The authors have declared that no competing interests exist.
Conceived and designed the experiments: AB AC. Performed the experiments: MB MF AC FG. Analyzed the data: NT AC PB. Contributed reagents/materials/analysis tools: FG FB. Wrote the paper: AC AB RF GF BD.
Marcus Gunn jaw-winking synkinesis (MGJWS) is characterized by eyelid ptosis, which disappears during jaw movement. Familial MGJWS is an extremely rare condition. Some authors suggested that MGJWS is due to neural misdirection in the brainstem whereas others suggested that aberrant reinnervation or ephapse may be responsible for synkinetic activity. Pathogenesis of this condition is therefore still unclear.
To investigate pathogenetic mechanism in familial MGJWS we performed neurophysiological (EMG, Blink Reflex, Recovery cycle of the R2 component of the blink reflex, Masseter inhibitory reflex, BAEPS and kinematic analysis) and neuroradiological (MRI, Diffusion Tensor Imaging) investigations in a member of a multigenerational family with autosomal dominant Marcus Gunn jaw-winking synkinesis (MGJWS). Kinematic analysis of eyelid and jaw movements disclosed a similar onset and offset of the eyelid and jaw in both the opening and closing phases. The excitability of brainstem circuits, as assessed by the blink reflex recovery cycle and recovery index, was normal. Diffusion Tensor Imaging revealed reduced fractional anisotropy within the midbrain tegmentum.
Kinematic and MRI findings point to a brainstem structural abnormality in our familial MGJWS patient thus supporting the hypothesis of a neural misdirection of trigeminal motor axons to the elevator palpebralis muscle.
Marcus Gunn jaw-winking synkinesis (MGJWS) is characterized by eyelid ptosis, which disappears during jaw movement. MGJWS is usually considered a sporadic condition, though familial cases have been documented
Neurophysiological studies have suggested that the Marcus-Gunn phenomenon may be due to a congenital neural misdirection of trigeminal motor axons of the external pterygoid muscle (responsible for jaw depression and protraction) to the elevator palpebralis muscle
Familial MGJWS is extremely rare. More information on the clinical, neurophysiological and neuroimaging features of patients with familial MGJWS is needed to provide an insight into the pathogenesis of this condition.
In the present paper we describe the clinical, neurophysiological (kinematic analysis of the jaw-winking synkinesis and Recovery cycle of the R2 component of the blink reflex) and neuroimaging (Magnetic Resonance Imaging - MRI, Diffusion Tensor Imaging -DTI) findings in a member of a multigenerational family with autosomal dominant MGJWS.
A 37-year-old man presented with right eyelid ptosis, which disappeared when the patient opened his mouth and reappeared when he closed his mouth. Synkinetic activation of the left orbicularis oculi muscle when attempting to voluntarily open the right eyelid was also present. Symptoms had been present since birth. The subject’s family history revealed that both his father and two paternal uncles were affected by the same disorder.
The neurological examination disclosed no further abnormality while the ophthalmological examination revealed eterophory at distance and vertical strabismus. Electromyography (EMG) recordings from the facial muscles were normal, as were the brainstem auditory evoked potentials.
The control group for the neuroradiological examinations comprised 29 age- and sex-matched healthy subjects (41±5.6 years). Twenty out of the 29 healthy volunteers were also involved in the neurophysiological investigations (age: 37±5.0 years). Both the MGJWS patient and the healthy subjects gave their written informed consent to the experimental procedures, which were approved by the Ethics Committee of University of Rome “Sapienza” and conducted in accordance with the Declaration of Helsinki.
The kinematics of the eyelid and jaw movement was recorded using a 3D optoelectronic motion system (SMART motion system, BTS, Milan, Italy). The displacement of the reflective marker taped on the centre of the lower margin of the upper eyelid and on the mental prominence of the jaw in three-dimensional space was reconstructed off-line by a dedicated software (SMART Analyzer, BTS, Milan, Italy). Onset, offset, duration, peak velocity and amplitude were automatically computed for each downward and upward eyelid and jaw movement
The blink reflex, the masseter inhibitory reflex and the blink reflex recovery cycle were performed according to previously described techniques
All the subjects underwent an MR imaging examination on a 3T scanner system (Intera Achieva, Philips Medical Systems, Best, The Netherlands). Diffusion-weighted images were corrected for head motion and eddy current distortions using FDT (FMRIB’s Diffusion Toolbox 2.0)
The patient’s clinical examination showed that jaw opening and closing movements elicited eyelid-jaw synkinetic activity. The kinematic analysis did not reveal any significant differences between the onset of eyelid and jaw opening and the offset of eyelid and jaw closing (p = 0.34). Pearson’s correlation coefficient disclosed a significant correlation between movement duration of the eyelid and jaw during both the opening (r = 0.58, r2 = 0.33, p = 0.01) and closing phases (r = 0.61, r2 = 0.37, p = 0.009) (
Black line represents velocity trace of jaw movement, gray line represents velocity trace of eyelid movement. The x-axis corresponds to time (ms) and the y-axis to velocity (mm/s). The first peak in the velocity trace corresponds to the peak velocity of the opening phase, the second peak-to-peak velocity of the closing phase. Right: Upper panel. Correlation between jaw opening duration and eyelid opening duration expressed in milliseconds. Lower panel. Correlation between jaw closing duration and eyelid closing duration expressed in milliseconds.
Conventional T1, T2 and FLAIR images were normal in all the brain regions. TBSS revealed a reduction in FA in the oculomotor nuclear complex, reticular formation and central tegmental tract areas (
The FA alterations are localized within the midbrain tegmentum, the reticular formation and the central tegmental tracts.
The kinematic analysis performed in this patient showed that the MGJWS was characterized by a similar onset and offset of the eyelid and jaw movements in both the opening and closing phases. We also found normal brainstem excitability, as assessed by the blink reflex recovery cycle and recovery index. Lastly, the neuroimaging investigation disclosed distinctive abnormalities in the FA value of the brainstem.
In normal subjects, eyelid activation involves three neural pathways: the elevator palpebralis muscle, which is innervated by the oculomotor nerve, raises the upper eyelid; gentle upper eyelid closure depends on the inhibition of motor axons directed to the elevator palpebralis muscle, which occurs in the brainstem at the level of trigeminal motor nucleus; forced eyelid closure depends on the orbicularis oculi muscle, which is innervated by the facial nerve. Previous observations of MGJWS have suggested that jaw and eyelid synkinetic activity is due to ephaptic activation of motorneurons directed to the elevator palpebralis muscle when the pterigoideus muscle is activated
Reduced FA in the brainstem of MGJWS, however, further supports the hypothesis of neural misdirection in the brainstem. The FA alterations were localized within the midbrain tegmentum, where the oculomotor nuclear complex, the reticular formation and the central tegmental tracts are located. These observations point to a structural basis of MGJWS. FA is highly sensitive to subtle differences in white matter architecture at the microstructural level and FA alterations reflect changes in the alignment of cellular structures within fiber tracts and in their structural integrity
The blink reflex recovery cycle is a technique specifically designed to evaluate the excitability of the orbicularis oculi reflex in the brainstem
To our knowledge, this is the first study conducted by means of both neurophysiological and neuroradiological techniques demonstrating a structural abnormality in the brainstem, thus supporting the hypothesis of a neural misdirection of trigeminal motor axons to the elevator palpebralis muscle.
The authors are grateful to Prof. Giovanni Simonetti, Head of the Department of Diagnostic Imaging, Molecular Imaging Interventional Radiology and Radiotherapy at “Tor Vergata” University of Rome, for his continual support.