Background: Hypertrophic olivary degeneration (HOD) is a rare phenomenon, probably related to transsynaptic degeneration of the inferior olivary nucleus. It usually occurs as a response to primary injury of dento-rubro-olivary pathways.

Case report: A young man developed Holmes' tremor 7 months after a cavernous malformation bleed in the midbrain. Typical findings of HOD were observed in the magnetic resonance images: bilateral and asymmetric hypertrophy of the olivary nucleus with slight hypersignal in T2-weighted images. Because of the striking disability related to drug-resistant tremor, the patient underwent stereotactic thalamotomy (nucleus ventralis intermedius of the thalamus/zona incerta) with pronounced functional improvement over time.

Discussion: Disruption of circuits in the Guillain–Mollaret triangle classically results in palatal myoclonus, however midbrain (Holmes') tremor can also occur, as we now describe.

Keywords: Olivary nucleus/pathology, tremor/etiology, magnetic resonance imaging, central nervous system vascular malformations, stereotaxic surgery

Citation: Menéndez DFS, Cury RG, Barbosa ER, et al. Hypertrophic olivary degeneration and Holmes' tremor secondary to bleeding of cavernous malformation in the midbrain. Tremor Other Hyperkinet Mov. 2014; 4. doi: 10.7916/D8PG1PX

Menéndez, Djalma F. S.

Cury, Rubens G.

Barbosa, Egberto R.

Teixeira, Manoel J.

Fonoff, Erich T.

Columbia University Academic Commons

Case ReportsHypertrophic Olivary Degeneration and Holmes’ Tremor Secondary to Bleedingof Cavernous Malformation in the MidbrainDjalma F. S. Mene´ndez1, Rubens G. Cury2, Egberto R. Barbosa2, Manoel J. Teixeira3& Erich T. Fonoff31Division of Functional Neurosurgery of the Institute of Psychiatry of the Hospital das Clinicas of the University of Sa˜o Paulo, 2Abnormal Movements Unit of theHospital das Clinicas of the University of Sa˜o Paulo, 3Discipline of Neurosurgery of the Sa˜o Paulo University Medical SchoolAbstractBackground: Hypertrophic olivary degeneration (HOD) is a rare phenomenon, probably related to transsynaptic degeneration of the inferior olivary nucleus. Itusually occurs as a response to primary injury of dento-rubro-olivary pathways.Case report: A young man developed Holmes’ tremor 7 months after a cavernous malformation bleed in the midbrain. Typical findings of HOD were observedin the magnetic resonance images: bilateral and asymmetric hypertrophy of the olivary nucleus with slight hypersignal in T2-weighted images. Because of thestriking disability related to drug-resistant tremor, the patient underwent stereotactic thalamotomy (nucleus ventralis intermedius of the thalamus/zona incerta) withpronounced functional improvement over time.Discussion: Disruption of circuits in the Guillain–Mollaret triangle classically results in palatal myoclonus, however midbrain (Holmes’) tremor can also occur, aswe now describe.Keywords: Olivary nucleus/pathology, tremor/etiology, magnetic resonance imaging, central nervous system vascular malformations, stereotaxic surgeryCitation: Mene´ndez DFS, Cury RG, Barbosa ER, et al. Hypertrophic olivary degeneration and Holmes’ tremor secondary to bleeding of cavernous malformationin the midbrain. Tremor Other Hyperkinet Mov. 2014; 4. doi: 10.7916/D8PG1PXTEditor: Elan D. Louis, Columbia University, USAReceived: July 11, 2014 Accepted: August 18, 2014 Published: October 8, 2014Copyright: ’ 2014 Mene´ndez et al. This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommercial–No Derivatives License, whichpermits the user to copy, distribute, and transmit the work provided that the original author(s) and source are credited; that no commercial use is made of the work; and that the work is notaltered or transformed.Funding: None.Financial Disclosures: None.Conflict of Interest: The authors report no conflict of interest.IntroductionHypertrophic olivary degeneration (HOD) is a rare form ofneuronal degeneration that occurs secondary to injuries that disruptnormal function of the afferent fibers to the inferior olivary nucleus(ION) as part of the dentate-rubro-olivary pathways (triangle ofGuillain–Mollaret).1 The first description of HOD was published byOppenheim in 1887, and the development of HOD was furtherdescribed by Guillain and Mollaret in 1931.2,3Insults to this pathway are commonly related to vascular disease,either infarction or hemorrhage. However, HOD may occur afterhead trauma, tumor, demyelinating or degenerative diseases, and aftersurgical manipulation.1,4 HOD is best observed using magneticresonance imaging (MRI), where it appears as an enlargement of theION, with increased signal on T2-weighted images.5Symptomatic palatal tremor is a well-defined movement disorderthat appears after lesions involving the Guillain–Mollaret triangle andis classically associated with HOD.2–4 Although almost all cases ofpalatal tremor present with HOD, not all cases of HOD areaccompanied by palatal tremor.6 Dentato-rubral tremor, or Holmes’tremor (HT), is a different clinical entity that can be (but isinfrequently) accompanied by HOD. HT is a symptomatic tremorthat presents with high-amplitude and low-frequency rhythmiccomplex movements. It usually arises as a delayed manifestation oflesions in the upper brainstem, often related to stroke or head trauma.The Consensus Statement of the Movement Disorder Society ontremor, published in 1998, stated that both the dopaminergicnigrostriatal and the cerebellum–thalamic systems are involved inthe occurrence of this type of tremor. Recently, HT associated with abrainstem lesion has been reported as a fairly rare type of tremor.7In the present report, a patient who was diagnosed with HT after ahemorrhage in the midbrain related to a cavernous malformationshowed signs of HOD on MRI scans.Freely available onlineTremor and Other Hyperkinetic Movementshttp://www.tremorjournal.orgThe Center for Digital Research and ScholarshipColumbia University Libraries/Information Services1Case reportA 27-year-old male with a past history of chronic headachepresented with a severe thunderclap headache followed by acute left-sided weakness, diplopia, right-eyelid ptosis, and moderate dysarthria.Seven months later he developed severe tremor on his left side.Initially, the tremor arose in his arm and gradually spread to his leg,with proximal involvement worse than distal involvement. Earlyfollow-up MRI showed a rim of low signal due to hemosiderin on agradient echo sequence without any mass effect or contrast enhance-ment (gadolinium), confirming a cavernous malformation in the rightmidbrain and evidence of prior surrounding hemorrhage. Four yearsafter onset of the original headache, the MRI revealed asymmetricenlargement of the olivary nuclei, slightly more prominent on theright, with pronounced hyperintensity in T2 images and reducedintensity in fluid-attenuation inversion recovery (FLAIR) imagesconsistent with HOD. No contrast enhancement (gadolinium) wasobserved (Figure 1).The patient was referred to our neurosurgical unit and examinationrevealed a severe rest tremor that was incessant, worsened withposture, and amplified during intentional movements, with a lowfrequency of 4 Hz and featuring a typical clinical picture of a severeHT. Furthermore, the tremor caused severe functional impairmentand prevented the patient from standing up.Despite medical treatment with various drugs (trihexyphenidyl6 mg/day, primidone 500 mg/day, clonazepam 6 mg/day, andpropranolol 120 mg/day), the patient did not experience satisfactorytremor control. At this point, the stereotactic procedure was presentedas a therapeutic option. An ablative procedure was performed in thezona incerta in the right side, including the bottom of the nucleusventralis intermedius of the thalamus (VIM). The tremor was markedlyreduced after the procedure. The previous clinical scenario of lefthemiparesis, right third nerve palsy, and dysarthria were unchanged.Over 95% of the improvement in the tremor was observed directlyafter the procedure. This improvement was maintained up to the latestfollow-up appointment, which was around 5 years after the operation.The patient also reported a significant improvement in quality of lifeand social interaction. The abolition of tremor made rehabilitationpossible, and the patient’s posture and muscle strength improved overtime. Neither palatal nor ocular tremor was observed during the lastfollow-up.DiscussionHOD is a unique transsynaptic neuronal degeneration caused bylesions in the circuit of the Guillain–Mollaret triangle. It is defined bythree anatomical structures: the dentate nucleus in the cerebellum, thecontralateral red nucleus at the level of the midbrain, and thecontralateral ION in the medulla oblongata. The dentate nucleusafferents travel via the superior cerebellar peduncle and cross themidline towards the contralateral red nucleus. From the red nucleus,fibers descend in the central tegmental tract to enter the ION. TheION sends its afferents via climbing fibers in the inferior cerebellarpeduncle to Purkinje cells of the contralateral cerebellar cortex. ThePurkinje cells send their afferents to the ipsilateral dentate nucleus, thuscompleting the triangle. This triangular circuit exhibits bi-directionalpathways between the dentate nucleus and the contralateral ION,creating a coupled feedback control system. The inferior olive tends todemonstrate a slow, rhythmic, spontaneous activity. ION deafferenta-tion may cause hypersensitivity denervation followed by HOD.3,8,9While transsynaptic neuronal degeneration associated with atrophyof the targeted structure is a common response to a confined lesion(e.g., atrophy of the mammillary bodies in lesions involving the fornix),such degeneration resulting in hypertrophy of the targeted region isunique to the ION.1,10 Post-mortem studies reveal large neuronal cellbodies approximately 3 weeks after the causative event, with a peak inneuronal and glial growth observed at 8–9 months. Pseudohyper-trophy (neuronal dissolution and gemistocytic astrocytic reaction)Figure 1. Four-year Follow-up Magnetic Resonance Imaging. (A,B) serial T2-weighted and (C,D) fluid-attenuation inversion recovery (FLAIR) images showingthe olivary nucleus. There is a hyperintense signal in the inferior olivary nucleus bilaterally, signal in T2 more pronounced than FLAIR, and enlargement of olives,slightly more prominent on the right, consistent with HOD. (E) T1-gadolinium image with no enhancement. (F) A rim of signal loss due to hemosiderin on gradient echosequence, confirming a cavernous malformation on the right midbrain and prior surrounding hemorrhage.Mene´ndez DFS, Cury RG, Barbosa ER, et al. Olivary Degeneration and Holmes’ TremorTremor and Other Hyperkinetic Movementshttp://www.tremorjournal.orgThe Center for Digital Research and ScholarshipColumbia University Libraries/Information Services2follows that stage and is usually maintained for several months. Finally,the olivary nucleus atrophies more than a year after injury.3,4,9,10HOD’s hallmarks include hypertrophy of the olive with increasedT2 signal intensity on MRI, which are correlated with the pathologicalfindings. In the first 6 months following the onset of HOD, there is anincreased signal on T2 with normal looking inferior olives. The secondstage lasts for about 3 to 4 years and demonstrates an increased signalwith evidence of olivary pseudohypertrophy. During the third stage,the atrophy follows the hypertrophy as it resolves, but persistent high-signal T2 can be observed.2,5The differential diagnosis of signal hyperintensity on T2-weightedimages within the pontomedullary region includes tumors (malignan-cies such as primary brainstem astrocytoma or metastasis), demyeli-nating lesions, infarction, and inflammatory processes (tuberculosis,sarcoidosis, or encephalitis). The lack of contrast enhancement,however, makes hypothetical malignancies and infectious disease lesslikely to be the cause, while the enlargement of the olivary nucleusitself weans chronic stages of infarction or multiple sclerosis. Therefore,in the setting of a T2-hyperintense non-contrast enhancing lesion,which is accompanied by enlargement of the olivary nucleus, HODremains the sole diagnosis that explains all of the imaging findings.Identifying an inciting lesion appropriately located to interrupt thedentate-rubro-olivary tracts with the correct timing of the signalchange and swelling is the key to diagnosis.1,4,10The clinical manifestation offered by alterations in the Guillain–Mollaret triangle can be quite diverse, and still no unifying theory ableto link the pathological changes and the resulting clinical picture hasbeen postulated.3 Classically, palatal tremor is the most reportedneurological sign that accompanies HOD. However, the incidence ofHOD after brainstem injury is unknown and the occurrence of palataltremor with HOD is also variable.4Unusually, other movement disorders can also occur in associationwith HOD, presenting as HT or ocular myoclonus. Recently, HTassociated with a brainstem lesion has been reported as an extremelyrare tremor, along with drug-induced tremor, orthostatic tremor, andpsychogenic tremor. Furthermore, descriptions of HT associated withHOD are even scarcer.7 Although lower brainstem hemorrhage isamong several common causes of HOD, it has not been appreciated as acause of midbrain (‘‘rubral’’) tremor. It is most likely that disynapticdentate-rubro-olivary tract degeneration (associated with tremor) andthe monosynaptic dentate-olivary tract (associated with HOD) are bothcomponents of the rubro-olive-cerebello-rubral loop implicated inmidbrain tremors. Their functional convergence makes the combinationof tremor and HOD after brainstem damage plausible and even likely.6Pharmacological treatment of HT is usually disappointing, sostereotactic ablative procedures (thalamotomy) or deep brain stimula-tion are often required in refractory cases and provide encouragingresults.11 Many treatment methods have been tried; however, no goldstandard treatments currently exist for HT.7HOD is a unique pathological entity that occurs variably after injuryto the brainstem. Specifically, injury to the dentate-rubro-olivarypathway can result in HOD, which may be associated with palataltremor and, less often, HT or ocular myoclonus. However, thepossibility of developing HOD and its clinical sequelae is a relevantconcern for clinicians and patients. Whenever changes are observed inthe MRI images that suggest HOD, a simple but careful examinationof the pharynx, larynx, and ocular movements should be performed.HOD after injury to any component of the triangle of Guillain–Mollaret should not be confused with neoplastic, vascular, or otherprimary pathological conditions of the medulla. When HOD isconsidered in the differential diagnosis, patients can be counseledappropriately, and treatment can be initiated.References1. Gatlin JL, Wineman R, Schlakman B, et al. Hypertrophic olivarydegeneration after resection of a pontine cavernous malformation: A casereport. J Radiol Case Rep 2011;5:24–29, doi: http://dx.doi.org/10.1186/1752-1947-5-24.2. Yun JH, Ahn JS, Park JC, et al. Hypertrophic olivary degenerationfollowing surgical resection or gamma knife radiosurgery of brainstemcavernous malformations: An 11-case series and a review of literature. ActaNeurochir (Wien) 2013;155:469–476, doi: http://dx.doi.org/10.1007/s00701-012-1567-y.3. Khoyratty F, Wilson T. The dentato-rubro-olivary tract: Clinicaldimension of this anatomical pathway. Case Rep Otolaryngol 2013;2013:934386.4. Hornyak M, Osborn AG, Couldwell WT. Hypertrophic olivarydegeneration after surgical removal of cavernous malformations of the brainstem: Report of four cases and review of the literature. Acta Neurochir (Wien)2008;150:149–156, doi: http://dx.doi.org/10.1007/s00701-007-1470-0.5. Goyal M, Versnick E, Tuite P, et al. Hypertrophic olivary degeneration:Metaanalysis of the temporal evolution of MR findings. AJNR Am J Neuroradiol2000;21:1073–1077.6. Shepherd GM, Tauboll E, Bakke SJ, et al. Midbrain tremor andhypertrophic olivary degeneration after pontine hemorrhage. Mov Disord 1997;12:432–437, doi: http://dx.doi.org/10.1002/mds.870120327.7. Woo JH, Hong BY, Kim JS, et al. Holmes tremor after brainstemhemorrhage, treated with levodopa. Ann Rehabil Med 2013;37:591–594, doi:http://dx.doi.org/10.5535/arm.2013.37.4.591.8. Shinohara Y, Kinoshita T, Kinoshita F, et al. Hypertrophic olivarydegeneration after surgical resection of brain tumors. Acta Radiol 2013;54:462–466.9. Conforto AB, Smid J, Marie SK, et al. Bilateral olivary hypertrophy afterunilateral cerebellar infarction. Arq Neuropsiquiatr 2005;63:321–323, doi: http://dx.doi.org/10.1590/S0004-282X2005000200022.10. Krings T, Foltys H, Meister IG, et al. Hypertrophic olivary degenerationfollowing pontine haemorrhage: Hypertensive crisis or cavernous haemangiomableeding? J Neurol Neurosurg Psychiatry 2003;74:797–799, doi: http://dx.doi.org/10.1136/jnnp.74.6.797.11. Nikkhah G, Prokop T, Hellwig B, et al. Deep brain stimulation of thenucleus ventralis intermedius for Holmes (rubral) tremor and associateddystonia caused by upper brainstem lesions: Report of two cases. J Neurosurg2004;100:1079–1083, doi: http://dx.doi.org/10.3171/jns.2004.100.6.1079.Olivary Degeneration and Holmes’ Tremor Mene´ndez DFS, Cury RG, Barbosa ER, et al.Tremor and Other Hyperkinetic Movementshttp://www.tremorjournal.orgThe Center for Digital Research and ScholarshipColumbia University Libraries/Information Services3

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Hypertrophic Olivary Degeneration and Holmes' Tremor Secondary to Bleeding of Cavernous Malformation in the Midbrain

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Hypertrophic Olivary Degeneration and Holmes' Tremor Secondary to Bleeding of Cavernous Malformation in the Midbrain

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