HOD has intrigued the medical community since Oppenheim's initial observation of enlarged ION during autopsy in 1887[4],followed by Guillain and Mollaret's description of a HOD patient in 1931[5]. Since then, a growing body of cases and research on HOD and its underlying causes has emerged. Remarkably, literature on HOD following pontine stroke (infarction or hemorrhage) remains predominantly confined to case reports. We hereby present the first comprehensive investigation of its clinical attributes, radiological features, and prognosis in English literature.
Our study underscores the significance of HOD following pontine stroke, constituting 10.6% of all pontine stroke cases. Additionally, the higher proportion of HOD cases post-pontine hemorrhage compared to pontine infarction aligns with prior findings. Gender distribution paralleled that of stroke cases, with a preponderance of male patients, while the age spectrum spanned from 33 to 81 years. The convergence of cerebrovascular risk factors—hypertension, diabetes mellitus, smoking, hyperlipidemia, and alcoholism—between HOD secondary to pontine stroke and stroke itself further substantiates the clinical link. Given the limitations of a single-center, small-sample study, broader multi-center investigations are required to verify the demographic correlations.
In our study, the interval between pontine stroke onset and HOD manifestation averaged 7 months (2-10 months), with the exception of one case that was diagnosed six years later. PT and HT emerged as hallmark indicators of HOD. PT, denoting rhythmic involuntary movements of the soft palate (see Additional File 2), falls into two categories: essential palatal tremor (EPT) and symptomatic palatal tremor (SPT)[6]. While the origin of EPT remains elusive, SPT arises from brainstem or cerebellar lesions, often within the GMT[6]. In our study, all patients exhibited SPT alongside other HOD symptoms. Nonetheless, isolated SPT can escape clinical detection if not specifically assessed. Pertinently, a case of HOD post-pontine
hemorrhage manifested a previously unnoticed 1.5Hz tremor of the soft palate and uvula[7]. This underscores the importance of thorough pharyngeal examinations during pontine stroke follow-up. HT is a slow tremor(less than 4.5 Hz) at rest, enhanced by posture and further exacerbated by kinetic action[8]. HT often materializes weeks to months after the GMT lesion[9,10] and has been documented as the sole HOD symptom following pontine hemorrhage[10-12].Although PT and HT define HOD, their coexistence is not universal. Patients could present with a spectrum of other involuntary movements, but without PT and HT[13-17]. Ocular myoclonus often combined with palatal tremor, constitute oculopalatal myoclonus. Our study detected oculopalatal myoclonus in three cases, akin to a case report by Wilks[18]. Ataxia, one of the most prevalent manifestations in our study, can either occur alone[14] or worsen[19] over time after a pontine stroke. Similarly, dysarthria can worsen after HOD onset, mirroring documented cases[19,20]. These evolving or exacerbated symptoms can lead to misdiagnosis as a pontine stroke recurrence, especially when PT and HT are absent.
Classical MRI manifestations of HOD encompass hypertrophy and hyperintense signal on T2WI sequences. Our study uniformly observed hypertrophy and hyperintensity on T2WI within the IONs, with an exception in case 5, which exhibited normal size and signal. This divergence in MRI presentation could stem from the dynamic nature of HOD, as its evolution aligns with pathophysiological stages.The hyperintense signal of olivary on T2WI emerges 1 month after the inciting lesion, and persisted for at least 3-4 years, while olivary hypertrophy initially developed 6 months after the acute event and resolved by 3 to 4 years[21]. Our investigation pinpointed the tegmental pons as the most prevalent locus for HOD emergence. Plausibly, HOD subsequent to pontine stroke may emanate from lesions impeding the central tegmental tract(CTT) within the deep dorsal pons or the tegmental pons. Additionally, a anterior pontomesencephalic junction lesion could disrupt the superior cerebellar peduncle, precipitating HOD[22]. We observed an equal distribution between bilateral HOD and unilateral HOD. Our findings diverged from prior literature, where bilateral HOD was reported to surpass unilateral occurrences[3].
The pattern of HOD hinges on the lesion's location within the GMT. Some authors have proposed four distinct patterns of HOD based on the primary lesion's location: (1) Ipsilateral HOD when the brainstem is the primary point of impact; (2) Contralateral HOD when the cerebellum or cerebellar peduncle is affected; (3) Bilateral HOD when both CTTs are compromised by a midline lesion in the region of the brachium conjunctivum; (4) Bilateral HOD when the primary lesion is situated within the unilateral brainstem and cerebellum[23]. Consequently, we propose that HOD following a pontine stroke could encompass five distinct patterns (Fig. 2): (a) Unilateral lesions in the deep dorsal pons induce ipsilateral HOD via involvement of the CTT; (b) Bilateral paramedian dorsal pontine lesions lead to bilateral HOD by disrupting both CTTs; (c) Lesions in the paramedian pontine region near the SCP result in bilateral HOD due to simultaneous disruption of the CTT and the superior cerebellar peduncles (SCP); (d) Lesions affecting unilateral deep dorsal pontine regions along with the ipsilateral cerebellum precipitate bilateral HOD through involvement of the CTT combined with the ipsilateral dentate nucleus (DN); (e) Unilateral deep dorsal pontine lesions combined with contralateral midbrain involvement lead to bilateral HOD via the engagement of the CTT combined with the contralateral red nucleus (RN).
The prognosis of HOD remains bleak, and no established treatment guidelines exist. Our study, consistent with previous findings, revealed a lack of symptom improvement despite one year of medication use. A retrospective study has found that the prognosis of unilateral HOD was better than that of bilateral HOD[2].Another retrospective study has found that among 123 patients with HOD treated with levodopa, 57.72% responded to levodopa[24].Notably,compared to the medically treated group, DBS provided greater tremor suppression[25].
Acknowledged limitations include the retrospective, single-center design with a limited sample size, the absence of sequential MRI monitoring, and potential bias. Extensive multi-center research is essential for validation.