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Abnormalities of Masseteric Inhibitory Reflex in Hereditary Geniospasm: Evidence for a Brainstem Myoclonus

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Authors:Antonella Macerollo MD, Tabish A. Saifee MRCP, Panagiotis Kassavetis MD, Giovanna Pilurzi MD, PhD, Susanne A. Schneider MD, PhD, Mark J. Edwards MRCP, PhD and Kailash P. Bhatia MD, PhD

Article first published online:  13 OCT 2014 | DOI: 10.1002/mdc3.12097


Abstract

We studied two unrelated families with several members suffering from geniospasm. Here, we aim to clarify the pathophysiology underlying the hereditary geniospasm through testing of brainstem excitability by the recovery cycles of the blink reflex (BR) and the masseteric inhibitory reflex (MIR). The R2 component of the BR and the SP2 component of the MIR and their recovery cycle were analyzed in 3 patients and 8 healthy, age-matched subjects as the control group. Patients with geniospasm exhibited a different excitability of the BR, compared to the control, group, as shown by the larger R2 component area of BR in controls than patients. Notably, the mean recovery index was 0.61 ± 0.19 in geniospasm patients and 0.40 ± 0.15 in controls (P ≤ 0.05). Interestingly, the recovery cycle of the MIR showed a loss of inhibition in both patients studied, as indicated by the behavior of the SP2 component. Our cases showed a partial impairment of the activity of brainstem inhibitory interneurons, indicated by the abnormal recovery cycle of MIR. These results would implicate a mechanism akin to brainstem myoclonus for the generation of geniospasm.

Hereditary geniospasm is a rare disorder characterized by tremor and spasms of the chin involving mentalis. Onset is typically in early childhood or soon after birth. Patients are unable to suppress the abnormal movement, being triggered by emotional stress or concentration. It has an autosomal-dominant inheritance pattern with high penetrance.[1] Notably, linkage to chromosome 9q13-q21 was found in a four-generation British family with hereditary geniospasm,[2] but not linked to this region in two further families, indicating genetic heterogeneity.[3]

The pathophysiology of this rare movement disorder is unclear. One study reported spread of facial reflex responses to mentalis suggesting facial nucleus hyperexcitability.[4]

Some researchers consider geniospasm a form of essential tremor, whereas others a form of dystonic tremor. Previously, the pathophysiology of dystonia was investigated through the evaluation of the brainstem excitability by testing the blink reflex (BR) recovery cycle (RC). Indeed, it is well known that patients with blepharospasm show abnormal excitability of BR RC with enhancement of the R2 component after an earlier conditioning shock.[5] In line with that, we wished to clarify the pathophysiological mechanism underlying geniospasm by testing brainstem excitability through examination of the RC of BR and masseteric inhibitory reflex (MIR).

Patients and Methods

A 68-year-old man and his daughter (37 years of age) from a large, previously unreported family with geniospasm and a 32-year-old female from another, also unreported, family with geniospasm were recruited from the Movement Disorders Clinic at The National Hospital for Neurology and Neurosurgery (London, UK). Neurological examination revealed spontaneous repetitive and rhythmic involuntary contractions of mentalis muscles with no other abnormalities. We recorded, in all patients, the BR and MIR and their RC. Furthermore, we recorded the two brainstem reflexes and their recovery cycle in 8 healthy, age-matched subjects as the control group.

The BR was evoked by electrical stimulation (0.2-ms duration) applied over the supraorbital notch with a bipolar stimulating electrode and constant current generator (Digitimer, Welwyn, UK) while subjects were at rest and eyelids gently closed. The stimulus intensity was adjusted to 3 times the threshold of the R2 component. Electromyography (EMG) signal was recorded from ipsilateral orbicularis oculi muscle using Ag-AgCl surface electrodes. It was amplified using D360 amplifiers (Digitimer, Welwyn, UK), bandpass filtered (5–2,500 Hz), and analog-to-digital converted using a 1401 AD converter (Cambridge Electronic Design, Cambridge, UK) at a sample rate of 5,000 Hz and collected on computer. Data were analyzed offline using Signal software (Cambridge Electronic Design). The raw blink recordings were direct current (DC) corrected and rectified. Latency, duration, and area of the R2 components were measured manually for both blink responses.

MIR was evoked by electrical stimulation (0.2-ms duration) of the mental nerve over the mental foramen with a bipolar stimulating electrode and constant current generator during 100% of maximal voluntary contraction of the masseter muscles. Stimulus intensity was adjusted to 3 times the threshold of the SP2 component. EMG signal was recorded from ipsilateral masseter muscle and was DC corrected and rectified. Latency and duration of the SP2 component were measured at the intersection of the rectified signal with a line indicating 80% of the background EMG level. The area of the silent period was automatically computed.

The RC of the R2 response of the BR and of the SP2 component of the MIR was studied with the double-shock technique validated in previous studies.[6] The BR RC was assessed at interstimulus intervals (ISIs) of 200, 300, 500, 1,000, and 3,000 ms. The MIR recovery cycle was assessed at ISIs of 200, 300, and 500 ms. For each time interval, a series of 8 to 12 trials was repeated in pseudorandomized order. The RC was calculated by expressing the area of the response to the second stimulus (test) as a percentage of the area of the response to the first stimulus (conditioning). Furthermore, the “R2 index” of the BR was calculated at ISIs of 200, 300, and 500 ms as the average of recovery values, with upper-normal limits defined as control group mean + 2 standard deviations (SDs).[7]

Statistical Analysis

Examples of the BR and MIR recordings are provided in Figure 1. SPSS Statistics software (version 21.0.0; SPSS, Inc., Chicago, IL) was used for statistical analysis. Kolmogorov-Smirnoff's test was used to test the normality of the data distribution. When not normally distributed, data were subjected to a log10 transformation. We conducted a repeated-measures multiway analysis of variance (ANOVA) on the data using the following factors: ISIs and GROUP (patients vs. controls). Post-hoc tests were conducted with Bonferroni's corrections for multiple comparisons. P < 0.05 were considered to be significant.

Examples of the BR and MIR recordingsFigure 1. BR recovery cycle at an ISI of 200 ms (10-row traces are superimposed) (A) and MIR recovery cycle at a 200-ms ISI in (10-row traces are superimposed) (B) in a control subject.

 

 

 

 

 

Results

The results of the blink and masseter reflex studies in patients and controls are given in Table 1. For all 3 participants, unilateral electrical stimulation of the supraorbital nerve evoked an R2 response in the orbicularis oculi muscle. Only 2 participants showed an SP2 response in the masseter muscle evoked by a unilateral electrical stimulation of the masseteric nerve. In the third participant, no SP2 was observed, even at high stimulation intensities.

Table 1. BR and MIR parameters (mean/SD) in geniospasm patients and healthy subjects
BR Patients (3/3) Healthy Subjects (8) P
R2 latency (ms) 41.57 ± 5.90 31.21 ± 5.26 <0.05
R2 area (mV) 0.0016 ± 0.0005 0.0039 ± 0.007 <0.05
MIR Patients (2/3) Healthy Subjects (8) P
SP2 latency (ms) 39.11 ± 1.96 43.04 ± 4.7 <0.05
SP2 duration (ms) 35.10 ± 1.71 44.87 ± 14 <0.05
 

BR Recovery Curve

Repeated-measures multiway ANOVA for conditioned R2 component area with ISI as the within-subject factor and GROUP as the between-subject factor showed a significant effect of ISI (P < 0.001) and a significant effect of GROUP (P = 0.004). Furthermore, there was a significant interaction for ISI*GROUP (P < 0.001). The independent sample t test between groups for ISIs showed significance for each ISI (200 ms: P = 0.021; 300 ms: P = 0.016; 500 ms: P = 0.015; 1,000 ms: P = 0.010; 3,000 ms: P = 0.003), showing that controls had a larger R2 component area than patients.

The mean recovery index was 0.61 ± 0.19 in geniospasm and 0.40 ± 0.15 in control subjects (P ≤ 0.05).

MIR Recovery Curve

Repeated-measures multiway ANOVA for SP2 duration with ISI as the within-subject factor and GROUP as the between-subject factor showed a significant effect of ISI (P = 0.015) and a significant effect of GROUP (P = 0.008). Furthermore, there was a significant interaction ISI*GROUP (P = 0.014) for SP2 duration. The independent sample t test between groups for ISIs showed significance for each ISI (200 ms: P = 0.005; 300 ms: P = 0.020; 500 ms: P = 0.012; 1,000 ms: P = 0.020; 3,000 ms: P = 0.004), showing that controls had longer SP2 duration than patients.

Discussion

We have studied 3 patients with hereditary geniospasm, a rare movement disorder. Our patients showed clinical features similar to previously reported cases.[1-3]In both families, the transmission was typically autosomal dominant with almost complete penetrance, and all members affected had an onset in early childhood. In all patients, chin tremor was worse or triggered by emotional situations and/or tasks requiring concentration. Unfortunately, other family members were not available for the neurophysiological study.

The pathophysiology of this peculiar disorder remains intriguing. The pacemaker of geniospasm has been postulated not to be cortically generated, given the lack of C-waves, normal median and trigeminal somatosensory-evoked potentials, and lack of cortical potentials from back-averaging of the EEG.[8, 9] From experimental studies in the monkey that demonstrate a strictly ipsilateral nuclear origin of the motoneurons of the mentalis muscle, Danek had concluded that the site of origin of geniospasm, which symmetrically affects the mentalis, should be sought either within the muscle itself or in neuronal structures superordinate to both facial nerve nuclei.[1] However, it has been argued that a peripheral mechanism, such as within the facial nerve, is not consistent, given the normal nerve conduction studies.[9] These results point toward a central subcortical node or network responsible for the movement observed in geniospasm. Devetag Chalaupka et al. demonstrated, in 3 patients, a hyperexcitability of the facial nucleus potentially driven by abnormalities in inhibition of the pontine reticular formation with consequent abnormal activation of motor neurons innervating mentalis muscle.[9] Notably, rapid eye movement (REM) sleep atonia with the cessation at (REM) phase of the paroxysmal episode of geniospasm in 1 of 3 patients reported in a sleep study make a supranuclear generator potentially likely, considering the role of the mesencephalic/pontine tegmentum in this phenomenon.[10] Devetag Chalaupka et al. argued for classification of geniospasm as a variant of myoclonus based on clinical features, characterized by sudden, brief involuntary movements,[9] and they concluded that the origin was subcortical. This description of geniospasm was supported by Destee et al.,[8] suggesting that it should be considered a focal variant of hereditary essential myoclonus (HEM). Of note, HEM is now known as a form of myoclonus dystonia, a genetic form of dystonia resulting from a mutation in the SGCE (epsilon (ε)-sarcoglycan) gene presenting with subcortical myoclonus and dystonia.

Patients with geniospasm exhibited a different excitability of the BR, compared the control group, as shown by the larger R2 component area of BR in controls than patients. Of note, patients with cranial dystonia were shown to have abnormal excitability of the recovery cycle of BR with enhancement of the R2 component of the blink reflex after an earlier conditioning shock. Interestingly, the RC of the MIR showed a loss of inhibition in both patients where it could be studied, as indicated by the behavior of the SP2 component. So, our cases show a partial impairment of the activity of brainstem inhibitory interneurons, as indicated by results of the RC of MIR. In the context of previous studies, our results may implicate a mechanism akin to brainstem myoclonus for the generation of geniospasm. Notably, the abnormalities in the brainstem excitability involve only the loss of inhibition of MIR with a topographical correspondence with the muscles involved in the clinical features. The precise localization of the abnormalities can explain the absence of spread of symptoms in other body parts, in all described families.

Although the findings of our study are promising to better classify this uncommon disorder, we appreciate the limitation of the number of subjects investigated. This limitation of our study did not allow us to compare both reflexes in the same analysis to show an effect of paradigm. More families need to be described and studied neurophysiologically to confirm or refute our results.

 

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