Transsynaptic degeneration in the cerebellum and brainstem may give rise
to a rare neurological condition with various clinical manifestations, namely
hypertrophic olivary degeneration. The classical manifestations of hypertrophic
olivary degeneration comprise myoclonus, palatal tremor, ataxia, and ocular
symptoms. Any lesions interrupting the dentate-rubro-olivary pathway, referred to
as the anatomic Guillain-Mollaret triangle, contribute to the broad aetiologies
of hypertrophic olivary degeneration. The clinical diagnosis depends primarily on
the associated symptoms and the characteristic magnetic resonance imaging
findings. Concerning treatment and prognosis, there are no widely accepted
guidelines. Here, we identified 11 cases of hypertrophic olivary degeneration
secondary to brainstem infarction from 1964 to the present. Combined with two of
our cases, the clinical and imaging findings of 13 patients with hypertrophic
olivary degeneration secondary to brainstem infarction were studied. A
meta-analysis of case studies gives the correlation coefficient between
infraction location and time to develop hypertrophic olivary degeneration as
0.217 (P = 0.393, P
Hypertrophic olivary degeneration (HOD) is a rare neuronal degenerative condition involving the inferior olivary nucleus (ION) (Sen et al., 2014). It usually results from a lesion along the dentate-rubro-olivary pathway, referred to as the Guillain-Mollaret triangle (GMT) (Yun et al., 2013). The GMT consists of the dentate nucleus in the cerebellum, the contralateral ION in the medulla oblongata, and the contralateral red nucleus at the level of the midbrain (Menendez et al., 2014). HOD is an unusual entity, as degeneration is accompanied by hypertrophy rather than the more commonly encountered atrophy (Sen et al., 2014). Histologically, the characteristics of HOD are glial demyelination, proliferation, neuronal vacuolation, and shrinkage (Meoded et al., 2013).
Hemorrhagic lesions (Wein et al., 2015), ischemic lesions (Sabat et al., 2016), and neurosurgical intervention of a brain tumor (Shinohara et al., 2013) involving the GMT are common causes of HOD. Moreover, HOD has been reported in head trauma, subarachnoid hemorrhage (Hayashi et al., 2014), and a few mitochondrial disorders (Bindu et al., 2014) such as the Leigh syndrome (Sonam et al., 2014). Studies have reported that an intact dentate-rubro-olivary pathway has been detected in a minority of patients with HOD (Van Eetvelde et al., 2016). Additionally, HOD can also be an occasional imaging finding in some asymptomatic patients, for which the underlying mechanism remains unclear and requires further research (Van Eetvelde et al., 2016). We present magnetic resonance imaging and clinical findings for two patients with HOD secondary to brainstem infarction, as well as a meta-analysis of 11 cases of HOD secondary to brainstem infarction from 1964 to the present in the literature.
A 67-year-old woman presented with ataxia. 5 months before hospital admission, she had experienced a loss of consciousness, as well as urinary and fecal incontinence, and was diagnosed with acute infarction of the medulla oblongata. After a week of treatment, she had residual gait unsteadiness. Neurological examination showed a positive Romberg’s sign and abnormal heel-to-shin and finger-to-nose results. Additionally, there was bilateral vertical nystagmus with an upward gaze. The remaining neurological symptoms were unremarkable. On her postinfarction cranial magnetic resonance imaging (MRI) examination at 5 months, slight enlargement and prominent T2 hyperintensity were observed for both IONs (Fig. 1). A diagnosis of HOD was made based on clinical manifestations and the results of imaging examinations. She received symptomatic therapy, which included aspirin, statin, and neuroprotective drugs, for about one week without any apparent substantial symptom alleviation. At the 4-year follow-up, she reported aggravation of the unsteady gait. She complained that she could not stand by herself because of poor balance.
Fig. 1.Increased signal intensity and enlargement of the bilateral inferior olivary nuclei (ION) (yellow arrow) resulting from brainstem infarction.
A 61-year-old man presented with ataxia, slurred speech, diplopia, and choking without any triggers, had a previous episode of these symptoms 7 months before hospital admission when he was diagnosed with an acute infarction of the pons and had residual unstable gait. Neurological examination revealed slurred speech, diplopia, and abnormal finger-to-nose, heel-to-shin, and Romberg’s sign test results. The remaining neurological signs were unremarkable. In a follow-up, MRI examination performed 7 months after the infarction, enlarged, and remarkable T2 hyperintense bilateral olives were observed (Fig. 2). Combined with the classical MRI findings and symptoms, a diagnosis of HOD was made. He received aspirin, statin, and neuroprotective drugs for about 8 days, without apparent substantial symptom alleviation. The patient reported no obvious symptom alterations and no appearance of new manifestations at the 1-year follow-up.
Fig. 2.Bilateral hypertrophic olivary degeneration and increased signal intensity (yellow arrow) secondary to brainstem infarction on the T2-weighted sequence on magnetic resonance imaging (MRI).
We conducted a meta-analysis of case studies of HOD after brainstem infarction and included cases reported from 1964 to the present. The meta-analysis of case studies were performed utilizing NCBI-PubMed using as keywords “hypertrophic olivary degeneration.” We also reviewed the bibliography of the selected articles. As shown in Table 1, of the 13 reported cases of brainstem infarction followed by HOD, 7 (53.8%) were male, 6 (46.2%) were female, the pons was involved in 9 cases (69.2%), bilateral olivary nuclei were implicated in 8 cases (61.5%), 4 cases (30.8%) were unilateral, 1 case was not reported. Ataxia (7 cases, 53.8%) was the most frequently observed clinical manifestation, followed by palatal myoclonus (5 cases, 38.5%) and ophthalmoplegia (5 cases, 38.5%), the next was nystagmus (4 cases, 30.8%). The time to develop HOD varied from several months to several years, the median of which was 4.5 months. There was little literature mentioned treatment and prognosis, and currently, there were no specific drugs for HOD with poor prognosis.
| Case | Age | Sex | Etiology/ location | Time to Develop HOD (month) | MRI findings | Symptoms | Treatment | Prognosis |
| Case 1 | 60 | F | Infarction/Pons | 12 | B | Tremor; Hemiparesis | Symptomatic therapeutic | Poor |
| Case 2 | 43 | F | Infarction/Pons | 4 | L | Palatal Myoclonus | - | - |
| Case 3 | 69 | F | Infarction/Midbrain | 4 | B | Ataxia; Ophthalmoplegia; Head tremor; Holmes’ tremor | Levodopa | Poor |
| Case 4 | 40 | M | Infarction/Pons and Midbrain | 4 | - | Palatal Myoclonus; Quadriplegia | - | - |
| Case 5 | 60 | M | Infarction/Midbrain | 3 | B | Palatal Myoclonus; Head tremor | - | - |
| Case 6 | 59 | M | Infarction/Left red nucleus | 84 | L | Ataxia; Ophthalmoplegia; Nystagmus | - | - |
| Case 7 | 77 | F | Infarction/Pons | 24 | B | Palatal Myoclonus | - | - |
| Case 8 | 50 | M | Infarction/Pons and Midbrain | 3 | B | Ataxia | - | - |
| Case 9 | 59 | M | Infarction/Pons | 9 | R | Ataxia; Palatal Myoclonus; Nystagmus; Hemiparesis | - | - |
| Case 10 | 50 | M | Infarction/Pons | - | R | Ataxia; Tremor | - | - |
| Case 11 | 39 | F | Infarction/Pons and Midbrain | 1 | B | Ophthalmoplegia; Nystagmus | - | - |
| Current study | 67 | F | Infarction/Medulla Oblongata | 5 | B | Ataxia; Ophthalmoplegia; Nystagmus | Aspirin; Statin | Poor |
| Current study | 61 | M | Infarction/Pons | 7 | B | Ataxia; Ophthalmoplegia | Aspirin; Statin; Neuroprotective drugs | Poor |
| F: Female; M: Male; HOD: hypertrophic olivary degeneration; B: bilateral; L: left; R: right; Case1 (Sen et al., 2014); Case2 (Van Eetvelde et al., 2016); Case 3 (Cosentino et al., 2016); Case 4 (Venkatesh et al., 2017); Case 5 (Zhou et al., 2017); Case 6 (Smets et al., 2017); Case 7 (Santos et al., 2015); Case 8 (Lai et al., 2018); Case 9 (Bruno and Wooten, 2012); Case 10 (Choh et al., 2009); Case 11 (Gerace et al., 2006). | ||||||||
As shown in Table 2, regarding infraction location and time to develop HOD,
we performed Spearman’s correlation analysis, and the results show that the
correlation coefficient between infraction location and time to develop HOD was
-0.217 (P = 0.393, P
| Infraction location | Time to Develop HOD | |||
| Correlation Coefficient | 1 | -0.217 | ||
| Infraction location | Significance (2-tailed) | 0.393 | ||
| Spearman’s correlation | Number of Valid Cases | 13 | 12 | |
| Correlation Coefficient | -0.217 | 1 | ||
| Time to Develop HOD | Significance (2-tailed) | 0.393 | ||
| Number of Valid Cases | 12 | 12 |
| MRI findings of HOD | Total | ||||
| Bilateral | Left | Right | |||
| Pons | 3 | 1 | 2 | 6 | |
| Infraction location | Midbrain | 2 | 0 | 0 | 2 |
| Pons and Midbrain | 2 | 0 | 0 | 2 | |
| Left red nucleus | 0 | 1 | 0 | 1 | |
| Medulla Oblongata | 1 | 0 | 0 | 1 | |
| Total | 8 | 2 | 2 | 12 | |
| value | df | Asymptotic Significance (2-sided) | |
| Pearson Chi-Square | 8.75 | 8 | 0.364 |
| Likelihood Ratio | 8.685 | 8 | 0.37 |
| Linear-by-Linear Association | 0.92 | 1 | 0.337 |
| Number of Valid Cases | 12 |
As shown in Table 1, of the 13 reported cases, 7 (53.8%) were male, 6 (46.2%) were female, no apparent gender differences were observed. Bilateral olivary nuclei were implicated in 8 cases (61.5%), and 4 cases (30.8%) were unilateral, which is in line with the available literature that a bilateral process was the most common presentation of the HOD (Carr et al., 2015). In Table 1, there were 8 patients with bilateral HOD, of whom 5 were female, and 3 were male. While according to literature, bilateral HOD was more frequently observed in males (Konno et al., 2016).
HOD patients usually present with Holmes’ tremor, palatal myoclonus, and ocular myoclonus (Sen et al., 2014). Holmes’ tremor is defined as a slow (2-5 Hz) rest and intentional tremor (and possible postural tremor) (Sen et al., 2014). The rhythmic involuntary movements of the oropharynx are the characteristic feature of palatal myoclonus, which is frequently attributed to the contractions of the levatorveli palatini muscle, and the facial, tongue and larynx muscles are occasionally involved (Van Eetvelde et al., 2016; Wein et al., 2015). Palatal myoclonus is the common manifestation of HOD, while myoclonus is not fundamental to confirm a diagnosis of HOD (Hirano et al., 2015). Additional clinical presentations of HOD vary from progressive ataxia to tremors of additional muscles such as the neck, facial, trunk, pharyngeal, and muscles of the extremities (Meoded et al., 2013). According to Table 1, ataxia was the most frequently observed clinical manifestation in patients with HOD secondary to brainstem infarction, followed by palatal myoclonus and ophthalmoplegia, and the next was nystagmus.
MRI is an essential tool for diagnosing HOD (Cosentino et al., 2016). Diffusion tensor imaging and MR fiber tractography can detect disruptions in the GMT pathways when changes with conventional MRI are equivocal (Sarawagi and Murugesan, 2015). The absence of diffusion restriction, contrast enhancement, and the spatial confinement of the lesion in the vicinity of the ION were valuable contributors to the accurate radiological diagnosis (Van Eetvelde et al., 2016). Inflammatory processes (tuberculosis, encephalitis or sarcoidosis), amyotrophic lateral sclerosis, neoplasia, Wallerian degeneration, adrenoleukodystrophy, and demyelination should be taken into account in the differential diagnosis of HOD (Van Eetvelde et al., 2016).
Currently, symptomatic treatment is the commonly accepted treatment method with varying results (Orman et al., 2014). Unfortunately, the symptoms of HOD are refractory, and patients usually show an inadequate response to the symptomatic therapeutic approaches, reporting little substantial symptom alleviation (Van Eetvelde et al., 2016). According to Table 1, in general, the prognosis of patients with HOD is poor.
For our patients, ataxia was the shared and main symptom, and neurological examination revealed a positive Romberg’s sign and abnormal finger-to-nose and heel-to-shin results, which is consistent with Table 1 that ataxia was the most frequently observed manifestation. It is worth pointing out that given the high recurrence rate of infarction and the low incidence of HOD, the symptoms such as ataxia reported by patients may be easily confused with the recurrence of infarction, especially when the common manifestations of HOD such as Holmes’ tremor, palatal myoclonus, and ocular myoclonus are not included in the chief complaint. It is of great importance to pay attention to the inferior olivary nucleus when there are no other lesions found in MRI.
For our patients, the time to develop HOD was 5 and 7 months, respectively. Based on the medical history, laboratory tests, cerebrospinal fluid tests, and MRI findings, we ruled out the possibility of other disorders. Combined with the classical MRI findings and symptoms, a diagnosis of HOD was made. Our patients received aspirin, statin, and neuroprotective drugs for about a week without apparent substantial alleviation. The patient of case 1 reported aggravation of the unsteady gait at the 4-year follow-up. In contrast, the patient of case 2 reported no apparent symptom alterations and no appearance of new manifestations at the 1-year follow-up. It is possible that the progression of symptoms is a long and gradual progress, and 1 year is not enough time for our patients to experience apparent changes in symptoms. Alternatively, any alterations in symptoms may have been too subtle.
When newly developed or progressive worsening motor symptoms are presented in patients with previous brainstem infarction, a diagnosis of HOD should be considered. The clinical diagnosis depends primarily on the associated symptoms and the characteristic MRI findings. Furthermore, there was no significant correlation between infraction location and time to develop HOD. Moreover, there was no significant correlation between infraction location and MRI findings of HOD. Based on the knowledge that the symptoms of HOD are refractory, and there is no effective targeted therapy to date, we believe that new specific treatments are necessary for a satisfactory prognosis.
Yi-Lin Wang reported the case and drafted the manuscript; Yan Gao, Ping-Ping He, Jiang-Ning Yin, Ruo-Fei Dong, Xin Li, and Yu Fu reviewed the relevant literature; Hong Zhang reviewed the literature and revised the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
This study was approved by the Ethics Committee of China Medical University. Written informed consent for publication of case details and pictures was obtained from each patient.
Thanks to all the peer reviewers and editors for their opinions and suggestions. The authors acknowledge support from Shenyang Science and Technology Project (Project No. 18014482) and 345 Talent Project of Shengjing Hospital of China Medical University.
The authors declare no conflict of interest.