ARTICLE IN PRESS Clinical Study on 3 Patients with Infarction of the Vermis/Tonsil in the Cerebellum D1X XKatsuhiko Ogawa, MD, D2X X * D3X XYutaka Suzuki, MD, D4X X † D5X XTakayoshi Akimoto, MD, D6X X * D7X XAkihiko Morita, MD, D8X X * D9X XMakoto Hara, MD, D10X X * D1X XHirokazu Yoshihashi, MD, D12X X ‡ D13X XSatoshi Kamei, MD, D14X X * and D15X XMasayoshi Soma, MD D16X X † Background: Infarction of the vermis and the tonsil in the cerebellum presents as truncal and gait ataxia. Acute rotatory vertigo is often present in infarction of the nodulus in the caudal vermis, which is closely associated with the vestibular pathway, but is minor in infarction of the rostral vermis. The rostral vermis receives input from the dorsal spinocerebellar tract (DSCT) which conveys unconsciousness proprioceptive signals from the ipsilateral lower trunk and leg. The present study investigated the characteristics of infarction of the vermis and the tonsil. Patients and Methods: Neuroradiological ﬁndings of 3 patients whose lesions were located in the vermis or the tonsil were analyzed. Results: All lesions were located in the anterior lobe in the rostral vermis, the nodulus in the caudal vermis, or the tonsil. Truncal and gait ataxia were exhibited by 3 patients. Rotatory vertigo was exhibited by 2 patients whose lesions were located in the nodulus and the tonsil, but absent in a patient with infarction of the anterior lobe. Lateropulsion opposite the lesion was apparent in a patient with infarction of the tonsil. Gaze-evoked nystagmus was observed in 2 patients with infarction of the nodulus and the tonsil. Conclusions: The tonsil and the nodulus were considered to have a close relationship with the vestibular pathway. Absence of rotatory vertigo indicated impairment of the DSCT. Our data suggested that the cause of truncal and gait ataxia differed between the rostral vermis and the caudal vermis/tonsil. Key Words: Vermis infarction—nodulus—tonsil—nodulovestibular Purkinje ﬁbers—anterior lobe—dorsal spinocerebellar tract © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved. The vermis exists at the median zone in the cerebellum.1,2 Dysfunction of the vermis causes truncal and gait ataxia, and is often accompanied by truncal lateropulsion.2,3 Magnetic resonance imaging (MRI) has made it possible to detect a small infarct in the cerebellum From the *Division of Neurology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan; †Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan; and ‡Department of Neurology, Kobari General Hospital, Chiba, Japan. Received March 27, 2018; revision received May 1, 2018; accepted May 25, 2018. Address correspondence to Yutaka Suzuki, MD, Division of General Medicine, Department of Medicine, Nihon University School of Medicine, 30 -1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo 1738610, Japan. E-mail: email@example.com 1052-3057/$ - see front matter © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.05.040 including in the vermis.4 Infarction of the vermis has been recently reported.5 9 In the previously reported patients,5 9 the nodulus in the caudal vermis was most commonly involved.5 9 Infarction of the nodulus presents as acute rotatory vertigo and truncal and gait ataxia including lateropulsion, whereas ataxia of the extremities was slight or absent.5 9 Thus, neurological ﬁndings of infarction of the nodulus mimicked those of peripheral vestibulopathy, such as benign paroxysmal positional vertigo, and it was referred to as pseudo-labyrinthine disease or isolated vascular vertigo.5 7,10 15 Additionally, infarction of the tonsil in the cerebellum, which demonstrated rotatory vertigo, was reported.16 The tonsil is adjacent to the caudal vermis and also supplied by the medial branch of the posterior inferior cerebellar artery (mPICA) as the caudal vermis.1,3 Furthermore, a patient with infarction of the rostral vermis was reported to exhibit isolated lateropulsion without rotatory vertigo.17 Here, we assessed the neurological characteristics for infarction of the vermis Journal of Stroke and Cerebrovascular Diseases, Vol. &&, N0. && (&&), 2018: pp 1-7 1 ARTICLE IN PRESS HTN, af CE Mild stenosis of the bil VA/BA ¡ AD of the rt VA A to A embolism DL Moderate stenosis of the bil VA Moderate stenosis of the rt VA ¡ Lateropulsion to the lt side. Lateralized to the lt side after 2 steps walking with assistance ¡ ¡ rt tonsil + (Rotatory) + (rt) + (Rotatory) + + (Rotatory) ¡ ¡ ¡ Vascular findings Ataxia of the extremities Nystagmus Truncal and gait ataxia + (Dizziness) Unstable in normal walking and tandem gait + (Rotatory) Unstable in standing with closed gait, Unstable in wide-based gait ¡ + (Dizziness) ¡ 3/86/F Three patients were enrolled in our study. Infarcts were located in the anterior lobe in the rostral vermis on the left side (patient 1) (Fig 1, A, B), in the nodulus in the caudal 2/22/M Distribution of Infarcts No./age/ Location of Nausea/ Headache/ gender infarction Acute vertigo Vomit Neck pain Vertigo Results (Table 1) Neurological symptoms upon admission Infarcts in the cerebellum were identiﬁed using 1.5-tesla MRI (DWIs, ﬂuid-attenuated inversion recovery imaging, and T2-weighted imaging). The extent of infarcts was measured on ﬁndings of T2-weighted images and DWIs. Vascular ﬁndings for the posterior circulation were evaluated, based on results of magnetic resonance angiography in 2 patients (patients 1, 3) and by 3-dimensional computed tomographic angiography in 1 (patient 2). The etiologies of infarction were comprised of (1) cardiogenic embolism (CE) associated with emboligenic heart disease such as atrial ﬁbrillation (af), (2) atherothrombotic large vessel disease (LVD) with angiographic evidence of moderate to severe stenotic and occluded arteries of the posterior circulation in the absence of emboligenic heart disease, and (3) arterial dissection (AD) in the vertebral artery (VA) or the basilar artery (BA). LVD was subdivided into branch atheromatous disease when moderate to severe stenosis of the main trunk artery (the BA or the VA) was adjacent to the lesions, or artery-to-artery (A to A) embolism when moderate to severe stenosis was found in the proximal region of the main trunk artery to the lesions. Identiﬁcation of AD was made when serrated irregularity of the wall (string sign) was detected in the VA or the BA in a patient with neck pain at onset. Small vessel disease (SVD) was considered when CE or LVD was not indicated. Initial symptoms Location of Infarcts and Vascular Findings Table 1. Clinical findings for 3 patients with infarction of the vermis/tonsil in the cerebellum We analyzed neurological and MRI ﬁndings of 2 patients with infarction of the vermis and 1 patient with infarction of the tonsil in the cerebellum (age, 22-86 years; male, n = 1). The elapsed time between the onset of the initial symptoms and MRI assessment ranged from 15 hours to 2 days. Brain infarction was diagnosed, based on the presence of a high-intensity area in diffusion-weighted images (DWIs). The medical charts of the patients were reviewed to identify initial symptoms, neurological ﬁndings upon admission, and vascular risk factors. A boardcertiﬁed specialist in neurology (K.O., Y.S., T.A., A.M., M. H., H.Y., and S.K.) performed neurological examinations. Nystagmus was assessed using the confrontation test. Etiology Characteristics of the Enrolled Patients (Table 1) lt anterior lobe rt nodulus Patients and Methods 1/66/F Risk factors and the tonsil in the cerebellum, based on neuroradiological ﬁndings in patients whose lesions were located in these areas. Abbreviations: AD, arterial dissection; af, arterial fibrillation; A to A: artery to artery; BA, basilar artery; BAD, branch atheromatous disease, bil, bilateral; CE, cardiogenic embolism; DL, dyslipidemia; HTN, hypertension; lt, left; rt, right; VA, vertebral artery. K. OGAWA ET AL. 2 ARTICLE IN PRESS CEREBELLAR VERMIS/TONSIL INFARCTION vermis on the right side (patient 2) (Fig 2, A-D), and in the tonsil on the right side (patient 3) (Fig 3, A, B). Initial Symptoms of the 3 Patients Three patients exhibited acute vertigo at onset. The type of vertigo was rotatory in 2 patients (patients 2, 3) and dizziness in the other patient (patient 1). Neck pain on the ipsilateral side of the lesion as well as nausea/vomiting were presented by 1 patient at onset (patient 2). Figure 1. An axial diffusion-weighted image and its schematic (A, B) (patient 1). An abnormal high-intensity area was noted in the anterior lobe in the rostral vermis on the left side. 3 Neurological Findings on Admission Vertigo was still present in all 3 patients on admission. The type of vertigo on admission was the same at onset in all. Truncal ataxia was present in 2 patients (patients 2, 3). Lateropulsion was identiﬁed in 1 patient (patient 3). The direction of lateropulsion was to the opposite side of the lesion (patient 3). Gait ataxia was exhibited by 3 patients. Two patients were able to walk without assistance (patients 1, 2). One patient was unstable during normal walking and tandem gait (patient 1). Another patient exhibited unstable wide-based gait (patient 2), which suggested that the gait ataxia in the 2 patients was not severe. Severe gait ataxia was exhibited by 1 patient (patient 3). This patient veered to the opposite direction of the lesion after 2 to 3 steps while walking with assistance (patient 3). No patients had ataxia of the extremities or ataxic speech. Gaze-evoked nystagmus was demonstrated by 2 patients (patients 2, 3) when looking to the side of the lesions (toward the right). The type of nystagmus was horizontal in patient 2 and horizontal/torsional in patient 3. Other neurological ﬁndings were normal in 3 patients. Vascular Findings, Etiology of Infarction, and Vascular Risk Factors The bilateral VAs demonstrated moderate stenosis; however, the BA was normal in patient 1 whose lesion was located in the rostral vermis (Fig 4). Accordingly, A to A embolism was considered as the etiology. Moderate stenosis with string sign was observed in the distal part of the right VA in patient 2 whose lesion was located in the right nodulus in the caudal vermis (Fig 5). In this patient, AD was considered as the etiology because of presence of neck pain at onset and string sign of the VA ipsilateral to the lesion. Blood analysis for the antiphospholipid antibody, protein-c, and protein-s was negative in this patient. The patient whose lesion was located in the tonsil had accompanying af (patient 3), but the degree of stenosis of the bilateral VAs and BA was mild Figure 2. T2-weighted images and their schematics (patient 2). An axial section showed an abnormal high-intensity area in the nodulus in the caudal vermis on the right side (A, B). This lesion was also delineated in a coronal section (C, D). Figure 3. An axial diffusion-weighted image and its schematic (A, B) (patient 3). An abnormal high-intensity area was noted in the tonsil on the right side. Figure 4. Magnetic resonance angiography (patient 1). Moderate stenosis was observed in the bilateral vertebral arteries. ARTICLE IN PRESS K. OGAWA ET AL. 4 Figure 5. Three-dimensional computed tomographic angiography (patient 2). The distal part of the right vertebral artery noted moderate stenosis with string sign (serrated irregularity of the wall), which indicated presence of arterial dissection. (Fig 6). Thus, CE was considered to be the etiology. Two patients had vascular risk factors of hypertension (patient 3) and dyslipidemia (patient 1). No patients were suspected of having SVD. Discussion The cerebellum is supplied by the superior cerebellar artery (SCA) in the rostral part and by the posterior inferior cerebellar artery (PICA) in the caudal part (Fig 7).1,18,19 The SCA arises from the distal region of the Figure 6. Magnetic resonance angiography (patient 3). Mild stenosis was found in the bilateral vertebral arteries and the basilar artery. BA,18,19 and the PICA arises from the distal region of the VA as usual.18,19 The SCA and the PICA have 3 branches each: the medial branch, the intermediate branch, and the lateral branch (Fig 7).1 The vermis is supplied by 2 arteries: the medial branch of the superior cerebellar artery (mSCA) (Fig 7) and the mPICA.1 The mPICA supplies the caudal vermis including the nodulus, and the tonsil (Fig 8).1,19 The vestibular signs of cerebellar infarction are caused by involvement of the uvulo-nodular complex in the caudal vermis which is supplied by the mPICA (Fig 8).3,5,9 The clinical features mimic those of peripheral vestibulopathy because other neurological ﬁndings including ataxia of the extremities are slight or absent.5 7,10 15 These cases are referred to as isolated vascular vertigo.10 In infarction of the territory of the anterior inferior cerebellar artery (AICA), isolated vertigo with hearing loss and tinnitus can occur due to ischemia of the labyrinthine artery originating from the AICA.10,11,20 In this situation, it is difﬁcult to differentiate between infarction of the territory in the AICA and the labyrinthine disease, based solely on the neurological ﬁndings because both the cochlear signs and the vestibular signs are present.10,11,20 Two patients whose lesions were located in the nodulus in the caudal vermis or the tonsil (patients 2, 3) exhibited truncal and gait ataxia and rotatory vertigo, without other neurological ﬁndings, mimicking peripheral vestibulopathy. Infarction of the vermis presenting as isolated vertigo has been recently reported.5 9 In these reported patients,5 9 the nodulus was most commonly involved. The vestibular nucleus in the lower pons is comprised of 4 subnuclei (superior, medial, lateral, and inferior subnuclei), and connects with the vestibule, the ipsilateral nodulus, and the ipsilateral fastigual nucleus through neuroﬁbers (Fig 9).21 Information from the vestibule approaches the 4 vestibular subnuclei in the lower pons via the vestibular ganglion.21 Part of the ﬁbers directly from the vestibule approach the nodulus without a junction in the vestibular nucleus.21 Fibers from the superior and lateral subnuclei in the vestibular nucleus component innervate the nodulus on the ipsilateral side,21 and then ﬁbers from the nodulus approach the fastigual nucleus.21,22 The fastigual nucleus innervates the bilateral vestibular nuclei.21,22 Additionally, the nodulus projects nodulovestibular Purkinje ﬁbers to the ipsilateral inferior and medial subnuclei in the vestibular nucleus, and exerts the inhibitory effects on the vestibular nucleus (Fig 9).5,8,21,22 If the nodulus is involved, the nodulovestibular Purkinje ﬁbers may be impaired,5,8 which leads to impairment in inhibition of the medial and inferior vestibular subnuclei by the nodulus.5,22 This condition can cause lateropulsion to the opposite side of the lesion (Table 2). In our patient (patient 2),5,6,8,22 rotatory vertigo and truncal and gait ataxia were observed, which suggested possibly involvement of the nodulovestibular Purkinje ﬁbers in the nodulus lesion, although lateropulsion was absent. ARTICLE IN PRESS CEREBELLAR VERMIS/TONSIL INFARCTION 5 Figure 7. Schematic of the arterial supply to the brainstem and cerebellum from a lateral view (modiﬁed from the original ﬁgure by Goto1). The medial branch of the superior cerebellar artery supplies the rostral part of the vermis. Infarction of the tonsil in the cerebellum is rare.16 Only 1 patient with infarction of the tonsil has been reported to date. This reported patient exhibited rotatory vertigo, but lateropulsion was not apparent.16 Our patient with infarction of the tonsil (patient 3) had rotatory vertigo and lateropulsion to the opposite side of the lesion. This was consistent with the typical symptoms of infarction of the nodulus.5,6,8,22 There was a possibility that the tonsil exerted inhibitory effects on the vestibular nucleus on the ipsilateral side, similar with the nodulus (Table 2), and the Figure 8. Schematic of the vermis and tonsil (modiﬁed from the original ﬁgure by Goto1). The anterior lobe is located in the rostral vermis and comprises the central lobe and the culmen. The nodulus is located in the anteroinferior part of the vermis. The tonsil is adjacent to the nodulus and the uvula. disinhibitory effect caused by the tonsil lesion on the vestibular nucleus resulted in rotatory vertigo and lateropulsion to the opposite side of the lesion. Truncal and gait ataxia were also presented by the patient with infarction of the rostral vermis which is supplied by the mSCA, but rotatory vertigo was absent (patient 1). This clinical feature is consistent with the lack Figure 9. Schematic of vestibulocerebellar connections in the vestibular pathway (modiﬁed from the original ﬁgure by England MA and Wakely J21). The vestibular nucleus which is composed of the 4 subnuclei (superior, medial, lateral, and inferior) is located in the lower pons. Information from the vestibule approaches the vestibular nucleus via the vestibular ganglion. The nodulus receives ﬁbers from the superior and lateral vestibular subnuclei, and those from the vestibule directly project to a part of the nodulus. The next ﬁbers from the nodulus approach the ipsilateral fastigual nucleus. The fastigual nucleus innervates the bilateral vestibular nuclei. The medial and inferior vestibular subnuclei are innervated from the ipsilateral nodulus through the inhibitory nodulovestibular Purkinje ﬁbers. ARTICLE IN PRESS K. OGAWA ET AL. The same side of the lesion The opposite side of the lesion The opposite side of the lesion + + + Abbreviations: PICA, posterior inferior cerebellar artery; SCA superior cerebellar artery. + + + ¡ ¡ ¡ Rostral vermis (anterior lobe) Caudal vermis (nodulus) Tonsil SCA PICA PICA Dorsal spinocerebellar tract Nodulovestibular Purkinje fibers Fibers between tonsil and vestibular nucleus ¡ + + Truncal and gait ataxia Ataxia of the extremities Rotatory vertigo The impaired tract The responsible artery Location Table 2. Clinical characteristics of infarction of the vermis/tonsil in the cerebellum Lateropulsion Direction of the lateropulsion 6 of association between the vestibular pathway and the rostral vermis.2,23 Lee et al17 reported a patient with isolated lateropulsion to the ipsilateral side of the lesion due to infarction of the rostral vermis, and considered involvement of the dorsal spinocerebellar tract (DSCT) as a cause of lateropulsion (Table 2). The DSCT conveys unconsciousness proprioceptive signals from the ipsilateral lower trunk and leg.22,24,25 The DSCT travels the dorsolateral surface of the caudal medulla and then enters the cerebellum through the inferior cerebellar peduncle, and ﬁnally approaches the anterior lobe in the rostral vermis and the gracile lobule on the ipsilateral side.17,24 26 In our patient (patient 1), truncal and gait ataxia without rotatory vertigo was observed. Involvement of the DSCT was considered in this patient, although lateropulsion was not noted. Calic et al4 previously reported the frequency, etiology, and outcome of small cerebellar infarction. The size of the lesions in our 3 patients was small. The lesions were conﬁned and did not spread to the cerebellar hemisphere. In this previous report,4 the main cause of small cerebellar infarction was CE and LVD, not SVD. Based on this result, Calic et al4 emphasized the need for investigation for a cardiac source of embolism and vascular risk factors in patients with small cerebellar infarction. In our study, dyslipidemia was accompanied in patient 1 whose etiology was A to A embolism in LVD. The etiology in patient 3 was CE caused by af. These results were consistent with the report of Calic et al.4 In contrast, infarction in patient 2 was juvenile-onset and occurred in the absence of vascular risk factors and emboligenic heart disease. AD of the VA tends to occur in juvenile patients without vascular risk factors,27,28 which was consistent with the clinical features in patient 2. In conclusion, infarction of the rostral and caudal vermis commonly presented as truncal and gait ataxia in common, but rotatory vertigo was absent in patients with infarction of the rostral vermis. This result indicated the difference in impaired ﬁbers between the rostral and caudal vermis, and suggested a close relationship of the vestibular pathway with the nodulus. Infarction of the tonsil caused lateropulsion to the opposite side of the lesion and rotatory vertigo, which suggested that the tonsil exerted an inhibitory effect on the vestibular nucleus on the ipsilateral side, similar with the nodulus. References 1. Goto N. Outline of anatomy of the central nerve system. Anatomy of brain vessels (in Japanese). Tokyo: Medical Tribune; 1986. p. 1-38. 2. Chaves CJ, Caplan LR, Chung CS, et al. Cerebellar infarcts. Curr Neurol 1990;14:143-177. 3. Ogawa K, Suzuki Y, Oishi M, et al. Clinical study of medial area infarction in the region of posterior inferior cerebellar artery. J Stroke Cerebrovasc Dis 2013;22:508-513. 4. Calic Z, Cappelen-Smith C, Cuganesan R, et al. Frequency, aetiology, and outcome of small cerebellar infarction. Cerebrovasc Dis Extra 2017;7:170-180. ARTICLE IN PRESS CEREBELLAR VERMIS/TONSIL INFARCTION 5. Lee H, Yi HA, Cho YW, et al. Nodulus infarction mimicking acute peripheral vestibulopathy. Neurology 2003;60:1700-1702. 6. Moon IS, Kim JS, Choi KD, et al. Isolated nodular infarction. Stroke 2009;40:487-491. 7. Lee H, Sohn SI, Cho YW, et al. Cerebellar infarction presenting isolated vertigo: frequency and vascular topographical patterns. Neurology 2006;67:1178-1183. 8. Lee H, Cho YW. A case of isolated nodulus infarction presenting vestibular neuritis. J Neurol Sci 2004;221:117119. 9. Kim HA, Yi HA, Lee H. Apogeotropic central positional nystagmus as a sole sign of nodular infarction. Neurol Sci 2012;33:1189-1191. 10. Lee H. Isolated vascular vertigo. J Stroke 2014;16:124-130. https://doi.org/10.5853/jos.2014.16.3.124. Epub 2014 Sep 30. 11. Kim HA, Yi HY, Lee H. Recent advances in cerebellar ischemic stroke syndromes causing vertigo and hearing loss. Cerebellum 2016;15:781-788. 12. Edlow JA, Newman-Taker DE, Savitz SI. Diagnosis and initial management of cerebellar infarction. Lancet Neurol 2008;7:951-964. 13. Kim SH, Kim HJ, Kim JS. Isolated vestibular syndromes due to brainstem and cerebellar lesions. J Neurol 2017;264(Suppl 1):S63-S69. 14. Choi KD, Lee H, Kim JS. Vertigo in brainstem and cerebellar strokes. Curr Opin Neurol 2013;26:90-95. 15. Casani AP, Dallan I, Cerchiani N, et al. Cerebellar infarctions mimicking acute peripheral vertigo: how to avoid misdiagnosis. Otolaryngol Head Neck Surg 2013;148:475-481. 16. Lee SH, Park SH, Kim JS, et al. Isolated unilateral infarction of the cerebellar tonsil: ocular motor ﬁndings. Ann Neurol 2014;75:429-434. 7 17. Lee H. Isolated lateropulsion caused by a lesion of the rostral vermis. J Neurol Sci 2006;249:172-174. 18. Tatu L, Moulin T, Bogousslavsky J, et al. Arterial territories of human brain: brainstem and cerebellum. Neurology 1996;47:1125-1135. 19. Rhoton Jr AL. The cerebellar arteries. Neurosurgery 2000;47(3 Suppl):S29-S68. 20. Ogawa K, Suzuki Y, Takahashi K, et al. Clinical study of seven patients with infarction in territories of the anterior inferior cerebellar arteries. J Stroke Cerebrovasc Dis 2017;26:574-581. 21. England MA, Wakely J. A colour atlas of the brain & spinal cord. Aylesbury: Wolfe Publishing Ltd; 1991. 22. Ye BS, Kim YD, Nam HS, et al. Clinical manifestations of cerebellar infarction according to speciﬁc lobular involvement. Cerebellum 2010;9:571-579. 23. Amarenco P, Hauw JJ. Cerebellar infarction in the territory of the superior cerebellar artery: a clinicopathological study of 33 patients. Neurology 1990;40:1383-1390. 24. Maeda K, Saikyo M, Mukose A, et al. Lateropulsion due to a lesion of the dorsal spinocerebellar tract. Intern Med 2005;44:1295-1297. 25. Th€ omke F, Marx JJ, Iannetti GD, et al. A topodiagnostic investigation on body lateropulsion in medullary infarcts. Neurology 2005;64:716-718. 26. Ogawa K, Suzuki Y, Oishi M, et al. Clinical study of fortysix patients with lateral medullary infarction. J Stroke Cerebrovasc Dis 2015;24:1059-1064. 27. Sacco RL, Freddo L, Bello JA, et al. Wallenberg’s lateral medullary syndrome: clinical-magnetic resonance imaging correlations. Arch Neurol 1993;50:609-614. 28. Akimoto T, Ogawa K, Morita A, et al. Clinical study of 27 patients with medial medullary infarction. J Stroke Cerebrovasc Dis 2017;26:2223-2231.