INTRODUCTION
Oculopalatal tremor (OPT) is a rare delayed complication of a brainstem or cerebellar lesion. OPT is characterized by the presence of an acquired pendular nystagmus synchronous with a tremor of the soft palate/pharynx, and sometimes other muscles. [Video 1–2 (Video 1: Palatal tremor. The soft palate oscillates vertically at about 2 Hz, https://links.lww.com/CONR/A19; Video 2: Nystagmus. The patient complained of left oscillopsia and examination revealed a dissociated nystagmus, more pronounced in the left eye. The frequency of the nystagmus was variable, but averaged about 2 Hz, https://links.lww.com/CONR/A20.)] Almost all patients exhibit a tremor frequency of 2–3 Hz, affecting muscles derived from branchial arches including muscles of the palate, pharynx, larynx, eye, head, neck and diaphragm.
The first full clinical description of OPT was made in 1866 by Spencer [1], who reported the case of a young girl with ‘palatal laryngeal nystagmus’ in the setting of a brain tumour. In 1887, Oppenheim [2] reported the first description of inferior olivary nucleus hypertrophy (IONH). In 1931, Guillain and Mollaret [3] described the connections existing between the cerebellar dentate nucleus, the red nucleus and the inferior olivary nucleus (ION) as well as their implications in the development of OPT.
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OPT results from a disruption of the Guillain–Mollaret triangle (GMT), a triangle formed by the contralateral dentate nucleus, the ipsilateral red nucleus and the ipsilateral ION. Connecting afferent axons depart from the dentate nucleus, pass through the contralateral superior cerebellar peduncle, cross the midbrain via the brachium conjunctivum, loop at the level of the red nucleus and descend to the ION via the ipsilateral central tegmental tract; efferent axons connect the ION to the contralateral deep cerebellar nuclei via the inferior cerebellar peduncle (Fig. 1). The GMT can also be referred to as the dentato-rubro-olivary pathway. Interruption of the afferent (dentato-olivary) pathway can induce subsequent changes in the ION resulting in the development of OPT.
FIGURE 1: Guillain–Mollaret triangle. On a sagittal (left) and a coronal (right) view of a normal brainstem, the dentate nucleus (DN), red nucleus (RN) and inferior olivary nucleus (ION) are depicted. The plain arrows schematize the afferences to the ION (dentato-rubro-olivary pathway), and the dashed arrow represents efferences (olivo-cerebellar pathways).
IONH can be unilateral or bilateral. Whereas IONH is necessary for the development of OPT, IONH is not always associated with OPT. Hence, IONH can be asymptomatic, can result in only palatal/pharyngeal tremor (symptomatic palatal tremor) or can result in OPT, that is palatal tremor with synchronous ocular nystagmus.
CLINICAL PRESENTATION
Causes of OPT are numerous. Brainstem infarcts or haemorrhages represent 60–70% of cases, with brainstem cavernous haemangiomas being the most frequent cause (Fig. 2). Apart from vascular lesions, trauma (including surgery), infection and inflammation, IONH has been reported as a possible result of toxic mechanisms on the GMT. However, the rare toxic cases reported thus far exhibited IONH without OPT. Metronidazole, lithium and carbamazepine, and ciprofloxacin have been implicated in single case reports [4–6]. Kinghorn et al.[7] reported three patients with mitochondriopathies associated with either polymerase gamma (two cases) or surfeit 1 (SURF1; Leigh syndrome, one case) mutations who exhibited bilateral IONH. None of these cases exhibited OPT, but all three patients suffered from ophthalmoplegia. The authors’ literature search disclosed seven other similar cases [7]. Paediatric cases of IONH have been reported but without palatal tremor and/or nystagmus [8▪].
FIGURE 2: Axial (left) and coronal (right) MRI, T2-weighted sequences, of a 52-year-old man who developed oculopalatal tremor 6 months after bleeding from a left pontine cavernoma (arrowhead). The left inferior olivary nucleus (arrow) exhibited a hypersignal and a slight hypertrophy, nonenhancing with gadolinium.
Disturbing oscillopsia (a visual illusion of to-and-fro movement of the environment) is almost universally present in OPT, whereas the palatal/pharyngeal tremor is almost always asymptomatic. Rarely, oscillopsia will subside, several years after the onset of OPT. Nystagmus can be unilateral, bilateral asymmetrical or bilateral symmetrical. Kim et al.[9] reported a series of 22 patients with OPT and correlated the MRI findings to the clinical presentation. Dissociated nystagmus was associated with unilateral IONH, whereas symmetrical nystagmus was associated with either bilateral or unilateral IONH [9]. There are only two reports of visually asymptomatic patients with OPT. One patient suffered from visual loss in the eye that developed OPT, and this might have prevented the onset of oscillopsia [10]. The other patient had a completely normal visual function and presented a very low amplitude monocular pendular nystagmus, which was better visualized during fundus examination [11]. Most patients exhibit pendular vertical nystagmus, with sometimes a torsional, and rarely a horizontal component [9]. Convergent–divergent nystagmus, palatal and head tremor, all oscillating at about 3 Hz, associated with bilateral olivary hypertrophy, was reported by Galvez-Ruiz et al.[12]. This very unusual presentation occurred several months after a pontine haemorrhage, which resulted in bilateral horizontal gaze palsy. Gabapentin 1200 mg/day resulted in improvement of vision by decreasing the amplitude but not the frequency of OPT [12]. A few additional case reports of classical OPT appeared in the literature [13–16]. An interesting observation was brought up by Lopez et al.[17], who reported on the increased amplitude of the vertical nystagmus during forced eye closure in a single patient.
A prospective series of 14 OPT patients was reported by Tilikete et al.[18▪▪] as part of a study comparing and characterizing the type of acquired nystagmus both in OPT and multiple sclerosis (MS) patients. Nystagmus in OPT was found to be of lower frequency (1–3 Hz), larger amplitude and velocity, and more irregular than acquired pendular nystagmus in MS patients. Also, the vision-specific health-related quality of life was worse in OPT, but this result did not correlate with either visual acuity (better in OPT) or the type of nystagmus [18▪▪].
Secondary ataxia and dysarthria can develop in some patients with OPT [19–24,25▪]. The occurrence of secondary ataxia has been linked to the presence of intraparenchymal brainstem haemosiderin deposits [25▪]. The authors speculated on a mechanism similar to superficial siderosis, a disorder resulting from chronic subarachnoid bleeding and haemosiderin deposits leading to delayed and insidious progressive ataxia [26].
Progressive ataxia and palatal tremor (PAPT) is a primary, presumably neurodegenerative disorder, which has been recently reported [27–29]. Samuel et al.[28] reported sporadic PAPT in six patients and reviewed the literature to collate 22 other cases. Only four out of 22 exhibited a nystagmus compatible with OPT, the other 18 patients presenting only with palatal tremor. They did not report familial cases of PAPT, but their review of the literature revealed 21 cases potentially with that diagnosis, all being autosomal dominant [28]. MRI findings included brainstem atrophy, cerebellar atrophy, olivopontocerebellar-like atrophy, and dentate and pallidal calcification (dark dentate signal on MRI). Wills et al.[30] incriminated excessive iron accumulation in the dentate and basal ganglia as the mechanism of palatal tremor in a patient with autososmal dominant neuroferritinopathy [26,30].
NEUROIMAGING
MRI will reveal unilateral or bilateral ION lesions in patients with OPT. Initially, a hypersignal on T2 or proton-density images can be detected as early as 1 week and as late as several years after the initial brainstem injury. Subsequently (weeks to months later), ION hypertrophy will occur. It is believed that the hypersignal is a permanent marker, whereas the hypertrophy will only last a few years, resolving and leading to ION atrophy [31]. The differential diagnosis of IONH on MRI includes ischaemia, demyelination, tumour, infection, inflammation and hypertrophic olivary degenerations [32].
There is a clear correlation between radiological appearance and the pathological stages of ION degeneration [33–35]. The initial hyperintense ION lesion on MRI corresponds to neuronal hypertrophy, gliosis, increased water content, demyelination and vacuolization. Further astrocytic and neuronal changes are responsible for ION hypertrophy. Ultimately, neuronal and astrocytic cell death will lead to ION atrophy.
Whereas MRI is excellent for anatomical studies of patients with OPT, it does not allow investigators to test hypotheses on the functional role of ION hypertrophy. PET-scan studies with 18F-fluorodeoxyglucose can provide such functional results, but the results in OPT patients have been contradictory. A significant increase in the metabolism of glucose within the medulla of seven patients with palatal myoclonus was reported by Dubinsky et al.[36] who also reported, in the same study, a single patient with OPT who did not show an increased metabolism within the medulla. Moon et al.[37] reported nine patients with OPT, and none of them showed any increased metabolism within the anterior medulla using the same technique, but hypermetabolism was detected in the contralesional thalamus. Increased metabolism in the region of both the hypertrophic ION and the contralateral inferior cerebellar vermis was reported in a single patient with symptomatic OPT. Successful treatment of oscillopsia with clonazepam did not result in a decrease of the ION metabolism, whereas the metabolism of the dentate nucleus significantly decreased by 25% [38].
Increased blood flow was clearly demonstrated by functional MRI (fMRI) in the left ION and the contralateral dentate nucleus of a 21 year-old man with voluntary palatal tremor (i.e. palatal tremor that can be elicited, modulated and stopped by a thinking process) [39]. Only one other patient has been studied with fMRI, and increased blood flow in the ION and contralateral dentate nucleus was also reported [40]. Indeed, the number of patients and studies are sparse, but results of fMRI support the role of dentato-olivary pathway dysfunction in the genesis of OPT.
Diffusion tensor imaging (DTI) is a recently developed imaging technique that allows a better evaluation of white matter. In a report of a single patient, fibre tractography disclosed unilateral decreased central tegmental tract volume and absent superior cerebellar decussating fibres [41]. In a series of 10 patients with ION hypertrophy (six with and four without palatal tremor), Dinçer et al.[42▪] demonstrated abnormal signals in every anatomical component of the GMT. The abnormal signals were compatible with both demyelination and neuronal hypertophy and correlated with the histopathologic changes of ION in OPT [42▪]. Both rubro-olivary and olivary-cerebellar tracts have been demonstrated in vivo using DTI [43,44]. Jang et al.[45▪] investigated 40 healthy individuals with DTI and questioned the connectivity of ION to both brainstem and brain. They demonstrated a high connectivity of ION with motor areas (brainstem and cerebral cortex) and, surprisingly, much lower connectivity between the ION and cerebellum [45▪]. The unexpectedly low level of connectivity between the ION and cerebellum might be artefactual, as visualization of crossing fibres can be obscured in regions of fibre complexity.
Susceptibility-weighted imaging (SWI) is a recent technique that allows better imaging of cerebral structures containing iron, namely the red nucleus. Red nucleus degeneration (i.e. relative hyperintensity on SWI) was found in two young patients with postoperative IONH [46▪]. SWI might be useful to better define the brainstem structural changes in OPT.
PHYSIOPATHOLOGY
Neurons from ION can oscillate spontaneously in vitro and their frequency of oscillation varies from 0.5 to 12 Hz. This contrasts with the dominant relatively fixed and predetermined frequency of 2–3 Hz in OPT patients, although irregular and aperiodic. A peculiar type of interneuronal connection exists between neurons of the ION: dendro-dendritic gap junctions, allowing electrotonic coupling. Electrotonic coupling favours synchronization of olivary neurons [47]. In vitro, ION neurons spontaneously organize into clusters of synchronized oscillating neurons, due to the presence of electrotonic coupling [48▪]. These clusters oscillate each at about the same frequency, but not simultaneously. Electrotonic coupling might not be the only reason for ION oscillations. Specific Ca2+ channels (Cav3.1 T-type) are highly expressed in ION neurons and are essential for intrinsic ION neuronal oscillations [49▪]. Abnormal modulation of Ca2+ channels might contribute to abnormal ION oscillations.
An elegant model combining an oscillator (ION) and a modulator (cerebellum) was recently proposed in order to explain OPT [50▪▪]. Following an interruption of the inhibitory gamma-aminobutyric acid-ergic afferences on the electrotonic gap junctions, ION neurons will start to oscillate. With ION neuronal hypertrophy, abnormal soma–somatic gap junctions will also develop, increasing the strength of the electrotonic coupling, and synchronization develops. ION output is however too small and will be modulated/amplified by the cerebellum. This dual-mechanism model was successfully compared with the results of 15 patients with OPT. Implications for therapy are obvious: an efficient treatment could be directed either towards reducing ION electrotonic coupling (such as quinine, carbenoxolone or mefloquine) or towards reducing the cerebellar modulation of ION signals (clonazepam, alprazolam, primidone, topiramate or memantine) [50▪▪]. A neural network model based on anatomical (cluster of neurons) and physiological (electrotonic coupling) data from ION successfully accounted for the enigmatic observations of frequent alterations in oscillations frequency and phase differences between ION neurons [51▪].
A thorough postmortem immunohistopathological study was performed by Ogawa et al.[52] who studied 10 hypertrophic ION patients. αB-crystallin (αBC) is a protein that is expressed in neurons only under pathological conditions. The authors reported on the presence of αBC positive neurons in all 10 studied olives, a signature of cellular stress. Also, they reported an increase in presynaptic terminals, which was interpreted as a compensatory phenomenon due to the deafferentiation of ION [52].
The dentate nucleus participates in the integration of ‘graviceptive input’. Adequate integration of graviceptive inputs can be easily assessed by measuring the subjective visual vertical (SVV). In OPT, hypertrophic ION will hyperstimulate the contralateral dentate nucleus. Hence, it would not be surprising that patients with OPT would exhibit a tilt in SVV. However, SVV was never studied in OPT until Tarnutzer et al.[53▪] reported on the evolution of SVV in a single patient with OPT. Initially (day 16 after pontine stroke), in the absence of OPT, they measured an ipsilateral tilt of SVV. At month 4, in the presence of OPT, the SVV tilt was now contralateral to the hypertrophic ION. The reversal of SVV tilt can be explained by the development over time of a hyperstimulation of the contralateral dentate nucleus by the now hypertrophic ION [53▪].
TREATMENT
According to the dual-mechanism hypothesis of OPT, inferior olivary neurons act as a pacemaker of low-amplitude signal, which is then amplified by the deep cerebellar nuclei [50▪▪]. Hence, treatment could be aimed at either reducing the ION output or decreasing the cerebellar output.
Thurtell et al.[54] performed a crossover trial of gabapentin 300 mg four times daily (q.i.d.) and memantine 10 mg q.i.d. in 10 patients with acquired nystagmus, four of them presenting with OPT. Both drugs reduced the median eye speed and improved visual acuity, the two primary outcomes of the study. Best improvement resulted from treatment with gabapentin in three OPT cases.
Shaikh et al.[55▪] tested the dual-mechanism hypothesis pharmacologically with memantine and gabapentin. Memantine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and can reduce the output of both the ION and cerebellum. Gabapentin blocks calcium channel subunit α2δ-1, which could decrease the output of cerebellar Purkinje cells and also block the ION somato-somatic gap junctions. Both drugs were able to reduce significantly the amplitude and the frequency content of the nystagmus. However, as predicted by the authors, the fundamental frequency of the nystagmus was unaltered by therapy [55▪]. Dosage of gabapentin is usually 300 mg q.i.d., sometimes up to 600 mg q.i.d. Recommendations for memantine are 10 mg q.i.d., some patients requiring up to 60 mg daily. Side effects include dizziness, somnolence and fatigue. In MS patients, gabapentin is preferred to memantine, as memantine can exacerbate symptoms of MS [56▪].
Wang et al.[57] reported on a patient with OPT resistant to medical therapy (gabapentin, baclofen, klonopin, depakote, meclizine, primidone, leveracetam). Due to his very poor quality of life, an approach similar to Parkinson disease was proposed, that is deep brain stimulation of the red nucleus. No significant improvement resulted from this attempt. Failure might have resulted from a wrong target choice, but technically (with the available probes at the time) implantation in the ION or the dentate nucleus was judged too risky [57].
CONCLUSION
The rather stereotypical presentation of patients with OPT has been puzzling for many years. How can a destructive lesion of the GMT be responsible for the delayed appearance of a rhythmical movement? This enigma is now partially solved as we now know that the descending dentato-olivary tract is inhibitory to the ION. Further, recent research results demonstrated the presence of electrotonic coupling between ION neurons and also the presence of specific Ca2+ channels (Cav3.1 T-type) in ION neurons, which are likely responsible for the synchronous oscillation of ION neurons.
Therapy with oral gabapentine or memantine can decrease the disabling visual symptoms of some patients with OPT. In view of the recent research results (see above), more specific therapy will probably be developed in the near future.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 106–107).
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