Hypertrophic Olivary Degeneration and Palatal or Oculopalatal Tremor

Abstract

Hypertrophic degeneration of the inferior olive is mainly observed in patients developing palatal tremor (PT) or oculopalatal tremor (OPT). This syndrome manifests as a synchronous tremor of the palate (PT) and/or eyes (OPT) that may also involve other muscles from the branchial arches. It is associated with hypertrophic inferior olivary degeneration that is characterized by enlarged and vacuolated neurons, increased number and size of astrocytes, severe fibrillary gliosis, and demyelination. It appears on MRI as an increased T2/FLAIR signal intensity and enlargement of the inferior olive. There are two main conditions in which hypertrophic degeneration of the inferior olive occurs. The most frequent, studied, and reported condition is the development of PT/OPT and hypertrophic degeneration of the inferior olive in the weeks or months following a structural brainstem or cerebellar lesion. This "symptomatic" condition requires a destructive lesion in the Guillain-Mollaret pathway, which spans from the contralateral dentate nucleus via the brachium conjunctivum and the ipsilateral central tegmental tract innervating the inferior olive. The most frequent etiologies of destructive lesion are stroke (hemorrhagic more often than ischemic), brain trauma, brainstem tumors, and surgical or gamma knife treatment of brainstem cavernoma. The most accepted explanation for this symptomatic PT/OPT is that denervated olivary neurons released from inhibitory inputs enlarge and develop sustained synchronized oscillations. The cerebellum then modulates/accentuates this signal resulting in abnormal motor output in the branchial arches. In a second condition, PT/OPT and progressive cerebellar ataxia occurs in patients without structural brainstem or cerebellar lesion, other than cerebellar atrophy. This syndrome of progressive ataxia and palatal tremor may be sporadic or familial. In the familial form, where hypertrophic degeneration of the inferior olive may not occur (or not reported), the main reported etiologies are Alexander disease, polymerase gamma mutation, and spinocerebellar ataxia type 20. Whether or not these are associated with specific degeneration of the dentato-olivary pathway remain to be determined. The most symptomatic consequence of OPT is eye oscillations. Therapeutic trials suggest gabapentin or memantine as valuable drugs to treat eye oscillations in OPT.

Keywords: Guillain–Mollaret triangle; dentato–olivary pathway; hypertrophic degeneration of inferior olive; pendular nystagmus; progressive ataxia and palatal tremor; symptomatic palatal tremor.

Figure 1

Eye position (in degrees) traces according to time (in seconds) for right (left panel) and left (right panel) eye in an oculopalatal tremor patient. Continuous line: horizontal position, discontinuous line: vertical position, and dotted gray line: torsional position. Adapted from Ref. (24).

Figure 2

Schematic representation of the Guillain–Mollaret triangle. The pathway coming from the contralateral dentate nucleus, through the contralateral brachium conjunctivum crosses the midline, turns around the ipsilateral red nucleus, and descends in the ipsilateral central tegmental tract to the inferior olive. Adapted from Ref. (36).

Figure 3

Pathological features of degenerative inferior olive hypertrophy. Hypertrophic inferior olive (A) compared to contralateral side (B) (Bodian Luxol, X200). Note the mild demyelination of the surrounding white matter. (C) Coronal section of the medulla oblongata showing hypertrophy of the left inferior olive (Loyez stain). (D) Swelled and vacuolated nerve cells (“fenestrated neurons”) observed in the hypertrophic inferior olive [from (A), Bodian Luxol, X400]. Courtesy of Charles Duyckaerts and Franck Bielle, Escourolle’s Lab, Pitie-Salpetriere Hospital, Paris, France. Adapted from Ref. (51).

Figure 4

Axial FLAIR or T2 MRI (1.5-T GE scanners) at (A) inferior olive level and (B) midpontine tegmentum level in five patients with symptomatic oculopalatal tremor. White arrows in (A) indicate the abnormal inferior olive hypersignal and in (B) the causative lesion. Adapted from Ref. (24).

Figure 5

Temporal evolution of right-sided inferior olive hypersignal in a patient with symptomatic oculopalatal tremor. The patient presented a right-sided pontine tegmental lesion in June 2014 seen on the diffusion MRI scan (A), and the medulla showed no abnormal hypersignal on FLAIR MRI (B). Subsequently, right inferior olive hypersignal was observed 6 months later (C), with increasing signal 1 year later (D) and right inferior olive hypertrophy was observed 2 years later (E).

Figure 6

Schematic representation of the Guillain–Mollaret triangle formed by connections between the deep cerebellar nuclei and contralateral inferior olive, which pass near the red nucleus (A). The conduction strength through the dendrodendritic gap junctions (schematized with yellow connexon channels; DD) between adjacent inferior olivary neurons are inhibited by projections from the deep cerebellar nuclei (blue projection) (B). Lesions in the Guillain–Mollaret triangle [red X in (A,B)] also result in hypertrophy of inferior olive neurons causing development of abnormal soma-somatic gap junction. Schematic representation of a model for classical delay conditioning (C,D). Model and traces from simulations after inferior olive hypertrophy but before cerebellar learning (C). Inferior olive and cerebellar modules after hypertrophy and learning (D). Lower left corner shows icon for semicircular canals (C,D). Simulated membrane potentials (black), eye oscillations (magenta). CF, climbing fibers; PF, parallel fibers; DD, dendrodendritic gap junction; SS, soma-somatic gap junction; Gr, granule cell layer; IN, interneurons; PC, Purkinje neurons [(27) with permission for reproduction of material].

Figure 7

Eye position (in degrees) traces over time (in seconds) in one oculopalatal tremor patient, without treatment (upper panel) and under gabapentin (lower panel). Dark line: horizontal position, gray line: vertical position, and light gray line: torsional position. Note the decrease in nystagmus amplitude, mainly in the torsional plane, under gabapentin.