was normal in 64% and R2 recovery index was normal in 54%. Patients with an abnormal R2 recovery index had an abnormal R1 recovery index significantly more often. All patients from EMG subclass 1 had an abnormal R2 recovery index, whereas all patients from EMG subclass 3 had normal recovery indices for both R1 and R2 responses. Seventy five per cent of the patients from EMG subclass 2 had normal recovery indices. The results provide further evidence that physiologically blepharospasm is not a homogeneous disease entity, and indicate that different pathophysiological mechanisms at the suprasegmental, or segmental level, or both are involved.     

The Effects of Botulinum Toxin a on Ephaptic Transmission in Idiopathic Hemifacial Spasm

Objective: Lateral spreading and synkinetic responses of blink reflex are a sign of ephaptic transmission in idiopathic hemifacial spasm (HFS). The aim of this study was to evaluate the effect of botulinum toxin A (Btx A) on ephaptic transmission in idiopathic HFS. Methods: Thirty-three patients with idiopathic HFS were investigated. Btx A was injected only into the affected orbicularis oculi (OC) muscle. Electrophysiological studies were performed before and three weeks after the Btx A injection. Results: After Btx A, the latencies of motor response and blink reflexes elicited from the OC muscle were significantly increased. The lateral spreading was not obtained in the OC muscle, while the orbicularis oris muscle response was not changed. There were no significant differences in the synkinetic responses of blink reflex. During needle EMG examination, positive sharp waves and fibrilation potentials were observed due to chemodenervation only in the OC muscle. Conclusion: Btx A affects only the neuromuscular junctions of the injected muscle and has no effect upon ephaptic transmission.     

Effect of photic conditioning on blink reflex recovery function in blepharospasm

Patients with blepharospasm may have selective sensitivity to photic stimuli, for their symptoms are often aggravated after exposure to brightness. To investigate the pathophysiology underlying this phenomenon, we compared the effects of electric and photic conditionings on electrically-evoked blink reflex in 21 patients with blepharospasm and 11 age-matched control subjects. With electric conditioning, R1 was facilitated at inter-stimulus intervals (ISIs) of up to 100 ms in both groups. R2 was inhibited at all ISIs longer than 20 ms in the normals, but to a much lesser extent in the patients, suggesting increased excitability of the multi-synaptic reflex pathway. Compared to electric conditioning, photic conditioning was less potent in inhibiting R2 in the normals. In contrast, photic conditioning in the patients produced R2 inhibition as powerful as electric conditioning. These findings indicate that, in patients with blepharospasm, photic input has a relatively more profound inhibitory effect on the test blink reflex than electric conditioning as compared with normal subjects. The greater susceptibility of the brainstem interneurons to photic conditionign in blepharospasm may be related to the clinically-observed light sensitivity.     

Alterations in excitatory and inhibitory brainstem interneuronal circuits in fibromyalgia: Evidence of brainstem dysfunction

ObjectivePatients with fibromyalgia syndrome (FMS) perceive stimuli differently and show altered cortical sensory representation maps following peripheral stimulation. Altered sensory gating may play a causal role.MethodsBlink reflex, blink reflex excitability recovery, and prepulse inhibition of the blink reflex – representing brainstem excitability – were assessed in 10 female patients with FMS and 26 female healthy controls.ResultsUnconditioned blink reflex characteristics (R1 latency and amplitude, R2 and R2c latency and area-under-the-curve) did not differ significantly between patients and controls. Blink reflex excitability recovery was enhanced in patients versus controls at all intervals tested. Prepulses significantly suppressed R2 area and increased R2 latency in patients and controls. However, R2 area suppression was significantly less in patients than in controls (patients: to 80.0 ± 28.9%, controls: to 47.8 ± 21.7%). The general pattern of corresponding changes in R2c was similar.ConclusionsBlink reflex is normal, whereas blink reflex excitability recovery is enhanced and blink reflex prepulse inhibition is reduced in patients with FMS, suggesting functional changes at the brainstem level in FMS.SignificanceReduced blink reflex prepulse inhibition concurs with altered sensory gating in patients with FMS.     

The management of blepharospasm and hemifacial spasm

Summary The aetiology of blepharospasm and hemifacial spasm is different, but both produce involuntary eye closure and facial movements which do not respond to systemic drug treatment. The introduction of therapeutic focal muscle weakening with botulinum toxin injections in the early 1980s appeared to offer great promise in the management of these conditions. In this paper the results of botulinum toxin treatment of 234 patients with blepharospasm and 73 patients with hemifacial spasm over a 7-year period have been analysed. Most patients receive sustained benefit from repeated injections whilst side-effects become less frequent. A clinically recognisable subgroup of patients with blepharospasm respond poorly and may be better treated surgically.     

Blink reflex recovery in facial weakness: an electrophysiologic study of adaptive changes

OBJECTIVE: To study the electrophysiologic effects of unilateral facial weakness on the excitability of the neuronal circuitry underlying blink reflex, and to localize the site of changes in blink reflex excitability that occur after facial weakness. BACKGROUND: Eyelid kinematic studies suggest that adaptive modification of the blink reflex occurs after facial weakness. Such adaptations generally optimize eye closure. A report of blepharospasm following Bell's palsy suggests that dysfunctional adaptive changes can also occur. METHODS: Blink reflex recovery was evaluated with paired stimulation of the supraorbital nerve at different interstimulus intervals. Comparisons were made between normal control subjects and patients with Bell's palsy who either recovered facial strength or who had persistent weakness. RESULTS: Blink reflex recovery was enhanced in patients with residual weakness but not in patients who recovered facial strength. Facial muscles on 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. CONCLUSION: Enhancement of blink reflex recovery is dependent on ongoing facial weakness. Faster recovery when stimulating the supraorbital nerve on the paretic side 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.     

Blink reflex excitability cycle in hemifacial spasm

We studied electrically elicited blink reflex responses in patients with hemifacial spasm (HFS) by applying single isolated, as well as paired (conditioning and test), stimuli at both sides of the face. Responses after single stimuli were of larger size on the side of the spasm compared with the uninvolved side and controls. With paired stimuli, the inhibitory effect of the conditioning stimuli upon the test stimuli late response (R2), which was always observed in normals, was significantly less pronounced at short interstimuli intervals. This resulted in an enhanced recovery curve of R2, which was observed on the side of the spasm and the contralateral, clinically normal side. Patients with longer disease duration showed more striking abnormalities of the recovery curve. We suggest that there is enhanced excitability of facial motoneurons and of those brainstem interneurons that mediate the blink reflex pathway in patients with HFS.     

Functional end-plate recovery in long-term botulinum toxin therapy of hemifacial spasm: a nerve conduction study

Botulinum toxin type-A is currently thought to be effective and safe for hemifacial spasm (HFS). The pre-synaptic block of acetylcholine release at the neuromuscular junction induces depression of orbicularis oculi muscle compound motor action potential (CMAP). The aim of our study was to evaluate at what extent end-plate functional recovery is possible even in botulinum toxin treatments lasting up to 15 years. We examined 81 outpatients with primary HFS (mean treatment duration = 7.2 ± 4.2 years) who underwent neurophysiologic study, once clinical effect of the previous treatment had vanished. The mean CMAP amplitude, mean rectified amplitude of response 1 (R1) of the blink reflex and area of response 2 (R2) of treated orbicularis oculi muscle were measured in comparison to the controlateral side. Mean amplitude of the above mentioned parameters was slightly lower (about 20%; p < 0.001) in the treated side at the end of the follow-up period (4.7 ± 1.7 months). The CMAP amplitude reduction weakly correlated with the interval from last treatment, while other neurophysiologic parameters did not change due to treatment duration or total toxin amount. Our study demonstrates that botulinum toxin affects compound motor action potential and blink-reflex responses for at least 4–5 months in HFS patients. The residual block is slight and does not increase with repeated injections after several years of treatment. Our study, beside confirming the long-term efficacy of botulinum toxin treatment for HFS, provides neurophysiologic evidence that therapeutic effect may be obtained without hindering the regenerative potential of the nerve-muscle complex.     

Blink reflex in Parkinson's disease with levodopa-induced dyskinesia

We have studied the electrically evoked blink reflex (R1 and R2 components) in 40 parkinsonian patients with levodopa-induced dyskinesia (15 with facial dyskinesia, 13 with limb-truncal dyskinesia and 12 with mixed dyskinesia). R2 latencies (both ipsilateral and contralateral) were significantly prolonged in dyskinetic patients. These findings are indicative of decreased excitability of brainstem interneurones in the dyskinetic parkinsonians. We found no correlation between the neurophysiological pattern of blink reflex and the localization of dyskinesia.     

Cervical dystonia: Improved treatment response to botulinum toxin after referral to a tertiary centre and the use of polymyography

RationaleCervical dystonia is the most common form of (primary) dystonia. The first line of treatment for cervical dystonia is intramuscular injections with botulinum toxin. To optimise the response to botulinum toxin proper muscles selection is required. Pre-treatment polymyographic EMG in addition to clinical evaluation is hypothesised to be a good tool to improve muscle selection and treatment outcome.ObjectiveTo determine the efficacy of botulinum toxin treatment after adjacent polymyographic EMG in cervical dystonia patients referred to our tertiary referral centre with an unsatisfactory response to botulinum toxin treatment elsewhere.MethodsWe performed a retrospective analysis of 40 consecutive second opinion cervical dystonia patients. Standard polymyographic EMG was performed before treatment. We retrieved the Tsui scores and subjective evaluations from the first visit, after 12 weeks and after one year of treatment. In addition, we assessed the final outcome of treatment in our centre based on the records and asked the patients for their personal opinion about the effect of referral to our centre on their treatment response.ResultsAfter one year of treatment there was a significant improvement on both the Tsui scores (p < 0.01) and the subjective treatment evaluation (p < 0.001.) On their last visit 60% of the patients still continued treatment with a reasonable to good response.ConclusionA substantial amount of CD patients with an unsatisfactory response to botulinum toxin improved after polymyography and subsequent treatment with botulinum toxin in a tertiary referral centre.     

Alteration of central motor excitability in a patient with hemimasticatory spasm after treatment with botulinum toxin injections.

Hemimasticatory spasm (HMS) is a condition characterized by paroxysmal involuntary contraction of masticatory muscles. We performed an electrophysiological investigation of a single patient with HMS to identify any pathophysiological changes associated with the condition. We identified a delayed M wave and jaw jerk on the affected side and an absent masseteric silent period during spasm. Botulinum toxin injections successfully treated the clinical symptoms and resulted in a significant reduction in the excitability of the blink reflex recovery cycle. These data suggest that HMS may be due to ectopic activity in the motor portion of the trigeminal nerve that is capable of inducing changes in the excitability of central reflex pathways. These changes can be altered by successful treatment with botulinum toxin.     

Muscle activity changes in spasmodic torticollis after botulinum toxin treatment

We assessed electromyographic (EMG) activity in neck muscles before and after botulinum toxin injections in 28 patients with spasmodic torticollis (ST) to investigate possible changes in muscle activation after treatment. A six-channel EMG with surface electrodes was used to record activity of sternocleiodomastoid, trapezius and splenius capitis bilaterally. Objective benefit (>25% reduction in Tsui's score) occurred in 22 patients (78%). Of the 168 muscles studied before botulinum toxin injections, 90 presented EMG activity. Sixty-eight of these muscles were injected and a decrease in EMG activity occurred in 44 (65%) of them. A decrease in EMG activity was also detected in 15 (68%) of those which were not injected. On the other hand, 70 of the 78 muscles without pre-botulinum toxin EMG activity were not injected. However, after treatment, EMG activity increased in 37 (52%) of these muscles. These changes involved 18 patients and occurred without concomitant change in the main direction of head deviation despite the improvement observed in most cases. These results suggest that in ST head turning results from an abnormal central motor program which results in non-specific neck muscle activation.     

Botulinum toxin in the treatment of focal dystonias: own experience with botulinum toxin

During the last 5 years, 75 patients with focal dystonias were longitudinally treated with injections of botulinum toxin A. Each patient received 2-6 injections. The improvement was assessed after each injection and estimated as significant after 68.47% of injections, as mediocre after 23.42% of injections and none after 8.11% of the injections. The most significant improvement was obtained in patients with blepharospasm and hemifacial spasm, the worst effect was obtained in spasmodic torticollis. Varying responses were observed following repeated injections of botulinum toxin, the clinically assessed improvement did not decrease after successively applied doses. Side-effects occurred after 18% of the injections and were mostly mild and disappeared after short time. This study confirms the usefulness of botulinum toxin, which is an effective and safe treatment of focal dystonias.     

Long‐term depression‐like plasticity of the blink reflex for the treatment of blepharospasm

Our previous work showed a beneficial therapeutic effect on blepharospasm using slow repetitive transcranial magnetic stimulation, which produces a long‐term depression (LTD)‐like effect. High‐frequency supraorbital electrical stimulation, asynchronous with the R2 component of the blink reflex, can also induce LTD‐like effects on the blink reflex circuit in healthy subjects. Patients with blepharospasm have reduced inhibition of their blink recovery curves; therefore, a LTD‐like intervention might normalize the blink reflex recovery (BRR) and have a favorable therapeutic effect. This is a randomized, sham‐controlled, observer‐blinded prospective study. In 14 blepharospasm patients, we evaluated the effects of high‐frequency supraorbital stimulation on three separate treatment days. We applied 28 trains of nine stimuli, 400 Hz, either before or after the R2 or used sham stimulation. The primary outcome was the blink rate, number of spasms rated by a blinded physician and patient rating before, immediately after and 1 hour after stimulation while resting, reading, and talking; secondary outcome was the BRR. Stimulation “before” and “after” the R2 both showed a similar improvement as sham stimulation in physician rating, but patients felt significantly better with the before condition. Improvement in recovery of the blink reflex was noted only in the before condition. Clinical symptoms differed in the three baseline conditions (resting, reading, and talking). Stimulation before R2 increased inhibition in trigeminal blink reflex circuits in blepharospasm toward normal values and produced subjective, but not objective, improvement. Inhibition of the blink reflex pathway by itself appeared to be insufficient for a useful therapeutic effect. © 2013 Movement Disorder Society     

Blink reflex in 57 parkinsonian patients with correlation between the clinical and electrophysiological parameters

An electrophysiological study of the blink reflex was undertaken in 25 control subjects and in 57 patients with Parkinson's disease. An increase in the ipsilateral and contralateral late response was the most evident finding. The excitability cycle of recovery of the R2 component of the blink reflex after a prior conditioning shock was enhanced in the patients. A statistically significant correlation was established between the increase in the late response and the severity of akinesia and rigidity.