Original Paper Eur Neurol 2014;72:144–149 DOI: 10.1159/000360531
Received: November 29, 2013 Accepted: February 9, 2014 Published online: August 16, 2014
Oculopalatal Tremor: Variations on a Theme by Guillain and Mollaret Liuna Jang François-Xavier Borruat Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
Abstract Background: Oculopalatal tremor (OPT) is a delayed complication of a brainstem lesion, characterized by involuntary contractions of the soft palate associated with a synchronized ocular pendular nystagmus. MRI reveals inferior olivary nucleus hypersignal/hypertrophy (IONH). Our objective was to refine the clinical profile of patients with OPT and to report a few oddities in both presentation and evolution. Methods: We performed a retrospective study of patients diagnosed with OPT and a literature search. Results: From our database, we retrieved 5 men and 3 women with a diagnosis of OPT. Eighty-two patients with OPT were retrieved from the literature and were compiled with our series. The average age was 54 years and there was a male predominance. Brainstem vascular lesion was the most common etiology (80%). Prominent vertical pendular nystagmus was found in 90%. Dissociated nystagmus was mostly associated to unilateral contralateral IONH on MRI, while bilateral symmetrical nystagmus was due to a bilateral IONH in the majority of cases. Three oddities were found amongst our 8 patients: prominent nystagmus ipsilateral to IONH; disappearance of IONH on MRI despite persisting nystagmus, and
© 2014 S. Karger AG, Basel 0014–3022/14/0724–0144$39.50/0 E-Mail [email protected] www.karger.com/ene
asymptomatic OPT. Conclusion: The clinical profile of OPT is rather stereotyped. Rarely do patients deviate from the classical description of OPT. © 2014 S. Karger AG, Basel
Introduction
Oculopalatal tremor (OPT) is a rare and delayed complication of a brainstem lesion, characterized by an acquired involuntary rhythmic and synchronized movement of muscles derived from branchial arches. The muscles most frequently involved include the extraocular muscles and the muscles of the soft palate and pharynx. Other muscles, such as laryngeal, facial, buccal and diaphragmatic, can also be involved. Oscillations in OPT are stereotyped with a frequency of 2–3 Hz in most cases [1, 2]. The very first clinical description of OPT was made by Spencer [3] in 1886 when he observed ‘pharyngeal and laryngeal nystagmus’ as a complication of a brain tumor. In 1931, Guillain and Mollaret [4] reported that OPT resulted from a lesion disrupting the dentato-rubro-olivary pathway, the so-called Guillain and Mollaret’s triangle (GMT). The GMT connects the cerebellar dentate nucleus to the contralateral inferior olivary nucleus (ION) via the central tegmental pathway. The red nucleus, initially François-Xavier Borruat Hôpital Ophtalmique Jules-Gonin Avenue de France 15 CH–1004 Lausanne (Switzerland) E-Mail francois.borruat @ fa2.ch
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Key Words Oculopalatal tremor · Nystagmus · Inferior olivary nucleus · Guillain-Mollaret triangle
Table 1. Demographics of 8 patients with OPT
Patient No.
Sex
Age, years
Delay, months
Etiology
PN waveform
PN type
IONH
1 2 3 4 5 6 7 8
M M M M F F M F
54 46 77 67 27 70 69 44
3 96 19 192 84 12 60 7
AVM AVM Stroke Radiation Surgery AVM Stroke AVM
V+T V V+T V V V V+H V
Dissociated (R) Dissociated (R) Dissociated (L>R) Dissociated (R>L) Dissociated (R>L) Dissociated (L>R) Dissociated (R) Symmetric
Unilateral (L) Unilateral (L) Unilateral (L) Unilateral (L) Bilateral (L>R) Bilateral MRI not possible Bilateral (L>R)
Delay represents the time elapsed to diagnosis of OPT. PN = Pendular nystagmus; AVM = arteriovenous malformation; V = vertical; T = torsional; H = horizontal; R = right; L = left.
To review the recent literature on OPT, we searched PubMed (1960–2012) with the following keywords: ‘oculopalatal tremor’ and ‘oculopalatal myoclonus’. When available, the same criteria as those studied for our own patients were extracted and collated. This study was approved by the Swiss Federal Department of Health (authorization No. 035.0003-48).
Results
We performed a retrospective chart review of patients examined and diagnosed as OPT by one of the authors (F.X.B.). Patients were retrieved from the Neuro-Ophthalmology Database of the Hôpital Ophtalmique Jules-Gonin. The studied criteria were: sex, age, etiology of the initial brainstem disorder, delay to develop OPT, and type of nystagmus. The results of MRI were correlated to the type of nystagmus.
Eight patients were diagnosed with OPT between 1996 and 2008. The charts of these 8 patients were analyzed and details are provided in table 1. There were 3 women and 5 men. The average age was 57 years (range 27–77). The time elapsed from the initial brainstem injury to the diagnosis of OPT varied from 3 to 192 months. The etiologies of the brainstem lesions included hemorrhage from an arteriovenous malformation (4 cases), ischemic stroke (2 cases), following radiotherapy of pontine cavernoma (1 case), and following surgery for cerebellar astrocytoma (1 case). Palatal or pharyngeal tremor was present in all 8 patients, but none were symptomatic of it (online suppl. video 1; for all online suppl. material, see www.karger. com/doi/10.1159/000360531). Disturbing oscillopsia was a major complaint in all but 1 patient (see Variations on OPT). All 8 patients exhibited pendular nystagmus. Clinically, the nystagmus waveform was pendular with a prominent vertical component in all patients, beating at 2 Hz. The nystagmus was dissociated or uniocular in 7 patients, and only 1 patient presented a bilateral symmetrical nystagmus (patient 8). An example of dissociated vertical pendular nystagmus is provided in online supplementary video 2. In addition to the main vertical compo-
OPT: Variations on a Theme by Guillain and Mollaret
Eur Neurol 2014;72:144–149 DOI: 10.1159/000360531
Methods
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described as being actively part of the GMT, was shown not to play a significant role in GMT. The term oculopalatal myoclonus, which was initially used, was replaced by OPT as none of the spontaneous movements have the characteristics of myoclonus. Patients with OPT are almost never symptomatic from the palatal/pharyngeal tremor, but disturbing oscillopsia are always present. Pathology and then neuroimaging studies have revealed hypertrophy of ION (IONH) which can be either unilateral or bilateral, depending on the extent of the initial brainstem lesion [2, 5]. In general, unilateral IONH is associated either with unilateral vertical nystagmus in the contralateral eye, or with a dissociated vertical nystagmus predominant in the contralateral eye. Bilateral IONH can be associated with either symmetrical vertical nystagmus or with a dissociated nystagmus [1, 6]. MRI revealed a sequence of changes within ION. First, a hypersignal, not enhancing with gadolinium, can be detected on T2weighted sequences. Second, hypertrophy will appear later and will slowly disappear as the ION becomes atrophic. The hypersignal of ION on T2 is thought to remain visible despite the atrophy of ION [5]. Here, we report a series of 8 patients with OPT and review the international literature on OPT.
Variations on OPT Amongst our series of 8 OPT patients, we found three oddities, which are detailed below. First, patient 3 showed a prominent vertical pendular nystagmus which was ipsilateral to IONH. As mentioned previously, unilateral IONH is typically associated with nystagmus solely or predominantly present in the contralateral eye. Second, asymptomatic OPT was discovered in 1 patient (patient 1) after clinical examination was prompted by the discovery on MRI of a hypersignal in one ION, 3 months after bleeding in a brainstem arteriovenous malformation. Absence of visual symptoms was explainable by the very small amplitude of a monocular vertical pendular nystagmus [7]. Third, MRI performed 2 years after the onset of OPT revealed disappearance of IONH (patient 3), whereas the patient’s clinical situation was unchanged (both oscillopsia and nystagmus; fig. 1). 146
Eur Neurol 2014;72:144–149 DOI: 10.1159/000360531
a
b
c
d
e
f
g
Fig. 1. Results of MRI studies (T2-weighted sequences, axial cut) performed at the time of OPT diagnosis for patients 1 (a), 2 (b), 3 (c, d), 4 (e), 6 (f) and 8 (g). Hypertrophy and/or hypersignal of the ION was present unilaterally in 4 patients (a–e) and bilaterally in 2 other patients (f, g). MRI was performed 2 years apart in patient
3: left hypersignal/hypertrophy of the ION was initially present in 2000 (c); 2 years later repeat MRI failed to show any lesion of the left ION, despite persisting oscillopsia and nystagmus (c).
Review of the Literature We found 24 publications on OPT for a total of 82 reported cases [1, 8–30]. We compiled them with our series of 8 patients, totaling 90 cases of OPT. The average age was 54 years (range 23–86, n = 90) with a male predominance (64 men, 25 women, n = 89). The mechanism of the initial brainstem injury was vascular in 80% (n = 90), with Jang/Borruat
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nent of the nystagmus, 2 patients also showed a torsional component, and 1 patient also presented a minor horizontal component. MRI was performed in 7/8 patients. Patient 7 could not be imaged by MRI due to uncontrollable and large movements of the head, at about 2 Hz. For patient 7, OPT was diagnosed clinically (synchronized acquired vertical nystagmus and pharyngo/palatal tremor) 5 years after a brainstem stroke, and only a CT scan was performed. On T2-weighted sequences, unilateral IONH was disclosed in 4 cases (patients 1–4) and bilateral IONH was present in the remaining 3 cases (patients 5, 6, 8; fig. 1). Unilateral IONH was associated with either a contralateral monocular nystagmus (patients 1 and 2) or with a dissociated nystagmus which was prominent in the contralateral eye (patient 4). Patient 3 exhibited unilateral IONH which was ipsilateral to the eye with the prominent nystagmus (see Variations on OPT). Bilateral IONH was associated with either a dissociated nystagmus (patients 5 and 6) or a bilateral symmetrical nystagmus (patient 8). Due to the retrospective nature of our study, follow-up varied amongst patients. Seven patients were followed from 1 month (patient 5) to 5 years (average 26 months). Only 1 patient had spontaneously improved 5 years after the onset of OPT (patient 2). He became completely asymptomatic with a complete disappearance of nystagmus. However, hypersignal within ION persisted on follow-up MRI. On the contrary, ION hypersignal spontaneously disappeared after 2 years in patient 3, whereas no clinical improvement was observed (unchanged oscillopsia and nystagmus, see Variations on OPT; fig. 1).
OPT is a peculiar and unique neurological syndrome in which a destructive brainstem lesion results in a delayed and stereotyped presentation. OPT is a combination of an often asymptomatic palatal/pharyngeal tremor with a symptomatic vertical pendular nystagmus. Pharyngeal tremor can result in the perception of a rhythmic ‘ear click’ in some patients, but does not produce other symptoms within the oropharyngeal area. Oscillopsia is always disturbing for the patient. Both involuntary movements are synchronized at a rhythm of about 2 Hz [1, 2].
The mechanisms of OPT have been recently uncovered. A condition sine qua non for the development of OPT is an initial disruption of the afferent inhibitory dentato-olivary pathways [4]. Neurons of the ION are unique in at least two specific points. First, they possess an intrinsic tendency to oscillate, and their spontaneous rate of oscillations ranges from 0.5 to 12 Hz [31–33]. Second, they possess specific connections, namely dendro-dendritic gap junctions allowing electrotonic coupling. Electrotonic coupling favors synchronization of ION neurons [34]. Under normal conditions, the deep cerebellar nucleus inhibits the electrotonic gap junctions of the contralateral ION. Following an interruption of this inhibitory pathway, the ION neurons start to oscillate, develop abnormal soma-somatic gap junctions, and become hypertrophic. Another contributory mechanism to ION neurons oscillation is an abnormal modulation of Ca2+ channels [35]. However, even with synchronization, the ION output is too small to induce ocular oscillations. To become clinically visible and symptomatic, the weak oscillations emanating from ION need to be amplified by the cerebellar cortex [36]. OPT then results from a dual mechanism, ignition of a generator, the inferior olivary pacemaker, followed by an amplification/modulation by the cerebellum. OPT is a delayed complication of a brainstem lesion. The delay is variable, and for our patients it ranged from 3 months to 16 years. Patient 4 developed symptoms of OPT 16 years after radiation treatment on a pontine cavernoma first thought to be a glioma. This delayed finding may be due to the slow evolution of radiation-induced lesions. But the reason for the variation in delay to detect OPT is not known and might depend on the nature, location and intensity of the primary injury. The earliest case of OPT was symptomatic 9 days after the initial brainstem injury [23]. MRI will ultimately reveal an increased signal of ION, visible on both T2- and proton density-weighted images, without gadolinium enhancement. Subsequently, hypertrophy of the olivary nucleus will develop, probably due to the astrocyte and neuron hypertrophy. The hypersignal on T2 sequences will remain for many years and may be permanent. Progressive atrophy of ION occurs over the next 3–4 years [5]. The pattern of nystagmus in OPT can vary, as can the MRI abnormalities (unilateral vs. bilateral IONH). The vast majority of patients exhibit a pendular vertical nystagmus sometimes with a torsional or, more rarely, a horizontal component to it [1]. Nystagmus can be strictly unilateral, bilateral symmetrical or dissociated, of higher amplitude on one side (the symptomatic one). Nakada
OPT: Variations on a Theme by Guillain and Mollaret
Eur Neurol 2014;72:144–149 DOI: 10.1159/000360531
patients)
Dissociated nystagmus (n = 38) Symmetric nystagmus (n = 19)
Unilateral IONH (n = 41)
Bilateral IONH (n = 16)
35 (62%) 6 (10%)
3 (6%) 13 (22%)
56/90 brainstem hemorrhage and 19/90 brainstem ischemia. The time elapsed between the initial brainstem injury and the report of OPT varied from 9 days to 18 years (average 40 months, n = 60). However, caution is needed as this elapsed time may not represent the actual delay to develop OPT in some patients, but merely represents the time elapsed to the diagnosis of OPT. A purely or predominantly vertical nystagmus was reported in 90% (n = 85). Details regarding both the type of nystagmus and MRI lesions were available for 57 patients. A unilateral/dissociated nystagmus was present in 68% of patients, whereas 32% of patients exhibited a bilateral symmetrical nystagmus. Unilateral/dissociated nystagmus was associated with unilateral IONH on MRI in the vast majority of cases, and only 3 cases demonstrating bilateral IONH. Two-thirds of patients with a bilateral symmetrical nystagmus presented a bilateral IONH, whereas one-third exhibited an unilateral IONH (table 2). Improvement of oscillopsia was scarcely reported. Only 2 patients were reported to improve, 18 and 6 years after the onset of OPT, respectively, whereas their IONH remained unchanged on MRI [1]. Spontaneous improvement occurred in only 1 of our patients (patient 2).
Discussion
147
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Table 2. Correlation of nystagmus type and MRI findings (n = 57
Variation 1 Patient 3 from our series exhibited IONH ipsilaterally to the prominent side of pendular vertical nystagmus. Interestingly, Kim et al. [1] reported that 6/8 OPT patients with dissociated pendular nystagmus showed more prominent pendular nystagmus on the side contralateral to the imaged olivary changes [1]. This implied that 2 OPT patients in their series exhibited prominent nystagmus on the same side as the IONH, like our patient 3. Similarly, Tilikete et al. [28] reported 1 patient with dissociated vertical pendular nystagmus that was also more prominent ipsilaterally to the IONH [28]. Both authors did not provide any explanation for this unusual presentation of OPT. Potential explanations include the presence of either a contralateral small ION lesion overshadowed by the prominent ipsilateral ION lesion or an earlier contralateral ION lesion which would have vanished by the time MRI was performed. For our patient 3, several control MRI examinations failed to reveal any contralateral lesion, and the delay between the onset of oscillopsia and MRI was 1 month. Like Kim et al. [1] and Tilikete et al. [28], we do not have a definite explanation for the presence of nystagmus prominent ipsilaterally to unilateral IONH. Variation 2 Patients who develop OPT are symptomatic of their nystagmus and complain either of monocular or binocular oscillations. Patient 1 in our series was completely asymptomatic and was found to harbor a palatal tremor associated with a micro pendular nystagmus, visible mostly during fundus examination only [7]. Only 1 case of asymptomatic OPT has been previously reported by Cackett et al. [8]. The patient they reported differed from ours as significant decreased visual acuity (3/10) was present in the eye with the nystagmus, possibly preventing the perception of oscillopsia. 148
Eur Neurol 2014;72:144–149 DOI: 10.1159/000360531
Variation 3 Neuroimaging studies in OPT show that the ION hypertrophy is a transient stage, with ION becoming atrophic after a few years. On the other hand, ION hypersignal is reported to remain unchanged [1, 5]. Follow-up MRI studies in 1 of our patients (patient 3) revealed that both ION hypertrophy and hypersignal had disappeared 2 years after the onset of OPT. However, disappearance of ION abnormalities was not accompanied by clinical improvement, as the nystagmus and the disturbing oscillopsia remained unchanged. This implies that, if MRI is performed late in the course of the disease, some rare patients with OPT might present without MRI evidence of IONH despite a full clinical picture of OPT. Oscillopsia in OPT can be very disturbing and OPT is a chronic disorder. Medical therapy is worth trying and gabapentin and memantin have been proposed, with clinical improvement in some patients [37, 38]. The dosage of gabapentin is usually 300 mg q.i.d., up to 600 mg q.i.d. Memantine is used at 10 mg q.i.d. Only 1 of our patients was treated with gabapentin and then memantin, without subjective clinical improvement, and treatment had to be discontinued due to side effects (fatigue, nausea, lightheadedness). In conclusion, the vast majority of patients with OPT exhibit a syndrome which is clearly defined and is stereotyped. They present an asymptomatic palatal/pharyngeal tremor with disturbing oscillopsia resulting from a vertical pendular nystagmus. The nystagmus can be unilateral or bilateral and MRI examination will reveal unilateral or bilateral ION lesions. In most cases, the condition remains unchanged over the years.
Disclosure Statement None; no conflicting relationship exists for any of the authors.
References
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and Kwee [6] hypothesized that a unilateral IONH would induce a dissociated vertical pendular nystagmus, the amplitude of which would be larger in the contralateral eye. Bilateral IONH would then induce a symmetrical pendular vertical nystagmus. This theoretical model is verified in the majority of OPT patients. Kim et al. [1] reported a series of 22 OPT patients and found that unilateral/dissociated nystagmus was associated with contralateral IONH, whereas bilateral symmetrical nystagmus could result from either unilateral or bilateral IONH. Our study and the review of the literature also support this general rule.
OPT: Variations on a Theme by Guillain and Mollaret
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Received: November 29, 2013 Accepted: February 9, 2014 Published online: August 16, 2014
Oculopalatal Tremor: Variations on a Theme by Guillain and Mollaret Liuna Jang François-Xavier Borruat Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
Abstract Background: Oculopalatal tremor (OPT) is a delayed complication of a brainstem lesion, characterized by involuntary contractions of the soft palate associated with a synchronized ocular pendular nystagmus. MRI reveals inferior olivary nucleus hypersignal/hypertrophy (IONH). Our objective was to refine the clinical profile of patients with OPT and to report a few oddities in both presentation and evolution. Methods: We performed a retrospective study of patients diagnosed with OPT and a literature search. Results: From our database, we retrieved 5 men and 3 women with a diagnosis of OPT. Eighty-two patients with OPT were retrieved from the literature and were compiled with our series. The average age was 54 years and there was a male predominance. Brainstem vascular lesion was the most common etiology (80%). Prominent vertical pendular nystagmus was found in 90%. Dissociated nystagmus was mostly associated to unilateral contralateral IONH on MRI, while bilateral symmetrical nystagmus was due to a bilateral IONH in the majority of cases. Three oddities were found amongst our 8 patients: prominent nystagmus ipsilateral to IONH; disappearance of IONH on MRI despite persisting nystagmus, and
© 2014 S. Karger AG, Basel 0014–3022/14/0724–0144$39.50/0 E-Mail [email protected] www.karger.com/ene
asymptomatic OPT. Conclusion: The clinical profile of OPT is rather stereotyped. Rarely do patients deviate from the classical description of OPT. © 2014 S. Karger AG, Basel
Introduction
Oculopalatal tremor (OPT) is a rare and delayed complication of a brainstem lesion, characterized by an acquired involuntary rhythmic and synchronized movement of muscles derived from branchial arches. The muscles most frequently involved include the extraocular muscles and the muscles of the soft palate and pharynx. Other muscles, such as laryngeal, facial, buccal and diaphragmatic, can also be involved. Oscillations in OPT are stereotyped with a frequency of 2–3 Hz in most cases [1, 2]. The very first clinical description of OPT was made by Spencer [3] in 1886 when he observed ‘pharyngeal and laryngeal nystagmus’ as a complication of a brain tumor. In 1931, Guillain and Mollaret [4] reported that OPT resulted from a lesion disrupting the dentato-rubro-olivary pathway, the so-called Guillain and Mollaret’s triangle (GMT). The GMT connects the cerebellar dentate nucleus to the contralateral inferior olivary nucleus (ION) via the central tegmental pathway. The red nucleus, initially François-Xavier Borruat Hôpital Ophtalmique Jules-Gonin Avenue de France 15 CH–1004 Lausanne (Switzerland) E-Mail francois.borruat @ fa2.ch
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Key Words Oculopalatal tremor · Nystagmus · Inferior olivary nucleus · Guillain-Mollaret triangle
Table 1. Demographics of 8 patients with OPT
Patient No.
Sex
Age, years
Delay, months
Etiology
PN waveform
PN type
IONH
1 2 3 4 5 6 7 8
M M M M F F M F
54 46 77 67 27 70 69 44
3 96 19 192 84 12 60 7
AVM AVM Stroke Radiation Surgery AVM Stroke AVM
V+T V V+T V V V V+H V
Dissociated (R) Dissociated (R) Dissociated (L>R) Dissociated (R>L) Dissociated (R>L) Dissociated (L>R) Dissociated (R) Symmetric
Unilateral (L) Unilateral (L) Unilateral (L) Unilateral (L) Bilateral (L>R) Bilateral MRI not possible Bilateral (L>R)
Delay represents the time elapsed to diagnosis of OPT. PN = Pendular nystagmus; AVM = arteriovenous malformation; V = vertical; T = torsional; H = horizontal; R = right; L = left.
To review the recent literature on OPT, we searched PubMed (1960–2012) with the following keywords: ‘oculopalatal tremor’ and ‘oculopalatal myoclonus’. When available, the same criteria as those studied for our own patients were extracted and collated. This study was approved by the Swiss Federal Department of Health (authorization No. 035.0003-48).
Results
We performed a retrospective chart review of patients examined and diagnosed as OPT by one of the authors (F.X.B.). Patients were retrieved from the Neuro-Ophthalmology Database of the Hôpital Ophtalmique Jules-Gonin. The studied criteria were: sex, age, etiology of the initial brainstem disorder, delay to develop OPT, and type of nystagmus. The results of MRI were correlated to the type of nystagmus.
Eight patients were diagnosed with OPT between 1996 and 2008. The charts of these 8 patients were analyzed and details are provided in table 1. There were 3 women and 5 men. The average age was 57 years (range 27–77). The time elapsed from the initial brainstem injury to the diagnosis of OPT varied from 3 to 192 months. The etiologies of the brainstem lesions included hemorrhage from an arteriovenous malformation (4 cases), ischemic stroke (2 cases), following radiotherapy of pontine cavernoma (1 case), and following surgery for cerebellar astrocytoma (1 case). Palatal or pharyngeal tremor was present in all 8 patients, but none were symptomatic of it (online suppl. video 1; for all online suppl. material, see www.karger. com/doi/10.1159/000360531). Disturbing oscillopsia was a major complaint in all but 1 patient (see Variations on OPT). All 8 patients exhibited pendular nystagmus. Clinically, the nystagmus waveform was pendular with a prominent vertical component in all patients, beating at 2 Hz. The nystagmus was dissociated or uniocular in 7 patients, and only 1 patient presented a bilateral symmetrical nystagmus (patient 8). An example of dissociated vertical pendular nystagmus is provided in online supplementary video 2. In addition to the main vertical compo-
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described as being actively part of the GMT, was shown not to play a significant role in GMT. The term oculopalatal myoclonus, which was initially used, was replaced by OPT as none of the spontaneous movements have the characteristics of myoclonus. Patients with OPT are almost never symptomatic from the palatal/pharyngeal tremor, but disturbing oscillopsia are always present. Pathology and then neuroimaging studies have revealed hypertrophy of ION (IONH) which can be either unilateral or bilateral, depending on the extent of the initial brainstem lesion [2, 5]. In general, unilateral IONH is associated either with unilateral vertical nystagmus in the contralateral eye, or with a dissociated vertical nystagmus predominant in the contralateral eye. Bilateral IONH can be associated with either symmetrical vertical nystagmus or with a dissociated nystagmus [1, 6]. MRI revealed a sequence of changes within ION. First, a hypersignal, not enhancing with gadolinium, can be detected on T2weighted sequences. Second, hypertrophy will appear later and will slowly disappear as the ION becomes atrophic. The hypersignal of ION on T2 is thought to remain visible despite the atrophy of ION [5]. Here, we report a series of 8 patients with OPT and review the international literature on OPT.
Variations on OPT Amongst our series of 8 OPT patients, we found three oddities, which are detailed below. First, patient 3 showed a prominent vertical pendular nystagmus which was ipsilateral to IONH. As mentioned previously, unilateral IONH is typically associated with nystagmus solely or predominantly present in the contralateral eye. Second, asymptomatic OPT was discovered in 1 patient (patient 1) after clinical examination was prompted by the discovery on MRI of a hypersignal in one ION, 3 months after bleeding in a brainstem arteriovenous malformation. Absence of visual symptoms was explainable by the very small amplitude of a monocular vertical pendular nystagmus [7]. Third, MRI performed 2 years after the onset of OPT revealed disappearance of IONH (patient 3), whereas the patient’s clinical situation was unchanged (both oscillopsia and nystagmus; fig. 1). 146
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a
b
c
d
e
f
g
Fig. 1. Results of MRI studies (T2-weighted sequences, axial cut) performed at the time of OPT diagnosis for patients 1 (a), 2 (b), 3 (c, d), 4 (e), 6 (f) and 8 (g). Hypertrophy and/or hypersignal of the ION was present unilaterally in 4 patients (a–e) and bilaterally in 2 other patients (f, g). MRI was performed 2 years apart in patient
3: left hypersignal/hypertrophy of the ION was initially present in 2000 (c); 2 years later repeat MRI failed to show any lesion of the left ION, despite persisting oscillopsia and nystagmus (c).
Review of the Literature We found 24 publications on OPT for a total of 82 reported cases [1, 8–30]. We compiled them with our series of 8 patients, totaling 90 cases of OPT. The average age was 54 years (range 23–86, n = 90) with a male predominance (64 men, 25 women, n = 89). The mechanism of the initial brainstem injury was vascular in 80% (n = 90), with Jang/Borruat
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nent of the nystagmus, 2 patients also showed a torsional component, and 1 patient also presented a minor horizontal component. MRI was performed in 7/8 patients. Patient 7 could not be imaged by MRI due to uncontrollable and large movements of the head, at about 2 Hz. For patient 7, OPT was diagnosed clinically (synchronized acquired vertical nystagmus and pharyngo/palatal tremor) 5 years after a brainstem stroke, and only a CT scan was performed. On T2-weighted sequences, unilateral IONH was disclosed in 4 cases (patients 1–4) and bilateral IONH was present in the remaining 3 cases (patients 5, 6, 8; fig. 1). Unilateral IONH was associated with either a contralateral monocular nystagmus (patients 1 and 2) or with a dissociated nystagmus which was prominent in the contralateral eye (patient 4). Patient 3 exhibited unilateral IONH which was ipsilateral to the eye with the prominent nystagmus (see Variations on OPT). Bilateral IONH was associated with either a dissociated nystagmus (patients 5 and 6) or a bilateral symmetrical nystagmus (patient 8). Due to the retrospective nature of our study, follow-up varied amongst patients. Seven patients were followed from 1 month (patient 5) to 5 years (average 26 months). Only 1 patient had spontaneously improved 5 years after the onset of OPT (patient 2). He became completely asymptomatic with a complete disappearance of nystagmus. However, hypersignal within ION persisted on follow-up MRI. On the contrary, ION hypersignal spontaneously disappeared after 2 years in patient 3, whereas no clinical improvement was observed (unchanged oscillopsia and nystagmus, see Variations on OPT; fig. 1).
OPT is a peculiar and unique neurological syndrome in which a destructive brainstem lesion results in a delayed and stereotyped presentation. OPT is a combination of an often asymptomatic palatal/pharyngeal tremor with a symptomatic vertical pendular nystagmus. Pharyngeal tremor can result in the perception of a rhythmic ‘ear click’ in some patients, but does not produce other symptoms within the oropharyngeal area. Oscillopsia is always disturbing for the patient. Both involuntary movements are synchronized at a rhythm of about 2 Hz [1, 2].
The mechanisms of OPT have been recently uncovered. A condition sine qua non for the development of OPT is an initial disruption of the afferent inhibitory dentato-olivary pathways [4]. Neurons of the ION are unique in at least two specific points. First, they possess an intrinsic tendency to oscillate, and their spontaneous rate of oscillations ranges from 0.5 to 12 Hz [31–33]. Second, they possess specific connections, namely dendro-dendritic gap junctions allowing electrotonic coupling. Electrotonic coupling favors synchronization of ION neurons [34]. Under normal conditions, the deep cerebellar nucleus inhibits the electrotonic gap junctions of the contralateral ION. Following an interruption of this inhibitory pathway, the ION neurons start to oscillate, develop abnormal soma-somatic gap junctions, and become hypertrophic. Another contributory mechanism to ION neurons oscillation is an abnormal modulation of Ca2+ channels [35]. However, even with synchronization, the ION output is too small to induce ocular oscillations. To become clinically visible and symptomatic, the weak oscillations emanating from ION need to be amplified by the cerebellar cortex [36]. OPT then results from a dual mechanism, ignition of a generator, the inferior olivary pacemaker, followed by an amplification/modulation by the cerebellum. OPT is a delayed complication of a brainstem lesion. The delay is variable, and for our patients it ranged from 3 months to 16 years. Patient 4 developed symptoms of OPT 16 years after radiation treatment on a pontine cavernoma first thought to be a glioma. This delayed finding may be due to the slow evolution of radiation-induced lesions. But the reason for the variation in delay to detect OPT is not known and might depend on the nature, location and intensity of the primary injury. The earliest case of OPT was symptomatic 9 days after the initial brainstem injury [23]. MRI will ultimately reveal an increased signal of ION, visible on both T2- and proton density-weighted images, without gadolinium enhancement. Subsequently, hypertrophy of the olivary nucleus will develop, probably due to the astrocyte and neuron hypertrophy. The hypersignal on T2 sequences will remain for many years and may be permanent. Progressive atrophy of ION occurs over the next 3–4 years [5]. The pattern of nystagmus in OPT can vary, as can the MRI abnormalities (unilateral vs. bilateral IONH). The vast majority of patients exhibit a pendular vertical nystagmus sometimes with a torsional or, more rarely, a horizontal component to it [1]. Nystagmus can be strictly unilateral, bilateral symmetrical or dissociated, of higher amplitude on one side (the symptomatic one). Nakada
OPT: Variations on a Theme by Guillain and Mollaret
Eur Neurol 2014;72:144–149 DOI: 10.1159/000360531
patients)
Dissociated nystagmus (n = 38) Symmetric nystagmus (n = 19)
Unilateral IONH (n = 41)
Bilateral IONH (n = 16)
35 (62%) 6 (10%)
3 (6%) 13 (22%)
56/90 brainstem hemorrhage and 19/90 brainstem ischemia. The time elapsed between the initial brainstem injury and the report of OPT varied from 9 days to 18 years (average 40 months, n = 60). However, caution is needed as this elapsed time may not represent the actual delay to develop OPT in some patients, but merely represents the time elapsed to the diagnosis of OPT. A purely or predominantly vertical nystagmus was reported in 90% (n = 85). Details regarding both the type of nystagmus and MRI lesions were available for 57 patients. A unilateral/dissociated nystagmus was present in 68% of patients, whereas 32% of patients exhibited a bilateral symmetrical nystagmus. Unilateral/dissociated nystagmus was associated with unilateral IONH on MRI in the vast majority of cases, and only 3 cases demonstrating bilateral IONH. Two-thirds of patients with a bilateral symmetrical nystagmus presented a bilateral IONH, whereas one-third exhibited an unilateral IONH (table 2). Improvement of oscillopsia was scarcely reported. Only 2 patients were reported to improve, 18 and 6 years after the onset of OPT, respectively, whereas their IONH remained unchanged on MRI [1]. Spontaneous improvement occurred in only 1 of our patients (patient 2).
Discussion
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Table 2. Correlation of nystagmus type and MRI findings (n = 57
Variation 1 Patient 3 from our series exhibited IONH ipsilaterally to the prominent side of pendular vertical nystagmus. Interestingly, Kim et al. [1] reported that 6/8 OPT patients with dissociated pendular nystagmus showed more prominent pendular nystagmus on the side contralateral to the imaged olivary changes [1]. This implied that 2 OPT patients in their series exhibited prominent nystagmus on the same side as the IONH, like our patient 3. Similarly, Tilikete et al. [28] reported 1 patient with dissociated vertical pendular nystagmus that was also more prominent ipsilaterally to the IONH [28]. Both authors did not provide any explanation for this unusual presentation of OPT. Potential explanations include the presence of either a contralateral small ION lesion overshadowed by the prominent ipsilateral ION lesion or an earlier contralateral ION lesion which would have vanished by the time MRI was performed. For our patient 3, several control MRI examinations failed to reveal any contralateral lesion, and the delay between the onset of oscillopsia and MRI was 1 month. Like Kim et al. [1] and Tilikete et al. [28], we do not have a definite explanation for the presence of nystagmus prominent ipsilaterally to unilateral IONH. Variation 2 Patients who develop OPT are symptomatic of their nystagmus and complain either of monocular or binocular oscillations. Patient 1 in our series was completely asymptomatic and was found to harbor a palatal tremor associated with a micro pendular nystagmus, visible mostly during fundus examination only [7]. Only 1 case of asymptomatic OPT has been previously reported by Cackett et al. [8]. The patient they reported differed from ours as significant decreased visual acuity (3/10) was present in the eye with the nystagmus, possibly preventing the perception of oscillopsia. 148
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Variation 3 Neuroimaging studies in OPT show that the ION hypertrophy is a transient stage, with ION becoming atrophic after a few years. On the other hand, ION hypersignal is reported to remain unchanged [1, 5]. Follow-up MRI studies in 1 of our patients (patient 3) revealed that both ION hypertrophy and hypersignal had disappeared 2 years after the onset of OPT. However, disappearance of ION abnormalities was not accompanied by clinical improvement, as the nystagmus and the disturbing oscillopsia remained unchanged. This implies that, if MRI is performed late in the course of the disease, some rare patients with OPT might present without MRI evidence of IONH despite a full clinical picture of OPT. Oscillopsia in OPT can be very disturbing and OPT is a chronic disorder. Medical therapy is worth trying and gabapentin and memantin have been proposed, with clinical improvement in some patients [37, 38]. The dosage of gabapentin is usually 300 mg q.i.d., up to 600 mg q.i.d. Memantine is used at 10 mg q.i.d. Only 1 of our patients was treated with gabapentin and then memantin, without subjective clinical improvement, and treatment had to be discontinued due to side effects (fatigue, nausea, lightheadedness). In conclusion, the vast majority of patients with OPT exhibit a syndrome which is clearly defined and is stereotyped. They present an asymptomatic palatal/pharyngeal tremor with disturbing oscillopsia resulting from a vertical pendular nystagmus. The nystagmus can be unilateral or bilateral and MRI examination will reveal unilateral or bilateral ION lesions. In most cases, the condition remains unchanged over the years.
Disclosure Statement None; no conflicting relationship exists for any of the authors.
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and Kwee [6] hypothesized that a unilateral IONH would induce a dissociated vertical pendular nystagmus, the amplitude of which would be larger in the contralateral eye. Bilateral IONH would then induce a symmetrical pendular vertical nystagmus. This theoretical model is verified in the majority of OPT patients. Kim et al. [1] reported a series of 22 OPT patients and found that unilateral/dissociated nystagmus was associated with contralateral IONH, whereas bilateral symmetrical nystagmus could result from either unilateral or bilateral IONH. Our study and the review of the literature also support this general rule.
OPT: Variations on a Theme by Guillain and Mollaret
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