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Motion Perception without Nystagmus—A Novel Manifestation of Cerebellar Stroke
Motion Perception without Nystagmus—A Novel Manifestation of Cerebellar Stroke Aasef G. Shaikh, MD, PhD
Objective: The motion perception and the vestibulo-ocular reflex (VOR) each serve distinct functions. The VOR keeps the gaze steady on the target of interest, whereas vestibular perception serves a number of tasks, including awareness of self-motion and orientation in space. VOR and motion perception might abide the same neurophysiological principles, but their distinct anatomical correlates were proposed. In patients with cerebellar stroke in distribution of medial division of posterior inferior cerebellar artery, we asked whether specific location of the focal lesion in vestibulocerebellum could cause impaired perception of motion but normal eye movements. Methods/Results: Thirteen patients were studied, 5 consistently perceived spinning of surrounding environment (vertigo), but the eye movements were normal. This group was called ‘‘disease model.’’ Remaining 8 patients were also symptomatic for vertigo, but they had spontaneous nystagmus. The latter group was called ‘‘disease control.’’ Magnetic resonance imaging in both groups consistently revealed focal cerebellar infarct affecting posterior cerebellar vermis (lobule IX). In the ‘‘disease model’’ group, only part of lobule IX was affected. In the disease control group, however, complete lobule IX was involved. Conclusions: This study discovered a novel presentation of cerebellar stroke where only motion perception was affected, but there was an absence of objective neurologic signs. Key Words: Perception— Purkinje neuron—posterior inferior cerebellar artery—velocity storage. Ó 2014 by National Stroke Association
Introduction In natural behavior, the brain computes precise estimate of self-motion to ensure appropriate reflexive behavior and perception of motion. Basic principles of reflexive eye movements, the vestibulo-ocular reflex (VOR), are well known. Direct and indirect pathways mediate VOR. The direct pathway featuring ‘‘three-neuron arc’’—vestibular afferents, premotor vestibular neurons, and ocular motor neurons—guarantees prompt compen-
From the Department of Neurology, Case Western Reserve University, Cleveland, Ohio. Received August 10, 2013; revision received September 24, 2013; accepted October 7, 2013. Grant support: None. Address correspondence to Aasef G. Shaikh, MD, PhD, Department of Neurology, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106-5040. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.10.005
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satory eye movement in response to head movement.1 The indirect pathway comprising the cerebellar cortex, deep cerebellar nuclei, and vestibular nuclei increases the bandwidth over which VOR is compensatory.2 Vestibular processing related to motion perception has enticed several recent investigations, some of these studies have emphasized the role of cerebellum.3-7 Two hypotheses were proposed. First, VOR and motion perception share same groups of brainstem and cerebellar neurons. Second, the neurons responsible for VOR and motion perception are anatomically distinct but abide the same physiological principles. Recent studies were in support of second hypothesis.5,7 These proposals, however, relied on indirect observations such as the differences in the dynamics of VOR and perceived angular velocity,5,6 disparity in the effects of drugs to reduce the decay time constant of the VOR and perceived angular velocity,7 and trends of altered motion perception in patients with ophthalmoplegia because of peripheral etiology.3,4,8 The second hypothesis was also supported by studies in macaques that revealed the
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 5 (May-June), 2014: pp 1148-1156
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presence of neurons in cerebellar nodulus, rostral fastigial nucleus, and the vestibular nuclei that have pure vestibular sensitivity but lack responsiveness to eye movements, that is, the ‘‘vestibular-only’’ neurons.9-17 Perception is one of the putative functions of such non– eye movement-sensitive central vestibular neurons. Perception as the possible function of these neurons became more evident with the discovery of the thalamic projections of the cerebellar and brain stem regions featuring the ‘‘vestibular-only’’ neurons in macaques.11 Signs and symptoms related to vestibular and ocular motor deficits in patients with focal cerebellar lesions might support experimental and theoretical framework depicting the differences between the neural mechanisms responsible for VOR and motion perception. For example, vertigo (perception of rotation), spontaneous nystagmus, gaze-evoked nystagmus, and body lateropulsion are known manifestations of focal stroke affecting the posterior cerebellar vermis.18,19 We asked whether focal cerebellar lesion exists that only manifests as vertigo but the absence of ocular motor deficits including nystagmus.
Methods Thirteen cases with acute cerebellar stroke were examined. The University Hospitals Case Medical Center institutional review board approved this retrospective study. Clinical assessment was performed as a part of hospital admission. Patients with acute onset of vertigo, ability to accurately provide history, qualitative description, duration, and severity of vertigo and an evidence of acute stroke on magnetic resonance imaging (MRI) were included in the study. Patients were excluded if there was a chronic history of vertigo without change in its quality and severity, if there was an evidence for the pathology affecting brainstem vestibular or eye movement–sensitive nuclei, if MRI did not reveal acute or subacute stroke affecting the vestibulocerebellum, and if there was a clinical or neuroimaging evidence of a degenerative cerebellar disease. The patients were scanned on 1.5 T scanner. Axial T1and T2-weighted images, diffusion-weighted images (DWIs), apparent diffusion coefficient (ADC), and FLAIR sequences were acquired. Slice thickness for each image was 5 mm. Picture Archiving and Communication System was used to determine the anatomical location of the affected cerebellar lobule in the MRI. The areas of diffusion restriction on DWI sequences were correlated with ADC to confirm the ischemic lesion. Cross-referencing tool in the PACS software was used to colocalize the area of diffusion restriction in the fluid-attenuated inversion recovery and T1-weighted axial and saggital sequences. The latter facilitated accurate anatomical localization of acute lesions that were identified on DWI and ADC sequences.
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Three-dimensional MRI atlas of cerebellum was used to accurately identify the lobules of interest in MRI.20 The areas of interest in vestibulo-cerebellum, identified in this article as lobules IX and X, were diversely labeled in the past. For lobule IX, some authors used the term paraflocculus21-25; the same area was also called tonsil26-32 or uvula.33 Schematic in Figure 1 identifies various lobules in the map of cerebellum in sagittal and axial sections in nomenclature proposed by Schmahmann et al.20
Results Clinical Presentation Thirteen patients (9 men and 4 women) with abrupt onset of vertigo, intractable nausea, and vomiting were assessed. Assessment was performed within 24 hours of symptom onset. Patients described vertigo as spinning sensation. Four patients could clearly describe the direction of spinning—one perceived spinning of surrounding environment from the left to right, whereas three perceived rightward to leftward motion. Eight patients were unclear about the direction of perceived spinning. In eight patients, the severity of the vertigo was dependent on the head orientation with respect to gravity. The details of symptoms are outlined in Table 1. Neurologic examination classified this cohort into two groups. One group had no nystagmus in primary or eccentric gaze or with removal of visual fixation using Frenzel goggles during upright, supine, left ear down, and right ear down orientations. The VOR was normal during head impulses and head shaking maneuver. Saccades and pursuit eye movements and optokinetic nystagmus were normal. The vertigo was severe in three patients to keep them confined to bed. Two patients could stand up, and they had body pulsion toward the side of cerebellar lesion. Remaining neurologic examination was normal. This was ‘‘disease model’’ group. The second group, the ‘‘disease control,’’ featured ocular motor deficits on examination. Nystagmus was present in at least one of the four head orientations with respect to gravity (ie, supine, upright, right ear down, or left ear down positions). In five of eight patients, the pattern of nystagmus was head position dependent. Saccadic hypometria was seen in one patient, and pursuit was interrupted by quick phase of nystagmus. Two patients had acute onset of hypoactive VOR in addition to gravity dependence of spontaneous nystagmus. It was concluded that the patients with hypoactive VOR and gravity-dependent nystagmus had acute stroke affecting the vascular distributions of anterior and posterior inferior cerebellar arteries.34 The VOR testing was deferred in one patient who presented with cerebellar stroke symptoms and neck pain after injury, concerning for vertebral artery dissection. All patients had profound imbalance and body lateropulsion. Table 1 illustrates the
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Figure 1. Diffusion-weighted magnetic resonance imaging sequences depict infarction of posterior cerebellar vermis in the vascular territory of the medial branch of posterior inferior cerebellar artery. Lobules VIIIa, VIIIb, and IX were affected in all patients, lobule VIIb in 7, lobule X in 2, and lobules V and VI in 1 patient. There was a complete involvement of lobule IX in ‘‘disease control,’’ but only the part of lobule IX was affected in ‘‘disease model’’ (arrows). The schematic in the center of the figure depicts locations of lobules in the cerebellar map in sagittal and axial section. (Color version of figure is available online.)
details of symptomatology and neurologic examination in ‘‘disease control’’ group.
Neuroimaging Features DWI and ADC sequences of MRI consistently revealed areas of diffusion restriction in posterior cerebellar vermis, suggesting acute cerebellar infarction in the vascular territory of the medial branch of posterior inferior cerebellar artery. Lobules VIIIa, VIIIb, and IX were affected in all patients. Lobule VIIb was affected in seven patients. In two patients, the infarct extended to the lobule X, whereas in one patient, lobules Vand VI were also involved. Hence, in addition to the involvement of vermis, in some subjects, the lesions extended into the hemispheres. It is noteworthy that involvement of lobule IX was consistent in all subjects, but the areas of hemisphere that were involved varied
among patients. The key discriminating feature between the ‘‘disease control’’ and ‘‘disease model’’ was the extent to which lobule IX was involved. In ‘‘disease control,’’ lobule IX was completely affected, but in ‘‘disease model,’’ the involvement of lobule IX was patchy. It appeared that dorsal aspect of lobule IX was affected in ‘‘disease model’’ group. Table 1 summarizes the lobular distribution of the stroke. Figure 1 illustrates the areas of diffusion restriction in DWI sequence in 13 patients.
Risk Factors, Clinical Course, Treatment, and Outcome There were no differences in the stroke risk factors between two groups. All patients had at least one of the risk factors for ischemic stroke. Six patients had the history of hypertension, one had diabetes, eight had untreated dyslipidemia, three had paroxysmal atrial fibrillation, two
Age Patient (y)
Symptom
Disease model 1 77 Vertigo in yaw plane, unclear of direction of spinning. Intractable nausea and vomiting.
Vertigo/head position dependence
Pattern of head position dependence of nystagmus
Other examination findings
Stroke risk factors
Time of examination since onset (h)
Maximal in left ear down, intermediate in supine, and upright head orientation, relatively less in right ear down orientation.
None
None
HTN, DLD
6
2
80 Vertigo in yaw plane, room was spinning from right to left. Intractable nausea and vomiting.
No position dependence.
None
None
HTN, Afib, NSTEMI
8
3
51 Vertigo in yaw plane, room was spinning from right to left. Intractable nausea, vomiting. and headache.
None
None
HTN, DM
4
4
61 Vertigo, unclear about direction of spinning. Intractable nausea and vomiting. Diaphoresis.
Maximal sensation in supine orientation, intermediate in right or left ear down position, minimal in upright head orientation. Vertigo did not have head position dependence.
None
None
DLD
6
5
66 Vertigo in yaw plane, as if room is spinning from the left to right. Intractable nausea and vomiting
Maximal in left or right ear down position, intermediate in supine orientation, relatively less when upright.
None
None
DLD
10
Affected cerebellar lobules (diffusionweighted MRI) Right cerebellum. Dorsal part of lobule IX, extending to caudal aspect of lobule X, patchy distribution in lobules VIIIb . VIIIa .. VIIb Right cerebellum. Dorsal aspect of lobule IX, partial extension into lobules VIIIb, VIIIa, and VIIb. Right cerebellum. Dorsal aspect of lobule IX, extends in lobules VIIIb and VIIIa Left cerebellum. Rostrally dorsal and caudally complete lobule IX, partial extension into lobule VIIIb. Right cerebellum. Dorsal of lobule IX, partial extension into lobules VIIIb and VIIIa (Continued)
PERCEPTION OF MOTION WITHOUT NYSTAGMUS IN CEREBELLAR STROKE
Table 1. Clinical features of patients with acute stroke affecting posterior cerebellar vermis
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Table 1. (Continued)
Symptom
Disease control 6 59 Sudden onset of vertigo. Nausea and vomiting.
Vertigo/head position dependence
Pattern of head position dependence of nystagmus
Torsional nystagmus Maximal vertigo on supine and left while supine and left ear down position. ear down, intermediate while upright, further improvement during right ear down position. Worse sensation of vertigo Clockwise beating torsional nystagmus during supine orientation, during supine improvement in upright position, horizontal head orientation. right beating nystagmus on left ear down, stable gaze in remaining orientations. No head position Torsional nystagmus. dependence.
54 Sudden onset of vertigo and associated nausea and vomiting.
8
77 Sudden onset of vertigo. Intractable nausea and vomiting.
9
28 Sudden onset of vertigo. Nausea and vomiting.
History was unclear of head position dependence.
10
74 Sudden onset of vertigo. Sudden onset of oscillopsia while walking.
Vertigo worsens with right ear down orientation.
Upright head orientation: steady gaze in upright position. Supine: right beating nystagmus on right gaze and left beating on left gaze. Right ear down position: left beating nystagmus on left gaze, steady right gaze. Left ear down: right beating nystagmus on right gaze and steady at central and left gaze. Steady central gaze in all head orientation. No change under Frenzel goggles. Rightward and upbeat nystagmus during right ear down orientation.
Time of examination since onset (h)
Affected cerebellar lobules (diffusionweighted MRI)
None
HTN, Afib
18
Right cerebellum. Complete lobule IX, extension to lobules VIIIb, VIIIa, and VIIb.
None
HTN, DLD
10
None
DLD, CAD
2
Left cerebellum. Complete lobule IX, extension to lobules VIIIb, VIIIa, and VIIb. Minimal extension into left inferior cerebellar peduncle. Left cerebellum. Complete lobule IX. Patchy involvement of lobule VIIb. Right cerebellum. Complete lobule IX and VIIIB. Part of lobules VIIIA and VIIB.
VOR examination None deferred because of neck pain concerning for dissection. Pursuit interrupted by quick phase of nystagmus.
14
Hypoactive VOR, hearing deficit.
12
HTN, DLD
Left cerebellum. Complete lobule IX. Part of lobules VIIIB, VIIIA, and VIIB.
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7
Stroke risk factors
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Age Patient (y)
Other examination findings
52 Sudden onset of vertigo. Sudden onset of oscillopsia while walking.
12
History is unclear 75 Sudden onset of vertigo about the head in yaw plane. Vertigo was position dependence. perceived as if the world is moving from the left to right.
13
81 Sudden onset of vertigo.
History is unclear about head position dependence.
Hypoactive Upright, supine, and right VOR, impaired ear down orientations: hearing on the right beating nystagmus right side. while looking straight Pursuit was ahead, increased velocity interrupted by of right beating nystagmus quick phase of during right gaze, stable left nystagmus. gaze. Left ear down position: stable gaze. Pursuit was Gaze-evoked nystagmus, interrupted worse on the right-ward by quick phase gaze holding. Upbeat of nystagmus. nystagmus during upgaze and downbeat nystagmus during downgaze. No head position dependence. Saccadic Gaze-evoked nystagmus dysmetria with higher slow-phase velocity during rightward gaze holding. Upbeat nystagmus during upgaze and downbeat during down gaze.
None
6
Left cerebellum. Complete lobule IX. Part of lobule VIIIB.
HTN
14
Left cerebellum. Complete lobules IX and VIIIB. Part of lobule VIIIA. Minimal extension into left inferior cerebellar peduncle.
HTN, Afib
12
Right cerebellum, complete lobule IX. Part of lobules VIIIA, VIIIB, X, and VIIB.
Abbreviations: Afib, atrial fibrillation; CAD, coronary artery disease; DM, diabetes mellitus; DLD, dyslipidemia; HTN, hypertension; NSTEMI, non-ST elevation myocardial infarction; MRI, magnetic resonance imaging; VOR, vestibulo-ocular reflex.
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Vertigo worsens with supine and left ear down position.
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had the history of coronary artery disease, and one had an evidence of vasculopathy. None of the patients had the indication for vascular intervention or administration of tissue plasminogen activator. All patients were assessed for and treated to minimize the stroke risk factors. Six patients were taking aspirin at the time of presentation; in these instances, the treatment was upgraded to either clopidogrel or warfarin. Eight patients were not on any antiplatelet agent; aspirin was started at the time of hospitalization. There were no differences in the rate of recovery between both groups. Both groups had rapid recovery from vertigo within 48 hours. In ‘‘disease control’’ group, the nystagmus improved within 72 hours. Both groups continued to experience imbalance and gait instability till the time of discharge. The patients were discharged to rehabilitation facility. To summarize, the patients with central acute vestibular syndrome consistently presented with vertigo (described as constant spinning sensation), intractable nausea, vomiting, and profound imbalance. This cohort was divided into two groups. The ‘‘disease control’’ group had typical ocular motor and vestibular deficits including nystagmus. The ‘‘disease model’’ group had severe vertigo, but eye movement examination was normal. In both groups, neuroimaging revealed acute to subacute stroke affecting posterior cerebellar vermis. The key difference between two groups was the extent of involvement of the lobule IX. In ‘‘disease model’’ group, only the part of lobule IX was affected, but ‘‘disease control’’ group had complete involvement of lobule IX. From clinical perspective, it is imperial to correctly identify patients with stroke who present with vertigo but in the absence of localizing deficit on neurologic examination. This study suggests putative identifiers of such ‘‘silent’’ cerebellar infarcts. The ‘‘disease model’’ group in this study identified persistent perception of spinning motion with intractable nausea and vomiting as putative manifestation of acute cerebellar infarct.
Discussion All our patients had vertigo, intractable nausea, and vomiting. The neurologic examination separated this cohort into two groups. The ‘‘disease model’’ group comprised patients who had constant vertigo but did not have nystagmus. The ‘‘disease control’’ group also presented for vertigo, but eye movement examination revealed nystagmus. Vertigo was described as persistent perception of spinning movement. I will first discuss the ‘‘disease control’’ group and then ‘‘disease model.’’ Nystagmus, as seen in patients from the ‘‘disease control’’ group, is a known manifestation of posterior inferior cerebellar artery infarct affecting the posterior cerebellar vermis.18,19 In five of eight patients, the direction of nystagmus was dependent on the head position with
A.G. SHAIKH
respect to gravity. The gravity dependence of nystagmus has been described in degenerative cerebellar syndromes35-37 and was rarely reported in patients with acute cerebellar stroke.38-40 What causes gravity-dependent modulation of nystagmus? The cerebellum calibrates the direction and the amplitude of the vestibular reflexes.35,41,42 It is proposed that impairment of such calibration causes gravity-dependent modulation of the nystagmus. A two-step process is speculated. In the first step, disinhibition of the deep cerebellar and vestibular nuclei occurs after the loss of cerebellar Purkinje neurons. For example, in macaques, resection of flocculus (ie, lobule X) causes gaze-evoked nystagmus because of the disinhibition and impairment of neural integrator circuit in the medial vestibular nuclei.43 The gaze-evoked nystagmus also occurs when there is a breach in the inflow to the cerebellum (from brainstem integrators) that passes through the inferior cerebellar peduncle; in other words, there is a disruption of cerebellar feedback pathway around the neural integrator.44 Gaze-evoked nystagmus was noted in patients 9, 12, and 13. The infarct extended to inferior cerebellar peduncle in patient 12, whereas there was an involvement of lobule X in patient 13; hence, gazeevoked nystagmus could be explained in both cases. There was no obvious acute structural deficit in DWI sequence to explain gaze-evoked nystagmus in patient 9. It is, however, possible that ischemic penumbra affecting lobule X had caused gaze-evoked nystagmus in this patient. The second step is the gravity-dependent modulation of nystagmus because of impaired central estimate of gravity. It is known that the lesions of the cerebellar nodulus in monkeys impair the ability to align the axis of eye rotation with the gravito-inertial axis during VOR.38-40 One could, therefore, predict that, in humans too, the strokes affecting the lobules VIII and IX might disrupt the calibration of axis of eye rotation with respect to gravity. Hence, disinhibition first causes nystagmus, when the axis of eye rotation is not systematically aligned with earth-fixed axis because of impaired central estimate of gravito-inertial axis, gravity-dependent modulation of the nystagmus occurs. In two patients, the gravity-dependent nystagmus had partial features of apogeotropic positional nystagmus, and the quick phase was away from the direction of the gravity. The key difference, however, from typical apogeotropic nystagmus characterizing the lateral canal benign paroxysmal positional vertigo (BPPV) was that in one patient nystagmus was only present during left ear down, but supine orientation revealed torsional nystagmus. In the other patient, the apogeotropic nystagmus was only seen when eye in the orbit position was eccentric and directed away from the side facing the ground. These features readily separated central positional nystagmus from typical lateral canal BPPV.45,46 In two patients, torsional and horizontal nystagmus was
PERCEPTION OF MOTION WITHOUT NYSTAGMUS IN CEREBELLAR STROKE
present, such nystagmus could not be explained by any known variant of BPPV.45,46 Furthermore, the nystagmus related to BPPV appears after latency of few seconds and it habituates within several seconds.45,46 The central gravity–dependent nystagmus in our patients appeared instantaneously after change in head orientation, and it did not habituate.44 The ‘‘disease model’’ group had vertigo, intractable nausea, and vomiting, but there was no deficit during eye movement and vestibular examination. Vertigo was described as consistent perception of spinning. One could attribute ‘‘pure’’ perceptual deficit to disinhibition of vestibular neurons that putatively serve vestibular perception pathway. In addition to the VOR, the vestibular signals also serve motion perception. Initial studies have showed that during constant velocity whole-body rotation in complete darkness, the perception of angular motion decays at the rate slower than the activity of the semicircular canals.47,48 This perceptual behavior was analogous to VOR.2 Hence, it was believed that perception of motion and VOR share the same pathways and mechanisms. Various authors suggested different locations for vestibular perception–related neurons. It was first proposed that perception-related vestibular processing occurs at cerebral cortex.49 Subsequent studies in subjects with cerebellar vermis lesions found similar deficits in the VOR and perceptual response, hence, suggesting cerebellum as a structural correlate for motion perception.50,51 It was subsequently proposed that motion perception and VOR abide same neurophysiological principles; both are under control of cerebellar cortex, but the groups of cerebellar neurons controlling VOR and perception might be independent.7 Consistent with the latter proposal, the patients in the ‘‘disease model’’ group featuring isolated perceptual deficits without nystagmus had only partial involvement of lobule IX. In contrast, the patients who had nystagmus in addition to perception of vertigo had more extensive stroke affecting complete lobule IX. Isolated perception of vertigo in three patients from the ‘‘disease model’’ group was dependent on the head orientation with respect to gravity. The pathophysiology of such gravity dependence of perceived severity of motion could be described by the same principle that explained gravity-dependent modulation of the nystagmus. Gravity-dependent modulation of perceived vertigo in ‘‘disease model’’ group and gravity-dependent modulation of nystagmus in ‘‘disease control’’ group further supported the hypothesis that central processing of motion perception and VOR abide same physiological principles. Occurrence of these two phenomena in different subgroups of patients where cerebellar lobule IX is involved at different extent supported the hypothesis that motion perception and VOR might be controlled by anatomically distinct groups of neurons.7
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In several instances, the cerebellar vermis infarct extended into the hemispheres. Such hemispheric extension is unlikely to cause variability in ocular motor deficits in our patients. It is known that isolated cerebellar hemisphere lesions do not cause ocular motor or vestibular deficits. Furthermore, vestibular and ocular motor deficits seen in all our patients could be readily described by the lesions in posterior cerebellar vermis.
Conclusions Group of patients with cerebellar stroke in distribution of posterior inferior cerebellar artery had isolated perception of vertigo in the absence of objective eye movement deficits. The vertigo was unequivocally described as constant perception of spinning of visual surround. Diffusion-weighted MRI suggested possible involvement of dorsal aspect of cerebellar lobule IX in these patients. These results suggested putative anatomical correlate of motion perception–related cerebellar neurons. This study discovered a disease that manifests in the form of ‘‘pure’’ motion perception deficit without objective neurologic signs. The cerebellar strokes, manifesting just as abnormal perception of motion with nausea and vomiting, have a potential to be misdiagnosed as nonorganic, benign, non-neurologic, or gasteroenteric illness. Therefore, it is emphasized that novel manifestation of cerebellar stroke presenting as isolated perception deficit should be considered in differential diagnosis of patients with acute onset of vertigo and imbalance but otherwise normal cerebellar examination. If such patients have vascular risk factors, the index of suspicion for cerebellar stroke should be even higher. Acknowledgments: I thank R. John Leigh, MD, and David S. Zee, MD, for mentorship and support.
References 1. Baker R, Evinger C, McCrea RA. Some thoughts about the three neurons in the vestibular ocular reflex. Ann N Y Acad Sci 1981;374:171-188. 2. Raphan T, Matsuo V, Cohen B. Velocity storage in the vestibulo-ocular reflex arc (VOR). Exp Brain Res 1979; 35:229-248. 3. Seemungal BM, Glasauer S, Gresty MA, et al. Vestibular perception and navigation in the congenitally blind. J Neurophysiol 2007;97:4341-4356. 4. Seemungal BM, Masaoutis P, Green DA, et al. Symptomatic recovery in Miller Fisher Syndrome parallels vestibular-perceptual and not vestibular-ocular reflex function. Front Neurol 2011;2:2. 5. Bertolini G, Ramat S, Laurens J, et al. Velocity storage contribution to vestibular self-motion perception in healthy human subjects. J Neurophysiol 2011;105:209-223. 6. Sinha N, Zaher N, Shaikh AG, et al. Perception of selfmotion during and after passive rotation of the body around an earth-vertical axis. Prog Brain Res 2008; 171:277-281.
1156 7. Shaikh AG, Palla A, Marti S, et al. Role of cerebellum in motion perception and vestibulo-ocular reflex—similarities and disparities. Cerebellum 2013;12:97-107. 8. Grunfeld EA, Shallo-Hoffmann JA, Cassidy L, et al. Vestibular perception in patients with acquired ophthalmoplegia. Neurology 2003;60:1993-1995. 9. Angelaki DE, Shaikh AG, Green AM, et al. Neurons compute internal models of the physical laws of motion. Nature 2004;430:560-564. 10. Green AM, Shaikh AG, Angelaki DE. Sensory vestibular contributions to constructing internal models of self-motion. J Neural Eng 2005;2:S164-S179. 11. Meng H, May PJ, Dickman JD, et al. Vestibular signals in primate thalamus: properties and origins. J Neurosci 2007;27:13590-13602. 12. Shaikh AG, Ghasia FF, Dickman JD, et al. Properties of cerebellar fastigial neurons during translation, rotation, and eye movements. J Neurophysiol 2005;93:853-863. 13. Shaikh AG, Green AM, Ghasia FF, et al. Sensory convergence solves a motion ambiguity problem. Curr Biol 2005;15:1657-1662. 14. Yakusheva TA, Shaikh AG, Green AM, et al. Purkinje cells in posterior cerebellar vermis encode motion in an inertial reference frame. Neuron 2007;54:973-985. 15. Buttner U, Fuchs AF, Markert-Schwab G, et al. Fastigial nucleus activity in the alert monkey during slow eye and head movements. J Neurophysiol 1991;65:1360-1371. 16. Siebold C, Anagnostou E, Glasauer S, et al. Canal-otolith interaction in the fastigial nucleus of the alert monkey. Exp Brain Res 2001;136:169-178. 17. Siebold C, Kleine JF, Glonti L, et al. Fastigial nucleus activity during different frequencies and orientations of vertical vestibular stimulation in the monkey. J Neurophysiol 1999;82:34-41. 18. Rubenstein RL, Norman DM, Schindler RA, et al. Cerebellar infarction—a presentation of vertigo. Laryngoscope 1980;90:505-514. 19. Lee H, Sohn SI, Cho YW, et al. Cerebellar infarction presenting isolated vertigo: frequency and vascular topographical patterns. Neurology 2006;67:1178-1183. 20. Schmahmann JD, Doyon J, McDonald D, et al. Threedimensional MRI atlas of the human cerebellum in proportional stereotaxic space. Neuroimage 1999;10:233-260. 21. Angevine JB, Mancall EL, Yakovlev PI. The human cerebellum: an atlas of gross topography in serial sections. Boston, MA: Little, Brown and Co 1961. 22. Dow RS. The evolution and anatomy of the cerebellum. Biol Rev 1942;17:179-220. 23. Jansen J, Brodal A. Das Kleinhirn. Berlin, Germany: Springer 1958. 24. Larsell O, Jansen J. The comparative anatomy and histology of the cerebellum—cerebellar connections, and cerebellar cortex. Minneapolis, MN: University of Minnesota Press 1972. 25. Riley HA. The lobules of the mammalian cerebellum and cerebellar nomenclature. Arch Neurol Psychiatry 1930; 24:227-256. 26. Flatau E, Jacobsohn L. Handbuch der Anatomie and vergleichende anatomie des Centralnervensystems der Saeugetiere. I. Berlin, Germany: Karger 1899. 27. Henle J. Grundriss der anatomie des menschen, Neu bearbeitet von F. Merkel, 4th Aufl. Atlas. Braunschweig, Germany: Friedrich Vieweg and Sohn 1901. 28. Ingvar S. Phylo- und Ontogenesae des Kleinhirns. Follia Neuro-Biologica 1918;11:205-495. 29. Kuithan W. Die Entwicklung des Kleinhirns von Saugetieren. Munchen; 1894.
A.G. SHAIKH 30. Press GA, Murakami J, Courchesne E, et al. The cerebellum in saggital plane—anatomic—MR correlation: 2. The cerebellar hemispheres. Am J Neurol Res 1989; 10:667-676. 31. Schafer EA, Symington J. Neurology. London: Longmans, Green and Co 1908. 32. Ziehen T. Central nerven system. Jena: Verlag von Gustav Fischer 1934. 33. langelaan JW. On the development of the external form of the human cerebellum. Brain 1919;42:130-170. 34. Shaikh AG, Miller BR, Sundararajan S, et al. Gravitydependent nystagmus and inner-ear dysfunction suggest anterior and posterior inferior cerebellar artery infarct. J Stroke Cerebrovasc Dis 2013;332:56-58. 35. Shaikh AG, Marti S, Tarnutzer AA, et al. Ataxia telangiectasia: a ‘‘disease model’’ to understand the cerebellar control of vestibular reflexes. J Neurophysiol 2011; 105:3034-3041. 36. Marti S, Palla A, Straumann D. Gravity dependence of ocular drift in patients with cerebellar downbeat nystagmus. Ann Neurol 2002;52:712-721. 37. Kattah JC, Gujrati M. Familial positional downbeat nystagmus and cerebellar ataxia: clinical and pathologic findings. Ann N Y Acad Sci 2005;1039:540-543. 38. Nam J, Kim S, Huh Y, et al. Ageotropic central positional nystagmus in nodular infarction. Neurology 2009; 73:1163. 39. Kim HA, Yi HA, Lee H. Apogeotropic central positional nystagmus as a sole sign of nodular infarction. Neurol Sci 2012;33:1189-1191. 40. Johkura K. Central paroxysmal positional vertigo: isolated dizziness caused by small cerebellar hemorrhage. Stroke 2007;38:e26-e27. author reply e8. 41. Walker MF, Zee DS. Cerebellar disease alters the axis of the high-acceleration vestibuloocular reflex. J Neurophysiol 2005;94:3417-3429. 42. Schultheis LW, Robinson DA. Directional plasticity of the vestibuloocular reflex in the cat. Ann N Y Acad Sci 1981; 374:504-512. 43. Zee DS, Yamazaki A, Butler PH, et al. Effects of ablation of flocculus and paraflocculus of eye movements in primate. J Neurophysiol 1981;46:878-899. 44. Leigh RJ, Zee DS. The neurology eye movements. 5th ed. New York: Oxford 2006. 45. Leigh RJ, Zee DS. Neurology of eye movements. 4th ed. New York: Oxford 2006. 46. Korres SG, Balatsouras DG. Diagnostic, pathophysiologic, and therapeutic aspects of benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg 2004; 131:438-444. 47. Guedry FE. Psychopysica of vestibular sensation. Handbook of sensory physiology. Berlin: Springer-Verlag 1974:3-154. 48. Young LR. Perception of the body in space: mechanisms. Handbook of physiology: the nervous system III. Bethesda: American Physiology Society 1983:1023-1066. 49. Okada T, Grunfeld E, Shallo-Hoffmann J, et al. Vestibular perception of angular velocity in normal subjects and in patients with congenital nystagmus. Brain 1999;122(Pt 7):1293-1303. 50. Bronstein AM, Grunfeld EA, Faldon M, et al. Reduced self-motion perception in patients with midline cerebellar lesions. Neuroreport 2008;19:691-693. 51. Bertolini G, Ramat S, Bockisch CJ, et al. Is vestibular selfmotion perception controlled by the velocity storage? Insights from patients with chronic degeneration of the vestibulo-cerebellum. PLoS One 2012;7:e36763.
Objective: The motion perception and the vestibulo-ocular reflex (VOR) each serve distinct functions. The VOR keeps the gaze steady on the target of interest, whereas vestibular perception serves a number of tasks, including awareness of self-motion and orientation in space. VOR and motion perception might abide the same neurophysiological principles, but their distinct anatomical correlates were proposed. In patients with cerebellar stroke in distribution of medial division of posterior inferior cerebellar artery, we asked whether specific location of the focal lesion in vestibulocerebellum could cause impaired perception of motion but normal eye movements. Methods/Results: Thirteen patients were studied, 5 consistently perceived spinning of surrounding environment (vertigo), but the eye movements were normal. This group was called ‘‘disease model.’’ Remaining 8 patients were also symptomatic for vertigo, but they had spontaneous nystagmus. The latter group was called ‘‘disease control.’’ Magnetic resonance imaging in both groups consistently revealed focal cerebellar infarct affecting posterior cerebellar vermis (lobule IX). In the ‘‘disease model’’ group, only part of lobule IX was affected. In the disease control group, however, complete lobule IX was involved. Conclusions: This study discovered a novel presentation of cerebellar stroke where only motion perception was affected, but there was an absence of objective neurologic signs. Key Words: Perception— Purkinje neuron—posterior inferior cerebellar artery—velocity storage. Ó 2014 by National Stroke Association
Introduction In natural behavior, the brain computes precise estimate of self-motion to ensure appropriate reflexive behavior and perception of motion. Basic principles of reflexive eye movements, the vestibulo-ocular reflex (VOR), are well known. Direct and indirect pathways mediate VOR. The direct pathway featuring ‘‘three-neuron arc’’—vestibular afferents, premotor vestibular neurons, and ocular motor neurons—guarantees prompt compen-
From the Department of Neurology, Case Western Reserve University, Cleveland, Ohio. Received August 10, 2013; revision received September 24, 2013; accepted October 7, 2013. Grant support: None. Address correspondence to Aasef G. Shaikh, MD, PhD, Department of Neurology, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106-5040. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.10.005
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satory eye movement in response to head movement.1 The indirect pathway comprising the cerebellar cortex, deep cerebellar nuclei, and vestibular nuclei increases the bandwidth over which VOR is compensatory.2 Vestibular processing related to motion perception has enticed several recent investigations, some of these studies have emphasized the role of cerebellum.3-7 Two hypotheses were proposed. First, VOR and motion perception share same groups of brainstem and cerebellar neurons. Second, the neurons responsible for VOR and motion perception are anatomically distinct but abide the same physiological principles. Recent studies were in support of second hypothesis.5,7 These proposals, however, relied on indirect observations such as the differences in the dynamics of VOR and perceived angular velocity,5,6 disparity in the effects of drugs to reduce the decay time constant of the VOR and perceived angular velocity,7 and trends of altered motion perception in patients with ophthalmoplegia because of peripheral etiology.3,4,8 The second hypothesis was also supported by studies in macaques that revealed the
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 5 (May-June), 2014: pp 1148-1156
PERCEPTION OF MOTION WITHOUT NYSTAGMUS IN CEREBELLAR STROKE
presence of neurons in cerebellar nodulus, rostral fastigial nucleus, and the vestibular nuclei that have pure vestibular sensitivity but lack responsiveness to eye movements, that is, the ‘‘vestibular-only’’ neurons.9-17 Perception is one of the putative functions of such non– eye movement-sensitive central vestibular neurons. Perception as the possible function of these neurons became more evident with the discovery of the thalamic projections of the cerebellar and brain stem regions featuring the ‘‘vestibular-only’’ neurons in macaques.11 Signs and symptoms related to vestibular and ocular motor deficits in patients with focal cerebellar lesions might support experimental and theoretical framework depicting the differences between the neural mechanisms responsible for VOR and motion perception. For example, vertigo (perception of rotation), spontaneous nystagmus, gaze-evoked nystagmus, and body lateropulsion are known manifestations of focal stroke affecting the posterior cerebellar vermis.18,19 We asked whether focal cerebellar lesion exists that only manifests as vertigo but the absence of ocular motor deficits including nystagmus.
Methods Thirteen cases with acute cerebellar stroke were examined. The University Hospitals Case Medical Center institutional review board approved this retrospective study. Clinical assessment was performed as a part of hospital admission. Patients with acute onset of vertigo, ability to accurately provide history, qualitative description, duration, and severity of vertigo and an evidence of acute stroke on magnetic resonance imaging (MRI) were included in the study. Patients were excluded if there was a chronic history of vertigo without change in its quality and severity, if there was an evidence for the pathology affecting brainstem vestibular or eye movement–sensitive nuclei, if MRI did not reveal acute or subacute stroke affecting the vestibulocerebellum, and if there was a clinical or neuroimaging evidence of a degenerative cerebellar disease. The patients were scanned on 1.5 T scanner. Axial T1and T2-weighted images, diffusion-weighted images (DWIs), apparent diffusion coefficient (ADC), and FLAIR sequences were acquired. Slice thickness for each image was 5 mm. Picture Archiving and Communication System was used to determine the anatomical location of the affected cerebellar lobule in the MRI. The areas of diffusion restriction on DWI sequences were correlated with ADC to confirm the ischemic lesion. Cross-referencing tool in the PACS software was used to colocalize the area of diffusion restriction in the fluid-attenuated inversion recovery and T1-weighted axial and saggital sequences. The latter facilitated accurate anatomical localization of acute lesions that were identified on DWI and ADC sequences.
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Three-dimensional MRI atlas of cerebellum was used to accurately identify the lobules of interest in MRI.20 The areas of interest in vestibulo-cerebellum, identified in this article as lobules IX and X, were diversely labeled in the past. For lobule IX, some authors used the term paraflocculus21-25; the same area was also called tonsil26-32 or uvula.33 Schematic in Figure 1 identifies various lobules in the map of cerebellum in sagittal and axial sections in nomenclature proposed by Schmahmann et al.20
Results Clinical Presentation Thirteen patients (9 men and 4 women) with abrupt onset of vertigo, intractable nausea, and vomiting were assessed. Assessment was performed within 24 hours of symptom onset. Patients described vertigo as spinning sensation. Four patients could clearly describe the direction of spinning—one perceived spinning of surrounding environment from the left to right, whereas three perceived rightward to leftward motion. Eight patients were unclear about the direction of perceived spinning. In eight patients, the severity of the vertigo was dependent on the head orientation with respect to gravity. The details of symptoms are outlined in Table 1. Neurologic examination classified this cohort into two groups. One group had no nystagmus in primary or eccentric gaze or with removal of visual fixation using Frenzel goggles during upright, supine, left ear down, and right ear down orientations. The VOR was normal during head impulses and head shaking maneuver. Saccades and pursuit eye movements and optokinetic nystagmus were normal. The vertigo was severe in three patients to keep them confined to bed. Two patients could stand up, and they had body pulsion toward the side of cerebellar lesion. Remaining neurologic examination was normal. This was ‘‘disease model’’ group. The second group, the ‘‘disease control,’’ featured ocular motor deficits on examination. Nystagmus was present in at least one of the four head orientations with respect to gravity (ie, supine, upright, right ear down, or left ear down positions). In five of eight patients, the pattern of nystagmus was head position dependent. Saccadic hypometria was seen in one patient, and pursuit was interrupted by quick phase of nystagmus. Two patients had acute onset of hypoactive VOR in addition to gravity dependence of spontaneous nystagmus. It was concluded that the patients with hypoactive VOR and gravity-dependent nystagmus had acute stroke affecting the vascular distributions of anterior and posterior inferior cerebellar arteries.34 The VOR testing was deferred in one patient who presented with cerebellar stroke symptoms and neck pain after injury, concerning for vertebral artery dissection. All patients had profound imbalance and body lateropulsion. Table 1 illustrates the
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Figure 1. Diffusion-weighted magnetic resonance imaging sequences depict infarction of posterior cerebellar vermis in the vascular territory of the medial branch of posterior inferior cerebellar artery. Lobules VIIIa, VIIIb, and IX were affected in all patients, lobule VIIb in 7, lobule X in 2, and lobules V and VI in 1 patient. There was a complete involvement of lobule IX in ‘‘disease control,’’ but only the part of lobule IX was affected in ‘‘disease model’’ (arrows). The schematic in the center of the figure depicts locations of lobules in the cerebellar map in sagittal and axial section. (Color version of figure is available online.)
details of symptomatology and neurologic examination in ‘‘disease control’’ group.
Neuroimaging Features DWI and ADC sequences of MRI consistently revealed areas of diffusion restriction in posterior cerebellar vermis, suggesting acute cerebellar infarction in the vascular territory of the medial branch of posterior inferior cerebellar artery. Lobules VIIIa, VIIIb, and IX were affected in all patients. Lobule VIIb was affected in seven patients. In two patients, the infarct extended to the lobule X, whereas in one patient, lobules Vand VI were also involved. Hence, in addition to the involvement of vermis, in some subjects, the lesions extended into the hemispheres. It is noteworthy that involvement of lobule IX was consistent in all subjects, but the areas of hemisphere that were involved varied
among patients. The key discriminating feature between the ‘‘disease control’’ and ‘‘disease model’’ was the extent to which lobule IX was involved. In ‘‘disease control,’’ lobule IX was completely affected, but in ‘‘disease model,’’ the involvement of lobule IX was patchy. It appeared that dorsal aspect of lobule IX was affected in ‘‘disease model’’ group. Table 1 summarizes the lobular distribution of the stroke. Figure 1 illustrates the areas of diffusion restriction in DWI sequence in 13 patients.
Risk Factors, Clinical Course, Treatment, and Outcome There were no differences in the stroke risk factors between two groups. All patients had at least one of the risk factors for ischemic stroke. Six patients had the history of hypertension, one had diabetes, eight had untreated dyslipidemia, three had paroxysmal atrial fibrillation, two
Age Patient (y)
Symptom
Disease model 1 77 Vertigo in yaw plane, unclear of direction of spinning. Intractable nausea and vomiting.
Vertigo/head position dependence
Pattern of head position dependence of nystagmus
Other examination findings
Stroke risk factors
Time of examination since onset (h)
Maximal in left ear down, intermediate in supine, and upright head orientation, relatively less in right ear down orientation.
None
None
HTN, DLD
6
2
80 Vertigo in yaw plane, room was spinning from right to left. Intractable nausea and vomiting.
No position dependence.
None
None
HTN, Afib, NSTEMI
8
3
51 Vertigo in yaw plane, room was spinning from right to left. Intractable nausea, vomiting. and headache.
None
None
HTN, DM
4
4
61 Vertigo, unclear about direction of spinning. Intractable nausea and vomiting. Diaphoresis.
Maximal sensation in supine orientation, intermediate in right or left ear down position, minimal in upright head orientation. Vertigo did not have head position dependence.
None
None
DLD
6
5
66 Vertigo in yaw plane, as if room is spinning from the left to right. Intractable nausea and vomiting
Maximal in left or right ear down position, intermediate in supine orientation, relatively less when upright.
None
None
DLD
10
Affected cerebellar lobules (diffusionweighted MRI) Right cerebellum. Dorsal part of lobule IX, extending to caudal aspect of lobule X, patchy distribution in lobules VIIIb . VIIIa .. VIIb Right cerebellum. Dorsal aspect of lobule IX, partial extension into lobules VIIIb, VIIIa, and VIIb. Right cerebellum. Dorsal aspect of lobule IX, extends in lobules VIIIb and VIIIa Left cerebellum. Rostrally dorsal and caudally complete lobule IX, partial extension into lobule VIIIb. Right cerebellum. Dorsal of lobule IX, partial extension into lobules VIIIb and VIIIa (Continued)
PERCEPTION OF MOTION WITHOUT NYSTAGMUS IN CEREBELLAR STROKE
Table 1. Clinical features of patients with acute stroke affecting posterior cerebellar vermis
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Table 1. (Continued)
Symptom
Disease control 6 59 Sudden onset of vertigo. Nausea and vomiting.
Vertigo/head position dependence
Pattern of head position dependence of nystagmus
Torsional nystagmus Maximal vertigo on supine and left while supine and left ear down position. ear down, intermediate while upright, further improvement during right ear down position. Worse sensation of vertigo Clockwise beating torsional nystagmus during supine orientation, during supine improvement in upright position, horizontal head orientation. right beating nystagmus on left ear down, stable gaze in remaining orientations. No head position Torsional nystagmus. dependence.
54 Sudden onset of vertigo and associated nausea and vomiting.
8
77 Sudden onset of vertigo. Intractable nausea and vomiting.
9
28 Sudden onset of vertigo. Nausea and vomiting.
History was unclear of head position dependence.
10
74 Sudden onset of vertigo. Sudden onset of oscillopsia while walking.
Vertigo worsens with right ear down orientation.
Upright head orientation: steady gaze in upright position. Supine: right beating nystagmus on right gaze and left beating on left gaze. Right ear down position: left beating nystagmus on left gaze, steady right gaze. Left ear down: right beating nystagmus on right gaze and steady at central and left gaze. Steady central gaze in all head orientation. No change under Frenzel goggles. Rightward and upbeat nystagmus during right ear down orientation.
Time of examination since onset (h)
Affected cerebellar lobules (diffusionweighted MRI)
None
HTN, Afib
18
Right cerebellum. Complete lobule IX, extension to lobules VIIIb, VIIIa, and VIIb.
None
HTN, DLD
10
None
DLD, CAD
2
Left cerebellum. Complete lobule IX, extension to lobules VIIIb, VIIIa, and VIIb. Minimal extension into left inferior cerebellar peduncle. Left cerebellum. Complete lobule IX. Patchy involvement of lobule VIIb. Right cerebellum. Complete lobule IX and VIIIB. Part of lobules VIIIA and VIIB.
VOR examination None deferred because of neck pain concerning for dissection. Pursuit interrupted by quick phase of nystagmus.
14
Hypoactive VOR, hearing deficit.
12
HTN, DLD
Left cerebellum. Complete lobule IX. Part of lobules VIIIB, VIIIA, and VIIB.
A.G. SHAIKH
7
Stroke risk factors
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Age Patient (y)
Other examination findings
52 Sudden onset of vertigo. Sudden onset of oscillopsia while walking.
12
History is unclear 75 Sudden onset of vertigo about the head in yaw plane. Vertigo was position dependence. perceived as if the world is moving from the left to right.
13
81 Sudden onset of vertigo.
History is unclear about head position dependence.
Hypoactive Upright, supine, and right VOR, impaired ear down orientations: hearing on the right beating nystagmus right side. while looking straight Pursuit was ahead, increased velocity interrupted by of right beating nystagmus quick phase of during right gaze, stable left nystagmus. gaze. Left ear down position: stable gaze. Pursuit was Gaze-evoked nystagmus, interrupted worse on the right-ward by quick phase gaze holding. Upbeat of nystagmus. nystagmus during upgaze and downbeat nystagmus during downgaze. No head position dependence. Saccadic Gaze-evoked nystagmus dysmetria with higher slow-phase velocity during rightward gaze holding. Upbeat nystagmus during upgaze and downbeat during down gaze.
None
6
Left cerebellum. Complete lobule IX. Part of lobule VIIIB.
HTN
14
Left cerebellum. Complete lobules IX and VIIIB. Part of lobule VIIIA. Minimal extension into left inferior cerebellar peduncle.
HTN, Afib
12
Right cerebellum, complete lobule IX. Part of lobules VIIIA, VIIIB, X, and VIIB.
Abbreviations: Afib, atrial fibrillation; CAD, coronary artery disease; DM, diabetes mellitus; DLD, dyslipidemia; HTN, hypertension; NSTEMI, non-ST elevation myocardial infarction; MRI, magnetic resonance imaging; VOR, vestibulo-ocular reflex.
PERCEPTION OF MOTION WITHOUT NYSTAGMUS IN CEREBELLAR STROKE
Vertigo worsens with supine and left ear down position.
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had the history of coronary artery disease, and one had an evidence of vasculopathy. None of the patients had the indication for vascular intervention or administration of tissue plasminogen activator. All patients were assessed for and treated to minimize the stroke risk factors. Six patients were taking aspirin at the time of presentation; in these instances, the treatment was upgraded to either clopidogrel or warfarin. Eight patients were not on any antiplatelet agent; aspirin was started at the time of hospitalization. There were no differences in the rate of recovery between both groups. Both groups had rapid recovery from vertigo within 48 hours. In ‘‘disease control’’ group, the nystagmus improved within 72 hours. Both groups continued to experience imbalance and gait instability till the time of discharge. The patients were discharged to rehabilitation facility. To summarize, the patients with central acute vestibular syndrome consistently presented with vertigo (described as constant spinning sensation), intractable nausea, vomiting, and profound imbalance. This cohort was divided into two groups. The ‘‘disease control’’ group had typical ocular motor and vestibular deficits including nystagmus. The ‘‘disease model’’ group had severe vertigo, but eye movement examination was normal. In both groups, neuroimaging revealed acute to subacute stroke affecting posterior cerebellar vermis. The key difference between two groups was the extent of involvement of the lobule IX. In ‘‘disease model’’ group, only the part of lobule IX was affected, but ‘‘disease control’’ group had complete involvement of lobule IX. From clinical perspective, it is imperial to correctly identify patients with stroke who present with vertigo but in the absence of localizing deficit on neurologic examination. This study suggests putative identifiers of such ‘‘silent’’ cerebellar infarcts. The ‘‘disease model’’ group in this study identified persistent perception of spinning motion with intractable nausea and vomiting as putative manifestation of acute cerebellar infarct.
Discussion All our patients had vertigo, intractable nausea, and vomiting. The neurologic examination separated this cohort into two groups. The ‘‘disease model’’ group comprised patients who had constant vertigo but did not have nystagmus. The ‘‘disease control’’ group also presented for vertigo, but eye movement examination revealed nystagmus. Vertigo was described as persistent perception of spinning movement. I will first discuss the ‘‘disease control’’ group and then ‘‘disease model.’’ Nystagmus, as seen in patients from the ‘‘disease control’’ group, is a known manifestation of posterior inferior cerebellar artery infarct affecting the posterior cerebellar vermis.18,19 In five of eight patients, the direction of nystagmus was dependent on the head position with
A.G. SHAIKH
respect to gravity. The gravity dependence of nystagmus has been described in degenerative cerebellar syndromes35-37 and was rarely reported in patients with acute cerebellar stroke.38-40 What causes gravity-dependent modulation of nystagmus? The cerebellum calibrates the direction and the amplitude of the vestibular reflexes.35,41,42 It is proposed that impairment of such calibration causes gravity-dependent modulation of the nystagmus. A two-step process is speculated. In the first step, disinhibition of the deep cerebellar and vestibular nuclei occurs after the loss of cerebellar Purkinje neurons. For example, in macaques, resection of flocculus (ie, lobule X) causes gaze-evoked nystagmus because of the disinhibition and impairment of neural integrator circuit in the medial vestibular nuclei.43 The gaze-evoked nystagmus also occurs when there is a breach in the inflow to the cerebellum (from brainstem integrators) that passes through the inferior cerebellar peduncle; in other words, there is a disruption of cerebellar feedback pathway around the neural integrator.44 Gaze-evoked nystagmus was noted in patients 9, 12, and 13. The infarct extended to inferior cerebellar peduncle in patient 12, whereas there was an involvement of lobule X in patient 13; hence, gazeevoked nystagmus could be explained in both cases. There was no obvious acute structural deficit in DWI sequence to explain gaze-evoked nystagmus in patient 9. It is, however, possible that ischemic penumbra affecting lobule X had caused gaze-evoked nystagmus in this patient. The second step is the gravity-dependent modulation of nystagmus because of impaired central estimate of gravity. It is known that the lesions of the cerebellar nodulus in monkeys impair the ability to align the axis of eye rotation with the gravito-inertial axis during VOR.38-40 One could, therefore, predict that, in humans too, the strokes affecting the lobules VIII and IX might disrupt the calibration of axis of eye rotation with respect to gravity. Hence, disinhibition first causes nystagmus, when the axis of eye rotation is not systematically aligned with earth-fixed axis because of impaired central estimate of gravito-inertial axis, gravity-dependent modulation of the nystagmus occurs. In two patients, the gravity-dependent nystagmus had partial features of apogeotropic positional nystagmus, and the quick phase was away from the direction of the gravity. The key difference, however, from typical apogeotropic nystagmus characterizing the lateral canal benign paroxysmal positional vertigo (BPPV) was that in one patient nystagmus was only present during left ear down, but supine orientation revealed torsional nystagmus. In the other patient, the apogeotropic nystagmus was only seen when eye in the orbit position was eccentric and directed away from the side facing the ground. These features readily separated central positional nystagmus from typical lateral canal BPPV.45,46 In two patients, torsional and horizontal nystagmus was
PERCEPTION OF MOTION WITHOUT NYSTAGMUS IN CEREBELLAR STROKE
present, such nystagmus could not be explained by any known variant of BPPV.45,46 Furthermore, the nystagmus related to BPPV appears after latency of few seconds and it habituates within several seconds.45,46 The central gravity–dependent nystagmus in our patients appeared instantaneously after change in head orientation, and it did not habituate.44 The ‘‘disease model’’ group had vertigo, intractable nausea, and vomiting, but there was no deficit during eye movement and vestibular examination. Vertigo was described as consistent perception of spinning. One could attribute ‘‘pure’’ perceptual deficit to disinhibition of vestibular neurons that putatively serve vestibular perception pathway. In addition to the VOR, the vestibular signals also serve motion perception. Initial studies have showed that during constant velocity whole-body rotation in complete darkness, the perception of angular motion decays at the rate slower than the activity of the semicircular canals.47,48 This perceptual behavior was analogous to VOR.2 Hence, it was believed that perception of motion and VOR share the same pathways and mechanisms. Various authors suggested different locations for vestibular perception–related neurons. It was first proposed that perception-related vestibular processing occurs at cerebral cortex.49 Subsequent studies in subjects with cerebellar vermis lesions found similar deficits in the VOR and perceptual response, hence, suggesting cerebellum as a structural correlate for motion perception.50,51 It was subsequently proposed that motion perception and VOR abide same neurophysiological principles; both are under control of cerebellar cortex, but the groups of cerebellar neurons controlling VOR and perception might be independent.7 Consistent with the latter proposal, the patients in the ‘‘disease model’’ group featuring isolated perceptual deficits without nystagmus had only partial involvement of lobule IX. In contrast, the patients who had nystagmus in addition to perception of vertigo had more extensive stroke affecting complete lobule IX. Isolated perception of vertigo in three patients from the ‘‘disease model’’ group was dependent on the head orientation with respect to gravity. The pathophysiology of such gravity dependence of perceived severity of motion could be described by the same principle that explained gravity-dependent modulation of the nystagmus. Gravity-dependent modulation of perceived vertigo in ‘‘disease model’’ group and gravity-dependent modulation of nystagmus in ‘‘disease control’’ group further supported the hypothesis that central processing of motion perception and VOR abide same physiological principles. Occurrence of these two phenomena in different subgroups of patients where cerebellar lobule IX is involved at different extent supported the hypothesis that motion perception and VOR might be controlled by anatomically distinct groups of neurons.7
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In several instances, the cerebellar vermis infarct extended into the hemispheres. Such hemispheric extension is unlikely to cause variability in ocular motor deficits in our patients. It is known that isolated cerebellar hemisphere lesions do not cause ocular motor or vestibular deficits. Furthermore, vestibular and ocular motor deficits seen in all our patients could be readily described by the lesions in posterior cerebellar vermis.
Conclusions Group of patients with cerebellar stroke in distribution of posterior inferior cerebellar artery had isolated perception of vertigo in the absence of objective eye movement deficits. The vertigo was unequivocally described as constant perception of spinning of visual surround. Diffusion-weighted MRI suggested possible involvement of dorsal aspect of cerebellar lobule IX in these patients. These results suggested putative anatomical correlate of motion perception–related cerebellar neurons. This study discovered a disease that manifests in the form of ‘‘pure’’ motion perception deficit without objective neurologic signs. The cerebellar strokes, manifesting just as abnormal perception of motion with nausea and vomiting, have a potential to be misdiagnosed as nonorganic, benign, non-neurologic, or gasteroenteric illness. Therefore, it is emphasized that novel manifestation of cerebellar stroke presenting as isolated perception deficit should be considered in differential diagnosis of patients with acute onset of vertigo and imbalance but otherwise normal cerebellar examination. If such patients have vascular risk factors, the index of suspicion for cerebellar stroke should be even higher. Acknowledgments: I thank R. John Leigh, MD, and David S. Zee, MD, for mentorship and support.
References 1. Baker R, Evinger C, McCrea RA. Some thoughts about the three neurons in the vestibular ocular reflex. Ann N Y Acad Sci 1981;374:171-188. 2. Raphan T, Matsuo V, Cohen B. Velocity storage in the vestibulo-ocular reflex arc (VOR). Exp Brain Res 1979; 35:229-248. 3. Seemungal BM, Glasauer S, Gresty MA, et al. Vestibular perception and navigation in the congenitally blind. J Neurophysiol 2007;97:4341-4356. 4. Seemungal BM, Masaoutis P, Green DA, et al. Symptomatic recovery in Miller Fisher Syndrome parallels vestibular-perceptual and not vestibular-ocular reflex function. Front Neurol 2011;2:2. 5. Bertolini G, Ramat S, Laurens J, et al. Velocity storage contribution to vestibular self-motion perception in healthy human subjects. J Neurophysiol 2011;105:209-223. 6. Sinha N, Zaher N, Shaikh AG, et al. Perception of selfmotion during and after passive rotation of the body around an earth-vertical axis. Prog Brain Res 2008; 171:277-281.
1156 7. Shaikh AG, Palla A, Marti S, et al. Role of cerebellum in motion perception and vestibulo-ocular reflex—similarities and disparities. Cerebellum 2013;12:97-107. 8. Grunfeld EA, Shallo-Hoffmann JA, Cassidy L, et al. Vestibular perception in patients with acquired ophthalmoplegia. Neurology 2003;60:1993-1995. 9. Angelaki DE, Shaikh AG, Green AM, et al. Neurons compute internal models of the physical laws of motion. Nature 2004;430:560-564. 10. Green AM, Shaikh AG, Angelaki DE. Sensory vestibular contributions to constructing internal models of self-motion. J Neural Eng 2005;2:S164-S179. 11. Meng H, May PJ, Dickman JD, et al. Vestibular signals in primate thalamus: properties and origins. J Neurosci 2007;27:13590-13602. 12. Shaikh AG, Ghasia FF, Dickman JD, et al. Properties of cerebellar fastigial neurons during translation, rotation, and eye movements. J Neurophysiol 2005;93:853-863. 13. Shaikh AG, Green AM, Ghasia FF, et al. Sensory convergence solves a motion ambiguity problem. Curr Biol 2005;15:1657-1662. 14. Yakusheva TA, Shaikh AG, Green AM, et al. Purkinje cells in posterior cerebellar vermis encode motion in an inertial reference frame. Neuron 2007;54:973-985. 15. Buttner U, Fuchs AF, Markert-Schwab G, et al. Fastigial nucleus activity in the alert monkey during slow eye and head movements. J Neurophysiol 1991;65:1360-1371. 16. Siebold C, Anagnostou E, Glasauer S, et al. Canal-otolith interaction in the fastigial nucleus of the alert monkey. Exp Brain Res 2001;136:169-178. 17. Siebold C, Kleine JF, Glonti L, et al. Fastigial nucleus activity during different frequencies and orientations of vertical vestibular stimulation in the monkey. J Neurophysiol 1999;82:34-41. 18. Rubenstein RL, Norman DM, Schindler RA, et al. Cerebellar infarction—a presentation of vertigo. Laryngoscope 1980;90:505-514. 19. Lee H, Sohn SI, Cho YW, et al. Cerebellar infarction presenting isolated vertigo: frequency and vascular topographical patterns. Neurology 2006;67:1178-1183. 20. Schmahmann JD, Doyon J, McDonald D, et al. Threedimensional MRI atlas of the human cerebellum in proportional stereotaxic space. Neuroimage 1999;10:233-260. 21. Angevine JB, Mancall EL, Yakovlev PI. The human cerebellum: an atlas of gross topography in serial sections. Boston, MA: Little, Brown and Co 1961. 22. Dow RS. The evolution and anatomy of the cerebellum. Biol Rev 1942;17:179-220. 23. Jansen J, Brodal A. Das Kleinhirn. Berlin, Germany: Springer 1958. 24. Larsell O, Jansen J. The comparative anatomy and histology of the cerebellum—cerebellar connections, and cerebellar cortex. Minneapolis, MN: University of Minnesota Press 1972. 25. Riley HA. The lobules of the mammalian cerebellum and cerebellar nomenclature. Arch Neurol Psychiatry 1930; 24:227-256. 26. Flatau E, Jacobsohn L. Handbuch der Anatomie and vergleichende anatomie des Centralnervensystems der Saeugetiere. I. Berlin, Germany: Karger 1899. 27. Henle J. Grundriss der anatomie des menschen, Neu bearbeitet von F. Merkel, 4th Aufl. Atlas. Braunschweig, Germany: Friedrich Vieweg and Sohn 1901. 28. Ingvar S. Phylo- und Ontogenesae des Kleinhirns. Follia Neuro-Biologica 1918;11:205-495. 29. Kuithan W. Die Entwicklung des Kleinhirns von Saugetieren. Munchen; 1894.
A.G. SHAIKH 30. Press GA, Murakami J, Courchesne E, et al. The cerebellum in saggital plane—anatomic—MR correlation: 2. The cerebellar hemispheres. Am J Neurol Res 1989; 10:667-676. 31. Schafer EA, Symington J. Neurology. London: Longmans, Green and Co 1908. 32. Ziehen T. Central nerven system. Jena: Verlag von Gustav Fischer 1934. 33. langelaan JW. On the development of the external form of the human cerebellum. Brain 1919;42:130-170. 34. Shaikh AG, Miller BR, Sundararajan S, et al. Gravitydependent nystagmus and inner-ear dysfunction suggest anterior and posterior inferior cerebellar artery infarct. J Stroke Cerebrovasc Dis 2013;332:56-58. 35. Shaikh AG, Marti S, Tarnutzer AA, et al. Ataxia telangiectasia: a ‘‘disease model’’ to understand the cerebellar control of vestibular reflexes. J Neurophysiol 2011; 105:3034-3041. 36. Marti S, Palla A, Straumann D. Gravity dependence of ocular drift in patients with cerebellar downbeat nystagmus. Ann Neurol 2002;52:712-721. 37. Kattah JC, Gujrati M. Familial positional downbeat nystagmus and cerebellar ataxia: clinical and pathologic findings. Ann N Y Acad Sci 2005;1039:540-543. 38. Nam J, Kim S, Huh Y, et al. Ageotropic central positional nystagmus in nodular infarction. Neurology 2009; 73:1163. 39. Kim HA, Yi HA, Lee H. Apogeotropic central positional nystagmus as a sole sign of nodular infarction. Neurol Sci 2012;33:1189-1191. 40. Johkura K. Central paroxysmal positional vertigo: isolated dizziness caused by small cerebellar hemorrhage. Stroke 2007;38:e26-e27. author reply e8. 41. Walker MF, Zee DS. Cerebellar disease alters the axis of the high-acceleration vestibuloocular reflex. J Neurophysiol 2005;94:3417-3429. 42. Schultheis LW, Robinson DA. Directional plasticity of the vestibuloocular reflex in the cat. Ann N Y Acad Sci 1981; 374:504-512. 43. Zee DS, Yamazaki A, Butler PH, et al. Effects of ablation of flocculus and paraflocculus of eye movements in primate. J Neurophysiol 1981;46:878-899. 44. Leigh RJ, Zee DS. The neurology eye movements. 5th ed. New York: Oxford 2006. 45. Leigh RJ, Zee DS. Neurology of eye movements. 4th ed. New York: Oxford 2006. 46. Korres SG, Balatsouras DG. Diagnostic, pathophysiologic, and therapeutic aspects of benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg 2004; 131:438-444. 47. Guedry FE. Psychopysica of vestibular sensation. Handbook of sensory physiology. Berlin: Springer-Verlag 1974:3-154. 48. Young LR. Perception of the body in space: mechanisms. Handbook of physiology: the nervous system III. Bethesda: American Physiology Society 1983:1023-1066. 49. Okada T, Grunfeld E, Shallo-Hoffmann J, et al. Vestibular perception of angular velocity in normal subjects and in patients with congenital nystagmus. Brain 1999;122(Pt 7):1293-1303. 50. Bronstein AM, Grunfeld EA, Faldon M, et al. Reduced self-motion perception in patients with midline cerebellar lesions. Neuroreport 2008;19:691-693. 51. Bertolini G, Ramat S, Bockisch CJ, et al. Is vestibular selfmotion perception controlled by the velocity storage? Insights from patients with chronic degeneration of the vestibulo-cerebellum. PLoS One 2012;7:e36763.