Clinical and Imaging Profile of Patients with Palatal Tremor (2024)

ABSTRACT

Keywords: palatal tremor, Guillain‐Mollaret triangle, inferior olivary nucleus, symptomatic, essential

Palatal tremor (PT), first described by Politzer in 1878, is a rare movement disorder characterized by rhythmic 0.5 to 5 Hz¹ movements of the soft palate. The nosology of PT has been variable, and several terms such as cephalic murmur, rhythmic palatal myoclonus, focal dyskinesia, and chorea of soft palate have been previously used to describe the movement disorder.²

PT may be classified as essential palatal tremor (EPT) and symptomatic palatal tremor (SPT). EPT is an isolated focal tremor,¹ and patients may report associated ear clicks. Typically, there are no other neurological symptoms or signs, and imaging is normal. The pathophysiology of EPT is uncertain and controversial. Recently, a functional basis has been suggested for EPT and demonstrated by electrophysiological studies.³ It has been suggested that functional PT is an underrecognized entity, and a large number of patients with EPT may have a functional origin.⁴ SPT occurs secondary to lesions involving the Guillain‐Mollaret Triangle (GMT) and has a variable etiology that includes vascular events, demyelination, infections, trauma, drugs, and several degenerative conditions.⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴ SPT is associated with eye signs, tremor, and ataxia attributed to the involvement of the brainstem and spinal motor neurons,¹ and imaging often shows inferior olivary (IO) hypertrophy in addition to the primary lesion.⁵

PT is a rare disorder with a vast etiological spectrum. There are relatively few studies that have described the varied clinical, etiological, and radiological features of PT. The present study describes the clinical profile, associated movement disorders, and radiological features of a large, single‐center cohort of patients with PT.

Patients and Methods

Results

Discussion

PT is a rare movement disorder with relatively few studies reporting the varied etiological, clinical, and radiological features. The present study adds to the currently limited database of PT. We described the clinical features, associated movement disorders, and radiological profile of 22 cases with PT. In the present study, we observed that SPT was the most common variant of PT. Patients with SPT typically present with other symptoms secondary to a primary disease, rather than the PT, and usually do not complain of a PT. These patients may often have AMDs such as tremor, dystonia, myoclonus, and ataxia, which could be secondary to lesions produced by the primary disease. Patients with EPT often report ear clicks rather than the sensation of involuntary movements in the throat. It is imperative to examine these patients thoroughly to avoid missing a PT.

The exact AAO of PT, especially SPT, is often uncertain as patients are unaware of the existence of the PT, and the PT is incidentally observed on examination. In several cases, the causal association between a possible etiology and PT is presumptive, as a significant latency may exist between the insult and development of PT. For instance, the latency between the stroke and onset of PT is highly variable and may range anywhere between 1 to 6 months after the initial disease, but may even occur 30 months after the stroke.¹⁶ In our cohort, we observed that the AAO of SPT was much later than in EPT. This is in concurrence with previous reports by Deuschl et al,⁶ who reported the AAO of SPT at 45.1 ± 17.3 years and EPT at 24.8 ± 12.9 years, and Stamelou et al,⁴ who reported the AAO of SPT at 53.6 ± 5.2 years and EPT at 37.2 ± 7.4 years.

There is significant etiological heterogeneity in PT, especially in SPT wherein the PT occurs secondary to a wide range of conditions that may damage the GMT. These include vascular, inflammation, demyelination, genetic, infectious, neoplastic, neurodegenerative, and miscellaneous causes such as traumatic brain injury, tardive, amyotrophic lateral sclerosis, and so on.¹⁷ Degenerative and genetic causes reported in the literature primarily include PAPT, polymerase γ–related mutations, neuroferritinopathy, spinocerebellar ataxia type 20, and so on.¹, ⁷, ¹⁸ Recent reports of PAPT have demonstrated the presence of 3‐repeat and 4‐repeat tau‐positive inclusions in the IO, midbrain, pons, and thalamus, and these results suggest the possibility of PAPT being a tauopathy.¹⁹, ²⁰ Although there are numerous case reports that describe various etiologies, there are limited large series of cases or systematic reviews that provide the prevalence of different etiologies (Table ​(Table2).2). In the present study, vascular lesions were the most common etiology, followed by degenerative, probable genetic, posttraumatic, postinfective, postradiation, and tardive. In a large review by Deuschl et al,⁶ a vascular etiology was the most common, whereas in studies by Stamelou et al⁴ and Nagappa et al,⁷ a genetic etiology was the most common. The former study⁴ reported 5 cases of PAPT, wherein 2 were negative for a GFAP mutation. Nagappa et al⁷ reported variations in POLG, WDR81, NDUFS8, TENM4, and EEF2. However, the prevalence of genetic etiologies in their study may have been biased as a result of patients being selected from a cohort evaluated for mitochondrial and neurogenetic disorders. We had 1 case of PT secondary to postradiation ponto‐medullary syndrome, and this is commonly reported and frequently occurs in cases with brainstem arteriovenous malformations.²¹

In the present study, all patients with SPT were found to have at least 1 AMD. Although several patterns of combinations were observed, no specific correlations were apparent between these patterns and the imaging abnormalities. A larger number of AMDs did not suggest a greater extent of imaging abnormality. Tremor, that is, other than PT, and ataxia were the most common AMDs. This could be secondary to the involvement of the cerebellum and its connections. Dystonia was also observed, and the majority of these patients had cervical dystonia. However, not all patients with dystonia had a lesion involving the basal ganglia, owing to which the cause of the dystonia is uncertain. Finally, myoclonus was relatively less prevalent and was always observed in combination with tremor, dystonia, and ataxia. From an etiological perspective, MRI lesions, correlated with suspected etiology, and all patients with suspected PAPT had tremor and ataxia in addition to the PT.

The pathophysiological basis for both SPT and EPT is enigmatic. In SPT, based on the presence of additional signs and symptoms and abnormalities on MRI, involvement of the GMT has been implicated. The GMT triangle is formed by the dentate nucleus, red nucleus, and IO nucleus (ION; Fig. ​Fig.4).4). Fibers from the contralateral dentate nucleus ascend through the superior cerebellar peduncle and cross the midline in the brachium conjunctivum to reach the ipsilateral red nucleus. From the red nucleus, fibers pass through the central tegmental tract to the ipsilateral ION, and finally fibers from the ION cross the midline to end in the contralateral dentate nucleus.²² Although ION changes, either hyperintensity or hypertrophy, are commonly associated with PT, it is imperative to know that these changes are not the cause of the PT, that is, olivary changes occur secondary to lesions involving structures that produce PT. In several cases, hypertrophic olivary degeneration (HOD) is suggested to occur because of deafferentation of the ION, and only pathologies that affect the dentato‐rubral or dentato‐olivary pathways lead to HOD.²³ Isolated lesions of the CTT may cause a PT without HOD. It has been hypothesized that lesions of the CTT may lead to denervation of the nucleus ambiguus, which supplies the soft palate, and this may present as a PT.²⁴ Furthermore, HOD may develop several months after the onset of the PT or the primary disease. This could be the reason why a few cases within our cohort did not show an IO lesion on the MRI. In addition, as demonstrated in Alexander disease,²⁵ and rarely in medullary infarcts,²⁶ PT may occur despite the profound atrophic degeneration of the IO without HOD. This suggests that HOD‐induced olivo‐cerebellar hypersynchrony may not be the only mechanism underlying PT. ION neurons have been suggested to possess a spontaneous oscillatory activity with a frequency of 0.5 to 12 Hz. Dendrito‐dendritic gap junctions exist between ION neurons and lead to electrotonic coupling, and this coupling in turn leads to clusters of synchronized activity. T type calcium channels exist in ION neurons, and the abnormal modulation of these also leads to synchronization.²⁷ A recent study demonstrated an increase in randomness of oculopalatal tremor with hyperventilation, which supports the role of calcium channels in PT.²⁸ As stated previously, lesions in the GMT lead to transsynaptic deafferentation, a reduction in inhibitory afferents, and a subsequent increase in electrotonic coupling attributed to a compensatory increase in the presynaptic terminals of the deafferented ION. Based on these properties of the ION, the “dual mechanism” theory suggests the role of ION as the “pacemaker” and involvement of the deep cerebellar nuclei in the genesis of PT.²⁴, ²⁷ Hence, in several cases, although the lesions on MRI do not directly appear to involve the ION, patients may develop PT. Interestingly, 1 patient with a suspected tardive etiology was found to have ION abnormalities, and the cause of this anomaly is a conundrum. It is plausible that the patient had a different underlying etiology that was not evident at the time of examination.

The theories behind the pathophysiology of EPT include central, peripheral, voluntary, or functional.¹⁷ A few studies using centrally acting drugs such as lamotrigine, sodium valproate, and flunarizine have reported alleviation of the PT and suggested the possibility of a central generator for EPT.² In several cases with EPT, local inflammation in the oral and nasal cavities has been reported, and pressure changes in the ear canal have been suggested to modulate PT, and in a few other cases EPT has been found to improve after tonsillectomy.² Based on these cases, a possible peripheral etiology has been suggested. In very few case reports, patients have been shown to demonstrate voluntary control over the PT and were able to control the frequency of tremor. It has been postulated that such patients have the ability to activate a central generator that permits them to modulate PT frequency.² Furthermore, a differential involvement of muscles had been suggested in SPT and EPT based on the higher presence of ear clicks in EPT.²⁹ The levator veli palatini is said to be involved in SPT, whereas the tensor veli palatini is involved in EPT. This also supports the clinically visible difference between SPT and EPT that was observed in our study. A functional basis also has been attributed as a possible cause for a majority of patients with EPT.², ⁴ A recent study by Vial et al³ used Bereitschaftspotential and demonstrated the functional nature of EPT in 2 cases. This observation is helpful as establishing a functional basis for the PT will prevent unnecessary medical interventions.

The treatment of EPT is far from satisfactory, and various drugs have been tried in the treatment of PT. Benzodiazepines, anticholinergics, calcium channel blockers, 5HT agonists, and nootropics (piracetam) have been tried with minimal benefit.³⁰ Gabapentin and memantine have been reported to produce modest benefits in oculopalatal tremor.²⁴ Botulinum toxin injections to the tensor veli palatine muscle are the most effective modality of treatment patients with PT, specifically EPT.³¹ The improvement typically lasts for 3 to 6 months. However, despite the benefits, caution should be exercised when injecting for PT as dysphagia may commonly occur following injection as a result of palatal palsy.¹⁵ SPT may not often undergo this intervention as patients seldom report any discomfort attributed to the PT. In our cohort, 2 patients underwent thalamic lesioning for the purpose of reduction of Holmes tremor, but there was no improvement in PT in either of them.

There are limitations to this study. This cohort of patients with PT was highly selective and obtained from within the movement disorder subspeciality, owing to which patients with other causes of PT such as demyelination, epileptic, genetic, and so on may have been missed. Hence, the current study does not represent a complete picture of causes of PT that may be seen at a referral center. We were unable to mention the exact AAO of the PT or the relationship with the onset of baseline neurological illness as patients were unaware of the PT, and this was observed only on examination. A genetic etiology was considered on the basis of clinical and imaging findings, as genetic studies were not performed for these patients. Few patients were lost to follow‐up; hence we were unable to ascertain if the PT persisted or subsided over time. Finally, owing to the retrospective nature of this study, we were unable to comment on how many patients with EPT could have had a functional etiology, as entrainability, variability, and sustainability of the PT were not specifically looked for in these patients.

In conclusion, PT is a rare condition with significant etiological heterogeneity. It can be easily missed owing to the lack of awareness by patients, and thorough clinical examination is necessary to ensure recognition of this condition. Although involvement of the ION is often considered pathognomonic of a palatal tremor, it may not be necessarily observed at the time of imaging and may develop later in the course of illness. A functional etiology should be considered in cases of EPT.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique.

B.K.S.: 1A, 1B, 1C, 2A, 2B, 3A

S.P.: 1A, 1B, 1C, 2A, 2B, 3B

V.V.H.: 1B, 1B, 1C, 3B

K.N.: 1C, 2C, 3B

N.K.: 1C, 2C, 3B

M.N.: 1C, 2C, 3B

R.Y.: 1A, 1C, 3B

P.K.P.: 1A, 1B, 2B, 2C, 3B

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an Institutional Review Board was not required for this work. Informed written consent was obtained from the patient. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.

Notes

Relevant disclosures and conflicts of interest are listed at the end of this article.

References