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Case Series *Corresponding author Kamal RM Woods, Department of Neurological Surgery, Loma Linda University Medical Center, Loma The Pathophysiological Basis Linda, California, USA, E-mail: [email protected] Submitted: 21 October 2013 for Hypertrophic Olivary Accepted: 13 December 2013 Published: 15 December 2013 Copyright Degeneration (HOD) Following © 2013 Woods et al. Brainstem Insult OPEN ACCESS Keywords Peter Bouz, Rafeek OJ Woods, and Kamal RM Woods* • Hypertrophic olivary degeneration Department of Neurological Surgery, Loma Linda University Medical Center, USA • Inferior olivary nucleus • Hypertrophy

Abstract Primary lesion of the dentatorubral-olivary pathway may lead to secondary degeneration of the inferior olivary nucleus (ION), resulting in a rare but clinically relevant condition called hypertrophic olivary degeneration (HOD). Patients with HOD often present with palatal myoclonus, ataxia, tremor, dysarthria and/or hemiparesis. Early MRI shows T2 lengthening in the dentate nucleus, superior cerebellar peduncle, red nucleus, or pontine tegmentum. By 6 months, hypertrophy of the ION is usually apparent. HOD is a self-limiting pathology and only symptomatic management is recommended.

ABBREVIATIONS CASE PRESENTATIONS GMT: Triangle of Guillain and Mollaret; ION: Inferior Olivary Case 1 Nucleus; HOD: Hypertrophic Olivary Degeneration, DTI: Diffusion A 16 year-old female presented with progressive gait ataxia, Tensor Imaging vertigo, and nausea. Investigational imaging revealed a large INTRODUCTION posterior fossa mass. At the time of surgical resection of this mass,

brain stem. Pathology demonstrated a low-grade astrocytoma in 1887 by Oppenheim;[1] however, it was not until the early (WHOit was found grade to 2). be MRIadherent done to 6 floor months of the post-operatively fourth ventricle showedand the Hypertrophic olivary degeneration (HOD) was first reported 20th century that the etiology was elucidated. In 1926, Foex et al. T2-lengthening of the ION bilaterally (Figure 1). At 12 months described a process referred to as “transsynaptic degeneration” post-operatively, the patient developed debilitating palatal where neurons undergo neuronal loss and reactive gliosis after myoclonus. Inte

This restingly, this finding was not appreciated during “deafferentation syndrome” is a unique form of degeneration losing synaptic input from injury to their afferent fibers [2]. because it results in enlargement of the affected structure rather than atrophy. Transsynaptic degeneration can occur in various locations in the central nervous system. For example, it has been well described in the lateral geniculate body after lesions in the eye, retina, optic nerve or optic tract. Similarly, HOD is regarded to be the result of transsynaptic degeneration of the inferior olivary nucleus (ION) following injury to the dentatorubral-

Mollaret in 1931 as the anatomical basis for palatal myoclonus, olivary pathway. This pathway was first described by Guillain and a common clinical feature associated with HOD. The triangle comprises connections between the ION, the red nucleus and the Figure 1 T2-weighted MRI was done 6 months after posterior fossa tumor contralateral dentate nucleus and is referred to as the “triangle of resection showing T2 lengthening in the interior olivary nucleus (ION) Guillain and Mollaret” (GMT) [3]. bilaterally.

Cite this article: Bouz P, Woods ROJ, Woods KRM (2013) The Pathophysiological Basis for Hypertrophic Olivary Degeneration (HOD) Following Brainstem Insult. JSM Neurosurg Spine 1(1): 1004. Woods et al. (2013) Email: [email protected] Central palatal myoclonus persisted and is being managed successfully withthe first repeated 12 months Botox afterinjections. surgery. The Two most years recent after MRI, surgery, which wasthe done 19 months after surgery, showed interval mild enlargement of the ION bilaterally and persistence of T2 lengthening (Figure 2). Case 2 A 37 year-old male diagnosed with trigeminal neuralgia underwent open right-sided microvascular decompression (MVD). Due to unsatisfactory outcome, he was retreated with gamma knife surgery a few months after the MVD. Three years later, his trigeminal neuralgia still had not improved, and he underwent endoscopic MVD. This endoscopic procedure was Figure 4 T2-weighted MRI was done 2 years after PICA stroke showing complicated by right posterior inferior cerebellar stroke (Figure hypertrophic olivary degeneration (HOD) of the right inferior olivary nucleus 3). Two years later, the patient presented to our institution with (ION). complaints of dysphasia and slurred speech. Physical examination demonstrated pendular nystagmus, and palatal myoclonus. MRI of the brain showed a hypertrophic lesion in the right medulla, consistent with HOD (Figure 4). The patient’s dysphagia, slurred speech, and nystagmus all slowly improved. Three years after

Figure 5 T2-weighted MRI was done 3 years after PICA stroke showing persistent hypertrophic olivary degeneration (HOD) of the right inferior olivary nucleus (ION).

the stroke, these essentially resolved. The palatal myoclonus, however, persisted but is improved with carbamazepine. The most recent MRI, which was done 3 years from the time of insult, still shows HOD (Figure 5). Figure 2 T2-weighted MRI was done 19 months after posterior fossa tumor resection showing persistence of T2 lengthening and mild enlargement of the DISCUSSION inferior olivary nucleus (ION) bilaterally. HOD is a unique form of degeneration because it results in enlargement of the affected structure rather than atrophy [4,5]. The mechanism underlying these unique pathologic changes is still not well understood. What has been clearly demonstrated is that HOD represents the end-result of a lesion that damages the neuronal connections between the dentate nucleus of the cerebellum, the red nucleus, and the inferior olivary nucleus. The condition carries a wide differential diagnosis that includes infarction, demyelination, primary tumor, metastasis, and infection. Even though the imaging characteristics of hypertrophic olivary degeneration resolve, the clinical hallmarks such as palatal myoclonus persist [6,7]. These clinical symptoms

through the dentatorubral pathway. Makoto et al. showed that palatalpresumably myoclonus, reflect loss and of other inhibitory involuntary control movements, that is transmitted appear prior to the peak in olivary hypertrophy and persist after the hypertrophy resolves. It appears that initial symptomatology is Figure 3 T2-weighted MRI was done immediately after microvascular decompression (MVD) showing evidence of right posterior inferior cerebellar caused by hyperactivity of the olivary neurons, as these neurons artery (PICA) distribution stroke. There is T2 lengthening without enlargement are released from inhibitory inputs, until the peak of olivary of the inferior olivary nucleus (ION). hypertrophy. However, the persistence of the symptoms after the

JSM Neurosurg Spine 1(1): 1004 (2013) 2/4 Woods et al. (2013) Email: [email protected] Central resolution of hypertrophy is probably due to both the disturbance involve both the central tegmental tract and the superior olivary of natural rhythmicity, and the lack of feedback [8]. nucleus [12]. In this paper, we presented examples of HOD related to a posterior fossa tumor and following brainstem stroke. Other mechanisms described in the literature include: head trauma, misdirected interventions. In fact, Case #2 was referred to our [13] posterior fossa surgery, [14,15] stroke, vascular lesions, and institutionCorrect for identification biopsy of a of presumed HOD is “medullary essential in glioma” preventing After idiopathic. careful review of the case; the diagnosis of HOD was made. Fortunately, as described above, the patient’s clinical course Radiological progression of HOD showed slow but steady improvement. HOD appears in a delayed fashion after insult to the Neurosurgeons and other clinicians must include HOD in the dentatorubral-olivary pathway. The radiologic hallmark of the differential diagnosis for enlarged medullary lesions, especially condition is T2 lengthening on MRI. The T2-hyperintense lesion in the setting of previous posterior fossa insult. The differential can be evident anywhere along the GMT: in the dentate nucleus, diagnosis should also include: tumor, multiple sclerosis or other superior cerebellar peduncle, red nucleus, or pontine tegmentum. demyelinating disorder, and stroke. The nearly pathognomonic feature of palatal myoclonus should heighten clinical suspicion increased olivary signal on T2-weighted images can appear as According to metaanalysis of the evolution of MR findings, the for HOD. early as 1 month post-insult, and persisted for at least 3-4 years. Fortunately, HOD is a self-limiting pathology and requires only symptomatic management. Palatal myoclonus has been Olivary hypertophy is another characteristic finding of this shown to respond to medications such as clonazepam, valproic development around 6 month and resolving at around 3-4 years entity on MRI. Olivary hypertrophy is a later finding, with initial acid, and carbamazepine. More severe cases of palatal myclonus (Figure 7). This resolution appears as a result of olivary atrophy. have been successfully treated with botulinum toxin injections Another new modality that can be utilized for evaluation of HOD into the tensor veli palatine muscle. Anatomy of the guillain-mollaret triangle T2 signal intensity Hypertrophy The ION is located in the anterolateral medulla and plays a red nucleus in the midbrain via the central tegmental tract, which traversesrole in coordination. the central Itbrainstem receives afferenttegmentum. fibers Next, from the the red ipsilateral nucleus thereceives dentatorubral afferent fibers tract. from The the dentatorubral contralateral tract dentate leaves nucleus the cerebellumof the cerebellum via the superior through cerebellar cerebellorubral peduncle fibers, and specificallydecussates in the inferior colliculus of the lower midbrain, before synapsing in the contralateral red nucleus. This pathway participates in a 0 0.1 1 10 100 Years after inciting event. reflex arc that controls fine voluntary motor movements. Finally, Figure 6 Temporal evolution of the hypertrophy and T2 signal intensity seen cerebellum, which cross midline through the medial lemniscus in HOD9. andcompleting enter the triangle cerebellum are the through efferent the fibers contralateral from the ION inferior to the cerebellar peduncle to synapse on the contralateral dentate nucleus (Figure 6).

the Theolivocerebellar fibers from tractthe ION then do project not project to the directly dentate to nucleusthe dentate [9]. nucleus; instead, they first synapse in the cerebellar cortex via isolated lesions of the inferior cerebellar peduncle (olivodentate tract)This is do of not clinical cause significance palatal myoclonus because or it HOD, has been which shown has been that postulated to be due to the lack of direct connections between the ION and the dentate nucleus [10]. Additionally, the olivodentate tract is an efferent tract and the pathophysiological basis of HOD is deafferentation of the ION. Nonetheless, the olivodentate tract is believed to play role in maintaining the cerebellar hemispheres, and lesions of this pathway have been reported to cause cerebellar atrophy [11]. Lesions in the brainstem involving the central tegmental tract cause ipsilateral HOD, while lesions in the cerebellum (dentate nucleus and superior cerebellar peduncle) cause contralateral HOD. Bilateral HOD has also been reported from lesions that Figure 7 The “triangle of Guillain and Mollaret” (GMT).

JSM Neurosurg Spine 1(1): 1004 (2013) 3/4 Woods et al. (2013) Email: [email protected] Central is diffusion tensor imaging (DTI). DTI may reveal increased 5. Kitajima M, Korogi Y, Shimomura O, Sakamoto Y, Hirai T, Miyayama H, radial diffusivity representing demyelination, and an increase in et al. Hypertrophic olivary degeneration: MR imaging and pathologic

Characteristic deviation, deformation and interruption were 6. findings. Radiology. 1994; 192: 539-543. notaxial observed diffusivity during that isthe reflective DTI in HOD of neuronal as would hypertrophy. be expected with[16] and essential palatal tremor. 1. Clinical, physiological and MRI brainstem tumors. [17] analysis.Deuschl G, Brain. Toro 1994;C, Valls-Solé 117 : 775-788. J, Zeffiro T, Zee DS, Hallett M. Symptomatic 7. Goyal M, Versnick E, Tuite P, Cyr JS, Kucharczyk W, Montanera W, et Pathological progression of HOD al. Hypertrophic olivary degeneration: metaanalysis of the temporal It has been implicated that the initial signal hyperintensity 1077. relates to the early phases of gliosis due to demyelination and evolution of MR findings. AJNR Am J Neuroradiol. 2000; 21: 1073- increased water content. [18] The hypertrophy of olivary nucleus, 8. Nishie M, Yoshida Y, Hirata Y, Matsunaga M. Generation of symptomatic therefore, is the stage of pathological changes that leads to cell palatal tremor is not correlated with inferior olivary hypertrophy. death of both neurons and astrocytes. This process eventually Brain. 2002; 125: 1348-1357. results in atrophy, and olivary shrinkage. 9. Lapresle J. La voie dento-olivaire: sa mise en evidence, son trajet, sa Neuronal hypertrophy begins 20–30days after the onset of the causative lesion, and reaches maximum size, accompanied 10. signification.Trelles JO. [Velo-palatal Bull Acad Natl myoclonus. Med 1984; Anatomical168:336-341. and physiological by prominent astrocytosis and synaptic and axonal remodeling, studies]. Rev Neurol (Paris). 1968; 119: 165-171. 6–7months later. Early hypertrophic changes correlate with 11. Kim SJ, Lee JH, Suh DC. Cerebellar MR changes in patients with olivary neuronal ballooning and the presence of increased numbers of hypertrophic degeneration. AJNR Am J Neuroradiol. 1994; 15: 1715- protoplasmic astrocytes. At 6 months, there is further olivary 1719. enlargement with the presence of vacuoles in the ballooned 12. Gerace C, Fele MR, Luna R, Piazza G. Neurological picture. Bilateral neurons, as well as prominence of gemistocytic astrocytes. hypertrophic olivary degeneration. J Neurol Neurosurg Psychiatry. The hypertrophic changes decrease with time in association 2006; 77: 73. with atrophy. At 2 years, there is a decreased in the number of 13. Suzuki M, Takashima T, Ueda F, Fujinaga Y, Horichi Y, Yamashita neurons. In patients surviving >6 years after the insult, there is J. Olivary degeneration after intracranial haemorrhage or trauma: >90% reduction in the normal number of neurons. follow-up MRI. Neuroradiology. 1999; 41: 9-12. CONCLUSION 14. Hornyak M, Osborn AG, Couldwell WT. Hypertrophic olivary degeneration after surgical removal of cavernous malformations of HOD is a rare pathological entity that presents with a the brain stem: report of four cases and review of the literature. Acta spectrum of physical manifestations. It appears to be the end- Neurochir (Wien). 2008; 150: 149-156. result of insult to a variety of structures along the GMT. Accurate 15. Sanverdi S, Oguz K, Haliloglu G. Hypertrophic Olivary Degeneration and timely diagnosis is essential to prevent untoward and in Children: new 4 cases and review of literature with emphasis on misdirected interventions. 511-16. REFERENCES the MR imaging findings. The British Journal of Radiology. 85 (2012), 16. 1. Oppenheim H. Uber olivendegeneration bei atheromatose der basalen Diffusion tensor imaging of Guillain-Mollaret triangle in patients with hrnarterien. Berl Klin Wochenshr 1887; 34: 638-639. hypertrophicDinçer A, Özyurt olivary O, degeneration. Kaya D, Koşak J Neuroimaging. E, Öztürk C, 2011;Erzen 21: C, et 145- al. 151. 2. Foix C, CHavany J, Hillemand P. Le Syndrome myoclonique de la calotte. Rev Neurol 1926; 33: 942-956. 17. Chen X, Weigel D, Ganslandt O, Buchfelder M, Nimsky C. Diffusion tensor imaging and white matter tractography in patients with 3. Guillan G, Mollaret P. Deux de myoclonies synchrones et rhythmees brainstem lesions. Acta Neurochir (Wien). 2007; 149: 1117-1131. velopharngo-laryngo-oculo-diaphragmatiques. Rev Neurol 1931; 12: 545-566. 18. Goto N, Kakimi S, Kaneko M. Olivary enlargement: stage of initial astrocytic changes. Clin Neuropathol. 1988; 7: 39-43. 4. of neurons and neuralgia. Neuropathology. 5th ed. New York, NY: Wiley,Duchen 1994; LW. Greenfield 20-21. H, Corsellis JA, Duchen LW. General pathology

Cite this article Bouz P, Woods ROJ, Woods KRM (2013) The Pathophysiological Basis for Hypertrophic Olivary Degeneration (HOD) Following Brainstem Insult. JSM Neurosurg Spine 1(1): 1004.

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