Abstract
The recovery cycle of the R2 component of the blink reflex was studied in five patients with stiff-person syndrome (SPS) and in seven healthy control subjects. R2 recovery was enhanced in patients with SPS. This result is suggestive of hyperexcitability of brainstem interneuronal circuits in SPS. Hyperexcitability may result from abnormal input from suprasegmental structures or loss of inhibition by interneurons and is compatible with the proposal that there is a widespread dysfunction of central inhibitory mechanisms in SPS.
Stiff-person syndrome (SPS) is a disorder of motor control with characteristic clinical features of fluctuating muscle stiffness with superimposed spasms predominantly affecting the axial and proximal limb musculature.1 Though not typical, symptoms may extend to the face, hands, and feet.1 The symptoms result from involuntary firing of motor units in a pattern that resembles a normal contraction but persists even during contraction of antagonist muscles.2 Widespread dysfunction of inhibitory mechanisms, in particular those related to the γ-aminobutyric acid (GABA)ergic system, has been implicated in the clinical manifestations of SPS.1,2⇓ This theory is supported by the presence of antibodies against the enzyme glutamic acid decarboxylase and the responsiveness of the symptoms to benzodiazepines in this patient population.1
To further determine the possible role of impaired inhibitory mechanisms in SPS, we studied electrically evoked blink reflexes in patients with SPS and control subjects. The blink reflex consists of two components: an early ipsilateral component, R1, which reflects activation of an oligosynaptic pathway, and a later bilateral polysynaptic component, R2, which is mediated by brainstem interneurons and is modulated by both segmental and suprasegmental influences.3 Excitability of these interneurons can be examined by obtaining R1 and R2 recovery curves after application of two shocks (conditioning and test stimuli) to the supraorbital nerve at varying intervals.3 Normally, the R2 response takes up to a second to recover after a conditioning shock.3 If there is a widespread dysfunction of central inhibitory circuits in SPS, enhanced R2 recovery in these patients would be expected.
Methods.
Seven healthy volunteers (ages 35 to 60 years; mean, 44 years) and five patients with a history of SPS (ages 47 to 60 years; mean, 51 years) gave written informed consent for the study protocol, which was approved by the Institutional Review Board. Patients selected for the study fulfilled clinical criteria for diagnosis of SPS.1 All five patients had autoantibodies against glutamic acid decarboxylase. Clinical characteristics of the SPS patients are given in thetable.
Table 1 Clinical characteristics in patients with stiff-person syndrome
Blink reflexes were elicited by delivering paired electrical pulses with a duration of 0.2 ms over the supraorbital nerve at the supraorbital foramen on the right side as described previously.3 Paired pulses were delivered at the following interstimulus intervals: 160, 300, 500, 700, and 1,000 ms. Electromyograms were recorded from the contralateral orbicularis oculi with surface electrodes using a Viking 1V (Nicolet, Madison, WI) electromyograph. Eight traces were recorded for each interval with at least a 15- to 20-second pause between each stimulation. The waveform traces were rectified and averaged. The R2 area was measured from the averaged waveform trace between 32 and 90 ms after the stimulus artifacts (figure 1). The ratio of the area of the second R2 (R2b) to the first R2 (R2a) was computed for each interstimulus interval in each subject from the averaged waveform. The means of this ratio for all subjects in the patient and control groups were calculated at each interval and plotted against the interstimulus intervals to construct a blink reflex recovery curve. Blink recovery curves were compared between patients and control subjects.
Figure 1. Blink reflexes to paired stimuli in one normal subject (A) and one patient with stiff-person syndrome (SPS) (B). Each trace is averaged rectified electromyogram from the contralateral orbicularis oculi. The right column of traces in each panel shows the response to the first stimulus (labeled R2a) and the left column shows the response to the second stimulus (R2b) for each of the tested intervals. Dotted lines indicate the time window (32 to 90 ms) over which the area was measured. The blink reflex to paired stimuli had the greatest suppression of R2b test response at 160 ms interstimulus intervals in subjects and less suppression in SPS.
Statistical analysis consisted of repeated-measures analysis of variance to determine the effects of groups (patients versus controls). Post hoc comparisons using the Dunnett test were used to determine the significant interstimulus intervals. Differences were considered significant at p values < 0.05.
Results.
Examples of blink reflex responses to paired stimuli in a normal subject and a patient with SPS are shown in figure 1. In both patients and control subjects, paired pulse stimulation produced suppression of the R2 component of the second blink reflex (R2b) (figure 2). Suppression was maximal at the shortest interstimulus interval tested and recovered gradually in the control group. The recovery curve was significantly different between patients and normal control subjects. Post hoc testing showed that patients had less suppression of the R2b at an interstimulus interval of 160 ms and 300 ms compared with normal control subjects (p < 0.05, with correction). Suppression of the R2b was not significantly different at longer interstimulus intervals.
Figure 2. Comparison of blink reflex recovery curves (mean R2b/R2a area ratio ± SD) for normal control subjects (•)and patients with SPS (▪).
Discussion.
These results demonstrate an enhanced recovery of the R2 component of blink reflexes in patients with SPS, suggesting increased brainstem interneuronal excitability. Anatomic and physiologic data indicate that the R2 component involves the spinal trigeminal complex, interneurons of the bulbopontine lateral reticular formation, and motoneurons of the facial nucleus innervating the orbicularis oculi muscles.3 The excitability of the R2 reflex is modulated by local inputs to the brainstem neurons mediating the reflex and by descending inputs from suprasegmental levels.3 Thus, increased recovery of the blink R2 could be produced by several mechanisms. It is probably not due to an increased excitability of trigeminal afferents or facial motoneurons, because other facial reflexes having an afferent trigeminal limb, such as the masseteric exteroceptive silent period, are reported to be normal in SPS.4 Inputs from the cerebral cortex and basal ganglia are known to modulate the blink reflex.3 Unilateral lesions of cerebral hemispheres depress responses of the R2 component,5 raising the possibility that increased cortical excitability, as occurs in SPS,6 may enhance recovery of the R2 component.
Enhanced blink reflex recovery has been described in several motor disorders with basal ganglia dysfunction, including PD, blepharospasm, and other focal dystonias.5 In focal dystonia, basal ganglia dysfunction produces decreased excitability of cortical inhibitory (GABAergic) circuits,7 such that cortical disinhibition could be a potential explanation for the hyperexcitability of the R2 response of the blink reflex in these disorders. An alternate possibility is that GABAergic inputs from the basal ganglia to the superior colliculus normally modulate excitability of the blink reflex.8 If so, changes in inhibitory drive from the basal ganglia to the superior colliculus could cause increased blink excitability in SPS.
In most disorders of motor control with an enhanced blink reflex recovery curve, the R2 component is maximally suppressed at the shortest intervals following the conditioning shock and recovers gradually as intervals approach 1 second. Our findings also showed maximum suppression of R2 in SPS at the shortest intervals. The physiologic mechanism for blink reflex hyperexcitability in SPS is unclear. There is evidence for differential effects of descending corticospinal inputs on early and late periods of blink reflex recovery—hyperexcitability of the blink reflex occurs at the earliest intervals in spastic cerebral palsy, whereas in athetoid cerebral palsy, hyperexcitability is present at both early and late intervals.9
Further evidence for differential effects of descending inputs on early and late periods of blink excitability comes from blink reflex studies during wakefulness and sleep. In contrast to suppression in wakefulness, R2 is potentiated in REM sleep, and this period is relatively short and most prominent at 250 ms: during non-REM sleep, R2 recovery continues for >1 second.10
GABAergic interneurons are involved in both basal ganglia and cortical circuits; thus, either or both could be responsible for the hyperexcitability of the blink reflex in SPS patients.
Acknowledgments
Acknowledgment
The authors thank the patients who participated in the study and Beverly McElroy for coordinating patient visits.
- Received October 19, 2001.
- Accepted April 6, 2002.
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