J Neurol DOI 10.1007/s00415-014-7614-2
ORIGINAL COMMUNICATION
Esophoria or esotropia in adulthood: a sign of cerebellar dysfunction? Katharina Hu¨fner • Claudia Frenzel • Olympia Kremmyda • Christine Adrion Stanislavs Bardins • Stefan Glasauer • Thomas Brandt • Michael Strupp
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Received: 9 September 2014 / Revised: 7 December 2014 / Accepted: 9 December 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Convergent strabismus is a common diagnosis in early childhood, when it is mostly considered benign. If it develops later in life, strabismus can, however, be a sign of neurological disease. In these cases the underlying pathophysiological mechanisms are largely unknown. In this retrospective case–control study we analyzed the neuro-ophthalmological examination reports of 400 adult patients who presented at the German Center for Vertigo and Balance Disorders to determine an association between ocular misalignment and cerebellar dysfunction. Patients with cerebellar signs (i.e., cerebellar ataxia and/or cerebellar ocular motor signs) had a 4.49 (95 % CI [1.60; 13.78]) times higher frequency of ocular misalignment and
K. Hu¨fner C. Frenzel O. Kremmyda M. Strupp Department of Neurology, University Hospital Munich, Ludwig-Maximilians University, Campus Grosshadern, Munich, Germany K. Hu¨fner O. Kremmyda C. Adrion S. Bardins S. Glasauer T. Brandt M. Strupp German Center for Vertigo and Balance Disorders, University Hospital Munich, Ludwig-Maximilians University, Campus Grosshadern, Munich, Germany K. Hu¨fner (&) Department of Psychiatry, Medical University of Innsbruck, Innsbruck, Austria e-mail: [email protected] C. Adrion Institute for Medical Informatics, Biometry und Epidemiology, University Hospital Munich, Ludwig-Maximilians University, Campus Grosshadern, Munich, Germany S. Glasauer T. Brandt Institute for Clinical Neurosciences, University Hospital Munich, Ludwig-Maximilians University, Campus Grosshadern, Munich, Germany
specifically a 13.3 (95 % CI [3.80; 55.73]) times increased frequency of esophoria/esotropia (ESO) during distant gaze than patients without cerebellar dysfunction. ESO when looking into the distance was associated with saccadic smooth pursuit, dysmetria of saccades, and downbeat nystagmus (DBN) (v2 test, p \ 0.0001 for all associations). Patients with cerebellar dysfunction also showed mildly impaired eye abduction (v2 test, left eye and right eye: p \ 0.0001), associated with horizontal gaze-evoked nystagmus (v2 test, p \ 0.0001). The association of ESO and DBN implicates a pathophysiological involvement of the cerebellar flocculus, while the association with dysmetric saccades suggests involvement of the oculomotor vermis. This is compatible with animal studies showing that the pathways of the flocculus/posterior interposed nucleus and vermis/nucleus fastigii are both involved in vergence movements and static binocular alignment. From a clinical point of view, a newly diagnosed esophoria/esotropia only during distant gaze may be a sign of a cerebellar disease. Keywords Esophoria Esotropia Distant gaze Cerebellar dysfunction
Introduction Strabismus is frequently found in young children, in whom its prevalence is between 2 and 5 % [10, 31]. The two major categories of early onset concomitant esotropia are accommodative and congenital (infantile). In concomitant strabismus the ocular deviation does not vary with direction of gaze as opposed to incomitant forms. While there is some disagreement on the exact pathophysiology of these strabismus disorders, there is a general consensus that they are not as a rule causally related to any serious underlying
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neurological pathology, even if the onset is sudden [13, 31, 41]. Subtle cases can go undiagnosed, becoming apparent in adult life when an affected individual experiences stress, a minor head trauma, or fatigue. All can lead to the decompensation of a previously latent strabismus and the sudden onset of diplopia. In cases when new ocular misalignment develops in adulthood, it is usually incomitant (i.e., varies with direction of gaze) and caused by a defined and localized neurological or ophthalmological disease such as cranial nerve palsies, brainstem pathologies or disease of the ocular muscles. A few case reports, case series, and commentaries have described the appearance of a new acute comitant esophoria/esotropia, which is larger when looking into the distance, in later childhood or adulthood in patients with cerebellar disease such as cerebellar tumors, including astrocytomas and medulloblastomas as well as Arnold–Chiari I malformations [13, 32, 37, 43]. Acquired esophoria/esotropia can be associated with other eye movement abnormalities, such as dysmetric saccades, gaze-evoked nystagmus, or downbeat nystagmus (DBN) [40]. After initially successful surgery for strabismus, patients with Arnold–Chiari malformation can also develop recurrent esotropia with diplopia, which resolves upon suboccipital decompression [8, 32]. Esotropia can also be caused by acute lesions of the thalamus [9] and the corpus callosum [1]. Finally, vertical misalignment of the eyes has also been described in patients with cerebellar disease [12]. In this retrospective case–control study we investigated whether there is a higher frequency of ocular misalignment, namely concomitant esophoria/tropia, in patients with cerebellar dysfunction than in patients without cerebellar symptoms, in order to evaluate the co-occurrence of these conditions in an adult patient population.
Methods Neuro-ophthalmological and orthoptic examination All subjects underwent a standardized neurological and neuro-ophthalmological examination at the German Center for Vertigo and Balance Disorders at the University Hospital Munich, Campus Grosshadern, between 1999 and 2009 as described previously (e.g., [14]). The following parameters were evaluated in the present study and dichotomised for statistical analysis: patient ID, age (in years), neurological diagnosis, control/patient status, presence of saccadic smooth pursuit (yes/no), downbeat nystagmus (yes/no), pathological vestibulo-ocular reflex (VOR) by the head-impulse test (yes/no), saccadic dysmetria (yes/no), rebound nystagmus (yes/no), gaze-evoked
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nystagmus (yes/no), visual fixation suppression of the VOR (normal/abnormal), motility of right and left eye during abduction in mm (0–10) [20], ocular alignment when looking at a near target and into the distance as well as during lateral gaze into the distance (i.e., orthophoria/eso deviation/exo deviation/vertical deviation/congenital strabismus), ocular motility (i.e., intact/abduction deficit/ abducting hypertropia). Observation of the fundus and fundus photography using a scanning laser ophthalmoscope was done online and the subjective visual vertical was also determined. Additional examinations were performed in all cerebellar patients in order to uncover underlying causes of the cerebellar disease. These included caloric irrigation (n = 136), cranial MRI (n = 136), laboratory examinations, including CSF (n = 38), laboratory examinations, excluding CSF analysis (n = 78). Study population A total of 400 subjects who presented with vertigo, dizziness or unsteadiness of gait at the German Center for Vertigo and Balance Disorders at the University Hospital Munich were included in the retrospective case control study. 199 of the participants had a known or newly diagnosed cerebellar dysfunction and were termed the cerebellar group (CBL). Patients with localized cerebellar or cerebral disease such as infarction, tumor or demyelination were not included. Cerebellar dysfunction included cerebellar ataxia [ataxia of stance (n = 67), ataxia of gait (n = 86), ataxia of speech (n = 33) and limb ataxia/dysdiadochokinesis/dysmetria/rebound phenomenon (n = 73)] and/or ocular motor cerebellar signs (all patients). Data on additional cerebellar signs were not available for 14 CBL patients. A specific etiology was identified in 68 of the CBL patients: cerebellar ataxia and bilateral pathological head-impulse test ± polyneuropathy syndrome ([22], n = 31) spinocerebellar ataxia (n = 9), episodic ataxia (n = 9), inflammatory or toxic (n = 7), multiple system atrophy (n = 3), Arnold–Chiari I (n = 3), miscellaneous known etiologies (n = 6); 131 had a degenerative cerebellar disease of unknown etiology. All patients with tropias complained of double vision. The CBL group was compared to an age- and gender-matched group of 201 control patients ‘‘CON’’ (age CBL: 66.3 ± 13.9 years (mean ± SD), CON: 67.1 ± 14.5 years; p = 0.57 and sex ratio CBL: 85 females, CON: 91 females) who, just as the cerebellar patients, had a leading symptom of vertigo, dizziness or unsteadiness of gait. The control patients (bilateral vestibulopathy, Menie`re’s disease, benign paroxysmal positioning vertigo and vestibular migraine) underwent the same neurological and neuro-ophthalmological examinations as the CBL.
J Neurol
Statistical analysis
Table 1 Oculomotor findings in patients with cerebellar dysfunction and controls
Statistical analyses included frequency and descriptive statistics. v2 or Fisher’s exact test was applied to compare proportions. Logistic regression adjusting for possible confounders (e.g., saccadic smooth pursuit, saccadic dysmetria, rebound nystagmus, disturbed fixation suppression, and gaze-evoked nystagmus) was applied to compare the prevalence of a certain disorder of ocular alignment in the cerebellar vs. control group. Statistical analyses were performed using RÒ software package version 2.11.1 (http:// www.r-project.org). All reported statistical tests were two sided, and the significance level was set to 5 %.
Oculomotor findings
Videooculography (VOG) recordings A dataset from a selected cerebellar patient was recorded using binocular videooculography (EyeseecamÒ). The VOG system consists of two cameras fixed on a head band. The patient had to fixate on a central target located either 30 cm (near target paradigm) or 4 m (distant target paradigm) away, during alternating monocular fixation (alternating cover test). The head rested on a chin rest.
Results Disturbances in ocular alignment of patients with cerebellar dysfunction The following factors were analyzed in the described models: ESO included the factors esotropia (ocular convergence during binocular view) and esophoria (ocular convergence during monocular view); EXO included the factors exotropia (ocular deviation during binocular view) and exophoria (ocular deviation during monocular view); VD (vertical deviation) included VD (left eye over right eye) and ?VD (right eye over left eye) (see Table 1 for exact numbers). Vertical divergence did not include any other features of skew deviation or isolated nerve/muscle palsies. In a first, exploratory analysis, the presence of abnormalities of ocular alignment (ESO, EXO, VD) was determined in CBL vs. CON during gaze straight ahead in the distance. In a bivariate analysis, anomalies in ocular alignment during gaze straight ahead in the distance were more prevalent in the CBL group than in the CON group (v2 test, p value \0.0001). A logistic regression model adjusting for saccadic smooth pursuit, rebound nystagmus, disturbed visual fixation suppression of the VOR, and gazeevoked nystagmus, revealed an estimated odds ratio (OR) of 4.49 for CBL vs. CON (95 % CI [1.60; 13.78]). Hence, CBL had a 4.49 times increased risk of displaying
CBL patientsa
CON patientsa
Saccadic smooth pursuit Yes
193/199
51/201
6/199
150/201
Yes
137/199
0/201
No
62/199
201/201
No Downbeat nystagmus
Bilaterally pathological head-impulse test Yes
71/199
86/201
No
128/199
115/201
Yes
73/199
8/201
No
126/199
193/201
Yes
64/199
1/201
No
135/199
200/201
Saccadic dysmetria
Rebound nystagmus
Gaze-evoked nystagmus Yes
185/199
No 14/199 Visual fixation suppression of VOR
31/201 170/201
Abnormal
147/199
Intact
52/199
2/201 199/201
Abduction RE in mmb
9.34 ± 1.00 (per 199)
9.97 ± 0.27 (per 201)
Abduction LE in mmb
9.30 ± 1.05 (per 199)
9.95 ± 0.40 (per 201)
ESO distant gaze straight ahead and/or lateral gaze Yes No
122/198 76/198
8/201 193/201
VD distant gaze straight ahead and/or lateral gaze Yes
48/195
7/201
No
147/195
194/201
Ocular alignment distant gaze straight ahead Orthophoria
83/198
177/201
ESO
95/198
5/201
EXO
9/198
14/201
VD
9/198
3/201
CS
2/198
2/201
Deviation angle distant gaze straight ahead in degreeb ESO
2.0 ± 1.8 (per 90)
1.8 ± 0.8 (per 5)
Deviation angle lateral gaze in the distance in degreeb ESO
3.3 ± 1.9 (per 110)
2.0 ± 0.8 (per 6)
Ocular alignment near gaze straight ahead Orthophoria ESO
21/188 15/188
24/200 1/200
EXO
144/188
170/200
VD
6/188
3/200
CS
2/188
2/200
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J Neurol Table 1 continued Oculomotor findings
CBL patientsa
CON patientsa
distance and the presence of cerebellar dysfunction (v2 test; p = 0.100). Vertical deviation and cerebellar dysfunction
Ocular motility Normal
79/199
193/201
Abduction deficit
64/199
5/201
Abducting hypertropia
34/199
3/201
Abduction deficit plus abducting hypertropia
22/199
0/201
CBL cerebellar, CON control, VOR vestibulo-ocular reflex, ESO esophoria/esotropia, EXO exophoria/exotropia, VD vertical deviation, CS congenital strabismus, RE right eye, LE left eye a
In a bivariate analysis a significant association between vertical deviation during gaze in the distance and cerebellar dysfunction was found (v2 test, p \ 0.0001). There was also an association between the occurrence of vertical deviation and saccadic smooth pursuit (v2 test, p \ 0.0001) and DBN (v2 test, p \ 0.0001), respectively. Impairment of ocular motility in patients with cerebellar dysfunction
The number of analyzed cases for each coding is indicated
b
Mean of all analyzed cases ± standard deviation, the number of analyzed cases is given in brackets
abnormalities in ocular alignment during gaze straight ahead in the distance (p = 0.005). When disturbances in ocular alignment (EXO, ESO, VD) were determined during near fixation no statistically significant association was found with the presence of a cerebellar dysfunction (v2 test, p = 0.916). This finding was confirmed using logistic regression (CBL vs. CON group: OR = 0.84; 95 % CI [0.208; 3.576]). Esophoria/esotropia, exophoria/exotropia during near and distant gaze in cerebellar dysfunction A significant association of ESO during gaze straight ahead in the distance and cerebellar dysfunction was detected (v2 test, p \ 0.0001). This association was also found during lateral gaze (v2 test, p \ 0.0001) and was confirmed using logistic regression adjusting for possible confounders (smooth pursuit, rebound nystagmus, visual fixation suppression of the VOR, and gaze-evoked nystagmus) (p = 0.0001). The risk for ESO during gaze in the distance was 13.3 times higher in the CBL than in the CON group (95 % CI [3.80; 55.73]). No association of ESO during near fixation and cerebellar dysfunction was found (v2 test, p = 0.709). No significant association between ESO during near fixation and during distant gaze was found (v2 test, p = 0.897). This reveals that patients exhibiting esophoria or esotropia during distant gaze do not tend to show esophoria or esotropia during near gaze. Binocular eye movement recordings (horizontal traces) were performed in a representative patient with cerebellar disease to visualize the occurrence of ESO alignment during distant but not during near gaze (Fig. 1). There was no evidence for an association between EXO during gaze straight ahead in the
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The presence of disturbances in ocular motility (abducting hypertropia or disturbance in ocular abduction) was more frequent in the CBL patients than in the CON (v2 test, p \ 0.0001). Ocular motility\10 mm during abduction was considered pathological, while 10 mm or more was considered normal [20]. A significant association between pathological ocular motility during eye abduction and cerebellar dysfunction was found in a bivariate analysis (v2 test, left eye: p \ 0.0001, right eye: p \ 0.0001). Patients with deficits in eye abduction were found to also have horizontal gaze-evoked nystagmus (v2 test, p \ 0.0001). When only the ocular motility of the right eye was considered for analysis, a significant association between the reduced eye abduction in mm and horizontal gaze-evoked nystagmus was found (v2 test, p \ 0.0001). This was confirmed using a Cochran–Armitage trend test for proportions to explore the association between pathological eye abduction and the occurrence of gaze-evoked nystagmus (p \ 0.0001). Esophoria/esotropia and cerebellar ocular motor disturbances To test for a possible abduction deficit as the cause of ESO in the distance, the presence of ESO during lateral gaze was investigated to determine if it was associated with gaze-evoked nystagmus. A significant association of the two parameters was found (v2 test, p \ 0.0001). ESO in the distance was also associated with saccadic smooth pursuit (v2 test, p \ 0.0001) and saccadic dysmetria (v2 test, p \ 0.0001). Patients with DBN were more frequently affected with ESO during distant gaze than patients without DBN (v2 test, p value \0.0001). Subjective visual vertical in patients with esophoria/ esotropia ESO in the distance or nearby was not associated with a displacement of the subjective visual vertical in our
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Fig. 1 Binocular eye movement recordings (horizontal traces) from a patient with cerebellar dysfunction. Cover tests during far (4 m) and near (30 cm) fixation are shown. Positive values indicate movement to the left. Traces for right eye (RE gray lines) and left eye (LE black lines) are shown. ESO (here of about 7°) is visible only during distant
fixation, as indicated by the re-fixation saccade towards the direction of the fixating eye (e.g., movement to the left, during left eye fixation or else right eye cover). In near fixation, there is no occurrence of refixating eye movements during the cover test (notice that both eyes are adducted about 7°, due to convergence)
patients (Fisher respectively).
and that floccular signals inhibit the medial rectus and excite the lateral rectus muscle [15]. Stimulation of the cerebellar flocculus can lead to movements of one eye only, which can be downwards or horizontal [3]. Thus, dysfunction of the cerebellar flocculus in animal studies can result in an increased inward tone of the eyes. Therefore, a likely pathophysiological mechanism of the observed ESO in patients with cerebellar dysfunction is an impaired abduction of the eyes due to floccular dysfunction. This view is supported by the observation that the esophoria/esotropia was associated with horizontal gazeevoked nystagmus and downbeat nystagmus. Our finding has also been supported by others [40]. Experiments on binocular eye alignment and coordination in monkeys have shown that the supraoculomotor area, which is located immediately adjacent to the oculomotor nucleus in the brainstem and projects monosynaptically to the medial rectus motoneurons, encodes vergence movements in healthy monkeys [26] as well as a signal related to the ocular misalignment in monkeys with strabismus [6]. This area is thought to receive input from the caudal
test:
p = 0.529
and
p = 0.086
Discussion The major finding of the current study is that cerebellar dysfunction is associated with distant esophoria/esotropia in adulthood. Second, esophoria/esotropia is associated with mildly impaired ocular motility, specifically eye abduction. Third, further ocular motor signs of cerebellar dysfunction co-occurred with esophoria/esotropia. Fourth, the statistically significant association of ESO with DBN points to a possible pathophysiological involvement of the cerebellar flocculus, while the association with saccadic dysmetria suggests involvement of the oculomotor vermis. The flocculus of primates contains neurons that discharge with the angle of vergence [28] and ablation of the cerebellum can lead to paralysis of vergence [42]. Experiments in rodents have shown that stimulation of floccular Purkinje cells can cause abduction of the ipsilateral eye [7]
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fastigial nuclei (cFN) and the posterior interposed nucleus (PIN, corresponding to the globose and emboliform nuclei in humans) in the cerebellum [25]. In one of the few available animal studies on the etiology of strabismus [18] cFN inactivation induced an exo (outwards) deviation of the eyes while PIN inactivation led to an eso (inward) tone of the eyes. The authors suggested that in esotropia the cFN/PIN-supraoculomotor area-medial rectus motoneuron circuit provides a convergence bias signal to the medial rectus muscle. The abducens nucleus must also receive these signals to allow for relaxation of the lateral rectus [19]. The reason for these erroneous signals remained unclear in the aforementioned studies. Experimental removal of the oculomotor vermis in monkeys led to, among other oculomotor disturbances, esodeviation of the eyes and disturbances in phoria adaptation [38]. This could be related to a disruption of the cFN-supraoculomotor areamedial rectus motoneuron circuit described above, since, in animal experiments, the oculomotor vermis has been shown to project to and inhibit the cFN [44], while the PIN is anatomically connected to the flocculus [39]. In agreement with these findings, patients with cerebellar lesions exhibit reduced divergence but not convergence velocity to ramp targets. These defects were particularly evident in patients with vermal lesions [36]. Functional imaging studies in humans have shown activation of the cerebellar vermis and hemispheres during the near response [35]. Esotropia with greater esodeviation at distance was described in patients with lesions to the dorsal cerebellar vermis [30]. The pathogenetic significance of the vestibulo-cerebellum in maintaining correct ocular alignment is underscored by case reports describing periodic alternating nystagmus, attributed to lesions in the vestibulo-cerebellum, in combination with alternating vertical misalignment of the eyes [33]. Both the floccular and also the vermal pathways possibly play a role in maintaining the correct static binocular alignment. It has been proposed that the floccular/PIN pathway may be involved in the control of divergence eye movements, while the dorsal vermis/cFN pathway may be more related to convergence, but such compartmentalization of functions remains a hypothesis [21]. These findings fit well with the results of our present study, which identified the reduced ocular abduction and associated horizontal gaze-evoked nystagmus as the probable mechanism of esophoria/esotropia in patients with cerebellar syndrome. Many types of oculomotor adaptation require an intact cerebellum for their normal performance [17, 24]. Patients with cerebellar lesions were shown to have significantly reduced horizontal phoria adaptation [27]. However, this could not be confirmed in a different study [11]. This
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discrepancy might be explained by the fact that in the latter study base-out prisms were used, which elicited a convergence response. The convergence reaction is not impaired in patients with cerebellar lesions. These patients, on the contrary, show ‘‘too much’’ convergence and thus esotropia/esophoria. This might explain why patients with cerebellar lesions can be found to have disturbed horizontal phoria adaptation when base-in prisms are used and intact adaptation when base-out prisms are used. Phoria adaptation to vertical binocular disparity is frequently impaired in patients with cerebellar dysfunction [23]. Unfortunately, fusional abilities were not measured in the current study. Also vertical misalignment was observed in patients with cerebellar lesions. It was previously termed ‘‘incomitant skew’’ or ‘‘abducting hypertropia’’. We prefer the latter term, since a true skew deviation is usually part of the ocular tilt reaction, which was not present in our patients. It has, however, been observed that true skew deviation, including SVV deviation, cyclorotation, and vertical deviation can be observed in patients with localized cerebellar lesions, which mainly include the dentate nucleus [2]. In our patients, the vertical misalignment changed with the direction of view, i.e., the deviations often showed a characteristic pattern of alternating skew deviation on right and left lateral gaze with the abducting eye higher (described before [40]). It is possible that otolith influences and their cerebellar processing play a role in the ocular misalignment observed in cerebellar patients. Lesions to the uvula, nodulus and flocculus influence the processing of vestibular information. Especially the otolith influences might be important for the observed effects [4]. However, not all cases of adult onset esophoria/esotropia during gaze in the distance are related to cerebellar disease. The term ‘‘divergence insufficiency esotropia’’ has been used to describe idiopathic cases in older adults as well as cases associated with neurological disorders such as pseudotumor cerebri or progressive supranuclear palsy [16, 34], while ‘‘age-related distance esotropia’’ or ‘‘sagging eye syndrome’’ describe cases caused by an involutional effect of orbital connective tissue degeneration [5, 29]. In our opinion these different terms describe the identical clinical syndrome which can be caused by a variety of underlying pathologies, one of which we propose to be cerebellar dysfunction. The present study has inherent limits which are due to the retrospective and cross-sectional approach. The study design did not allow for a follow-up of patients. Until prospective, longitudinal data are available we would like to propose a practical clinical approach: In patients with a newly diagnosed esotropia/esophoria during gaze only in the distance, a further neurological evaluation for a cerebellar dysfunction should be performed.
J Neurol Acknowledgments This study was not industry sponsored. The study was supported by the German Federal Ministry of Education and Research (BMBF 01EO0901). We thank Judy Benson and Katie Ogston for carefully copy-editing the manuscript. Conflicts of interest
None declared.
Ethical standard The study was approved by the ethics committee of the Ludwig-Maximilians University, Munich, Germany and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained for the videooculography recordings.
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43. Williams AS, Hoyt CS (1989) Acute comitant esotropia in children with brain tumors. Arch Ophthalmol 107:376–378 44. Yamada J, Noda H (1987) Afferent and efferent connections of the oculomotor cerebellar vermis in the macaque monkey. J Comp Neurol 265:224–241
ORIGINAL COMMUNICATION
Esophoria or esotropia in adulthood: a sign of cerebellar dysfunction? Katharina Hu¨fner • Claudia Frenzel • Olympia Kremmyda • Christine Adrion Stanislavs Bardins • Stefan Glasauer • Thomas Brandt • Michael Strupp
•
Received: 9 September 2014 / Revised: 7 December 2014 / Accepted: 9 December 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Convergent strabismus is a common diagnosis in early childhood, when it is mostly considered benign. If it develops later in life, strabismus can, however, be a sign of neurological disease. In these cases the underlying pathophysiological mechanisms are largely unknown. In this retrospective case–control study we analyzed the neuro-ophthalmological examination reports of 400 adult patients who presented at the German Center for Vertigo and Balance Disorders to determine an association between ocular misalignment and cerebellar dysfunction. Patients with cerebellar signs (i.e., cerebellar ataxia and/or cerebellar ocular motor signs) had a 4.49 (95 % CI [1.60; 13.78]) times higher frequency of ocular misalignment and
K. Hu¨fner C. Frenzel O. Kremmyda M. Strupp Department of Neurology, University Hospital Munich, Ludwig-Maximilians University, Campus Grosshadern, Munich, Germany K. Hu¨fner O. Kremmyda C. Adrion S. Bardins S. Glasauer T. Brandt M. Strupp German Center for Vertigo and Balance Disorders, University Hospital Munich, Ludwig-Maximilians University, Campus Grosshadern, Munich, Germany K. Hu¨fner (&) Department of Psychiatry, Medical University of Innsbruck, Innsbruck, Austria e-mail: [email protected] C. Adrion Institute for Medical Informatics, Biometry und Epidemiology, University Hospital Munich, Ludwig-Maximilians University, Campus Grosshadern, Munich, Germany S. Glasauer T. Brandt Institute for Clinical Neurosciences, University Hospital Munich, Ludwig-Maximilians University, Campus Grosshadern, Munich, Germany
specifically a 13.3 (95 % CI [3.80; 55.73]) times increased frequency of esophoria/esotropia (ESO) during distant gaze than patients without cerebellar dysfunction. ESO when looking into the distance was associated with saccadic smooth pursuit, dysmetria of saccades, and downbeat nystagmus (DBN) (v2 test, p \ 0.0001 for all associations). Patients with cerebellar dysfunction also showed mildly impaired eye abduction (v2 test, left eye and right eye: p \ 0.0001), associated with horizontal gaze-evoked nystagmus (v2 test, p \ 0.0001). The association of ESO and DBN implicates a pathophysiological involvement of the cerebellar flocculus, while the association with dysmetric saccades suggests involvement of the oculomotor vermis. This is compatible with animal studies showing that the pathways of the flocculus/posterior interposed nucleus and vermis/nucleus fastigii are both involved in vergence movements and static binocular alignment. From a clinical point of view, a newly diagnosed esophoria/esotropia only during distant gaze may be a sign of a cerebellar disease. Keywords Esophoria Esotropia Distant gaze Cerebellar dysfunction
Introduction Strabismus is frequently found in young children, in whom its prevalence is between 2 and 5 % [10, 31]. The two major categories of early onset concomitant esotropia are accommodative and congenital (infantile). In concomitant strabismus the ocular deviation does not vary with direction of gaze as opposed to incomitant forms. While there is some disagreement on the exact pathophysiology of these strabismus disorders, there is a general consensus that they are not as a rule causally related to any serious underlying
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neurological pathology, even if the onset is sudden [13, 31, 41]. Subtle cases can go undiagnosed, becoming apparent in adult life when an affected individual experiences stress, a minor head trauma, or fatigue. All can lead to the decompensation of a previously latent strabismus and the sudden onset of diplopia. In cases when new ocular misalignment develops in adulthood, it is usually incomitant (i.e., varies with direction of gaze) and caused by a defined and localized neurological or ophthalmological disease such as cranial nerve palsies, brainstem pathologies or disease of the ocular muscles. A few case reports, case series, and commentaries have described the appearance of a new acute comitant esophoria/esotropia, which is larger when looking into the distance, in later childhood or adulthood in patients with cerebellar disease such as cerebellar tumors, including astrocytomas and medulloblastomas as well as Arnold–Chiari I malformations [13, 32, 37, 43]. Acquired esophoria/esotropia can be associated with other eye movement abnormalities, such as dysmetric saccades, gaze-evoked nystagmus, or downbeat nystagmus (DBN) [40]. After initially successful surgery for strabismus, patients with Arnold–Chiari malformation can also develop recurrent esotropia with diplopia, which resolves upon suboccipital decompression [8, 32]. Esotropia can also be caused by acute lesions of the thalamus [9] and the corpus callosum [1]. Finally, vertical misalignment of the eyes has also been described in patients with cerebellar disease [12]. In this retrospective case–control study we investigated whether there is a higher frequency of ocular misalignment, namely concomitant esophoria/tropia, in patients with cerebellar dysfunction than in patients without cerebellar symptoms, in order to evaluate the co-occurrence of these conditions in an adult patient population.
Methods Neuro-ophthalmological and orthoptic examination All subjects underwent a standardized neurological and neuro-ophthalmological examination at the German Center for Vertigo and Balance Disorders at the University Hospital Munich, Campus Grosshadern, between 1999 and 2009 as described previously (e.g., [14]). The following parameters were evaluated in the present study and dichotomised for statistical analysis: patient ID, age (in years), neurological diagnosis, control/patient status, presence of saccadic smooth pursuit (yes/no), downbeat nystagmus (yes/no), pathological vestibulo-ocular reflex (VOR) by the head-impulse test (yes/no), saccadic dysmetria (yes/no), rebound nystagmus (yes/no), gaze-evoked
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nystagmus (yes/no), visual fixation suppression of the VOR (normal/abnormal), motility of right and left eye during abduction in mm (0–10) [20], ocular alignment when looking at a near target and into the distance as well as during lateral gaze into the distance (i.e., orthophoria/eso deviation/exo deviation/vertical deviation/congenital strabismus), ocular motility (i.e., intact/abduction deficit/ abducting hypertropia). Observation of the fundus and fundus photography using a scanning laser ophthalmoscope was done online and the subjective visual vertical was also determined. Additional examinations were performed in all cerebellar patients in order to uncover underlying causes of the cerebellar disease. These included caloric irrigation (n = 136), cranial MRI (n = 136), laboratory examinations, including CSF (n = 38), laboratory examinations, excluding CSF analysis (n = 78). Study population A total of 400 subjects who presented with vertigo, dizziness or unsteadiness of gait at the German Center for Vertigo and Balance Disorders at the University Hospital Munich were included in the retrospective case control study. 199 of the participants had a known or newly diagnosed cerebellar dysfunction and were termed the cerebellar group (CBL). Patients with localized cerebellar or cerebral disease such as infarction, tumor or demyelination were not included. Cerebellar dysfunction included cerebellar ataxia [ataxia of stance (n = 67), ataxia of gait (n = 86), ataxia of speech (n = 33) and limb ataxia/dysdiadochokinesis/dysmetria/rebound phenomenon (n = 73)] and/or ocular motor cerebellar signs (all patients). Data on additional cerebellar signs were not available for 14 CBL patients. A specific etiology was identified in 68 of the CBL patients: cerebellar ataxia and bilateral pathological head-impulse test ± polyneuropathy syndrome ([22], n = 31) spinocerebellar ataxia (n = 9), episodic ataxia (n = 9), inflammatory or toxic (n = 7), multiple system atrophy (n = 3), Arnold–Chiari I (n = 3), miscellaneous known etiologies (n = 6); 131 had a degenerative cerebellar disease of unknown etiology. All patients with tropias complained of double vision. The CBL group was compared to an age- and gender-matched group of 201 control patients ‘‘CON’’ (age CBL: 66.3 ± 13.9 years (mean ± SD), CON: 67.1 ± 14.5 years; p = 0.57 and sex ratio CBL: 85 females, CON: 91 females) who, just as the cerebellar patients, had a leading symptom of vertigo, dizziness or unsteadiness of gait. The control patients (bilateral vestibulopathy, Menie`re’s disease, benign paroxysmal positioning vertigo and vestibular migraine) underwent the same neurological and neuro-ophthalmological examinations as the CBL.
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Statistical analysis
Table 1 Oculomotor findings in patients with cerebellar dysfunction and controls
Statistical analyses included frequency and descriptive statistics. v2 or Fisher’s exact test was applied to compare proportions. Logistic regression adjusting for possible confounders (e.g., saccadic smooth pursuit, saccadic dysmetria, rebound nystagmus, disturbed fixation suppression, and gaze-evoked nystagmus) was applied to compare the prevalence of a certain disorder of ocular alignment in the cerebellar vs. control group. Statistical analyses were performed using RÒ software package version 2.11.1 (http:// www.r-project.org). All reported statistical tests were two sided, and the significance level was set to 5 %.
Oculomotor findings
Videooculography (VOG) recordings A dataset from a selected cerebellar patient was recorded using binocular videooculography (EyeseecamÒ). The VOG system consists of two cameras fixed on a head band. The patient had to fixate on a central target located either 30 cm (near target paradigm) or 4 m (distant target paradigm) away, during alternating monocular fixation (alternating cover test). The head rested on a chin rest.
Results Disturbances in ocular alignment of patients with cerebellar dysfunction The following factors were analyzed in the described models: ESO included the factors esotropia (ocular convergence during binocular view) and esophoria (ocular convergence during monocular view); EXO included the factors exotropia (ocular deviation during binocular view) and exophoria (ocular deviation during monocular view); VD (vertical deviation) included VD (left eye over right eye) and ?VD (right eye over left eye) (see Table 1 for exact numbers). Vertical divergence did not include any other features of skew deviation or isolated nerve/muscle palsies. In a first, exploratory analysis, the presence of abnormalities of ocular alignment (ESO, EXO, VD) was determined in CBL vs. CON during gaze straight ahead in the distance. In a bivariate analysis, anomalies in ocular alignment during gaze straight ahead in the distance were more prevalent in the CBL group than in the CON group (v2 test, p value \0.0001). A logistic regression model adjusting for saccadic smooth pursuit, rebound nystagmus, disturbed visual fixation suppression of the VOR, and gazeevoked nystagmus, revealed an estimated odds ratio (OR) of 4.49 for CBL vs. CON (95 % CI [1.60; 13.78]). Hence, CBL had a 4.49 times increased risk of displaying
CBL patientsa
CON patientsa
Saccadic smooth pursuit Yes
193/199
51/201
6/199
150/201
Yes
137/199
0/201
No
62/199
201/201
No Downbeat nystagmus
Bilaterally pathological head-impulse test Yes
71/199
86/201
No
128/199
115/201
Yes
73/199
8/201
No
126/199
193/201
Yes
64/199
1/201
No
135/199
200/201
Saccadic dysmetria
Rebound nystagmus
Gaze-evoked nystagmus Yes
185/199
No 14/199 Visual fixation suppression of VOR
31/201 170/201
Abnormal
147/199
Intact
52/199
2/201 199/201
Abduction RE in mmb
9.34 ± 1.00 (per 199)
9.97 ± 0.27 (per 201)
Abduction LE in mmb
9.30 ± 1.05 (per 199)
9.95 ± 0.40 (per 201)
ESO distant gaze straight ahead and/or lateral gaze Yes No
122/198 76/198
8/201 193/201
VD distant gaze straight ahead and/or lateral gaze Yes
48/195
7/201
No
147/195
194/201
Ocular alignment distant gaze straight ahead Orthophoria
83/198
177/201
ESO
95/198
5/201
EXO
9/198
14/201
VD
9/198
3/201
CS
2/198
2/201
Deviation angle distant gaze straight ahead in degreeb ESO
2.0 ± 1.8 (per 90)
1.8 ± 0.8 (per 5)
Deviation angle lateral gaze in the distance in degreeb ESO
3.3 ± 1.9 (per 110)
2.0 ± 0.8 (per 6)
Ocular alignment near gaze straight ahead Orthophoria ESO
21/188 15/188
24/200 1/200
EXO
144/188
170/200
VD
6/188
3/200
CS
2/188
2/200
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J Neurol Table 1 continued Oculomotor findings
CBL patientsa
CON patientsa
distance and the presence of cerebellar dysfunction (v2 test; p = 0.100). Vertical deviation and cerebellar dysfunction
Ocular motility Normal
79/199
193/201
Abduction deficit
64/199
5/201
Abducting hypertropia
34/199
3/201
Abduction deficit plus abducting hypertropia
22/199
0/201
CBL cerebellar, CON control, VOR vestibulo-ocular reflex, ESO esophoria/esotropia, EXO exophoria/exotropia, VD vertical deviation, CS congenital strabismus, RE right eye, LE left eye a
In a bivariate analysis a significant association between vertical deviation during gaze in the distance and cerebellar dysfunction was found (v2 test, p \ 0.0001). There was also an association between the occurrence of vertical deviation and saccadic smooth pursuit (v2 test, p \ 0.0001) and DBN (v2 test, p \ 0.0001), respectively. Impairment of ocular motility in patients with cerebellar dysfunction
The number of analyzed cases for each coding is indicated
b
Mean of all analyzed cases ± standard deviation, the number of analyzed cases is given in brackets
abnormalities in ocular alignment during gaze straight ahead in the distance (p = 0.005). When disturbances in ocular alignment (EXO, ESO, VD) were determined during near fixation no statistically significant association was found with the presence of a cerebellar dysfunction (v2 test, p = 0.916). This finding was confirmed using logistic regression (CBL vs. CON group: OR = 0.84; 95 % CI [0.208; 3.576]). Esophoria/esotropia, exophoria/exotropia during near and distant gaze in cerebellar dysfunction A significant association of ESO during gaze straight ahead in the distance and cerebellar dysfunction was detected (v2 test, p \ 0.0001). This association was also found during lateral gaze (v2 test, p \ 0.0001) and was confirmed using logistic regression adjusting for possible confounders (smooth pursuit, rebound nystagmus, visual fixation suppression of the VOR, and gaze-evoked nystagmus) (p = 0.0001). The risk for ESO during gaze in the distance was 13.3 times higher in the CBL than in the CON group (95 % CI [3.80; 55.73]). No association of ESO during near fixation and cerebellar dysfunction was found (v2 test, p = 0.709). No significant association between ESO during near fixation and during distant gaze was found (v2 test, p = 0.897). This reveals that patients exhibiting esophoria or esotropia during distant gaze do not tend to show esophoria or esotropia during near gaze. Binocular eye movement recordings (horizontal traces) were performed in a representative patient with cerebellar disease to visualize the occurrence of ESO alignment during distant but not during near gaze (Fig. 1). There was no evidence for an association between EXO during gaze straight ahead in the
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The presence of disturbances in ocular motility (abducting hypertropia or disturbance in ocular abduction) was more frequent in the CBL patients than in the CON (v2 test, p \ 0.0001). Ocular motility\10 mm during abduction was considered pathological, while 10 mm or more was considered normal [20]. A significant association between pathological ocular motility during eye abduction and cerebellar dysfunction was found in a bivariate analysis (v2 test, left eye: p \ 0.0001, right eye: p \ 0.0001). Patients with deficits in eye abduction were found to also have horizontal gaze-evoked nystagmus (v2 test, p \ 0.0001). When only the ocular motility of the right eye was considered for analysis, a significant association between the reduced eye abduction in mm and horizontal gaze-evoked nystagmus was found (v2 test, p \ 0.0001). This was confirmed using a Cochran–Armitage trend test for proportions to explore the association between pathological eye abduction and the occurrence of gaze-evoked nystagmus (p \ 0.0001). Esophoria/esotropia and cerebellar ocular motor disturbances To test for a possible abduction deficit as the cause of ESO in the distance, the presence of ESO during lateral gaze was investigated to determine if it was associated with gaze-evoked nystagmus. A significant association of the two parameters was found (v2 test, p \ 0.0001). ESO in the distance was also associated with saccadic smooth pursuit (v2 test, p \ 0.0001) and saccadic dysmetria (v2 test, p \ 0.0001). Patients with DBN were more frequently affected with ESO during distant gaze than patients without DBN (v2 test, p value \0.0001). Subjective visual vertical in patients with esophoria/ esotropia ESO in the distance or nearby was not associated with a displacement of the subjective visual vertical in our
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Fig. 1 Binocular eye movement recordings (horizontal traces) from a patient with cerebellar dysfunction. Cover tests during far (4 m) and near (30 cm) fixation are shown. Positive values indicate movement to the left. Traces for right eye (RE gray lines) and left eye (LE black lines) are shown. ESO (here of about 7°) is visible only during distant
fixation, as indicated by the re-fixation saccade towards the direction of the fixating eye (e.g., movement to the left, during left eye fixation or else right eye cover). In near fixation, there is no occurrence of refixating eye movements during the cover test (notice that both eyes are adducted about 7°, due to convergence)
patients (Fisher respectively).
and that floccular signals inhibit the medial rectus and excite the lateral rectus muscle [15]. Stimulation of the cerebellar flocculus can lead to movements of one eye only, which can be downwards or horizontal [3]. Thus, dysfunction of the cerebellar flocculus in animal studies can result in an increased inward tone of the eyes. Therefore, a likely pathophysiological mechanism of the observed ESO in patients with cerebellar dysfunction is an impaired abduction of the eyes due to floccular dysfunction. This view is supported by the observation that the esophoria/esotropia was associated with horizontal gazeevoked nystagmus and downbeat nystagmus. Our finding has also been supported by others [40]. Experiments on binocular eye alignment and coordination in monkeys have shown that the supraoculomotor area, which is located immediately adjacent to the oculomotor nucleus in the brainstem and projects monosynaptically to the medial rectus motoneurons, encodes vergence movements in healthy monkeys [26] as well as a signal related to the ocular misalignment in monkeys with strabismus [6]. This area is thought to receive input from the caudal
test:
p = 0.529
and
p = 0.086
Discussion The major finding of the current study is that cerebellar dysfunction is associated with distant esophoria/esotropia in adulthood. Second, esophoria/esotropia is associated with mildly impaired ocular motility, specifically eye abduction. Third, further ocular motor signs of cerebellar dysfunction co-occurred with esophoria/esotropia. Fourth, the statistically significant association of ESO with DBN points to a possible pathophysiological involvement of the cerebellar flocculus, while the association with saccadic dysmetria suggests involvement of the oculomotor vermis. The flocculus of primates contains neurons that discharge with the angle of vergence [28] and ablation of the cerebellum can lead to paralysis of vergence [42]. Experiments in rodents have shown that stimulation of floccular Purkinje cells can cause abduction of the ipsilateral eye [7]
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fastigial nuclei (cFN) and the posterior interposed nucleus (PIN, corresponding to the globose and emboliform nuclei in humans) in the cerebellum [25]. In one of the few available animal studies on the etiology of strabismus [18] cFN inactivation induced an exo (outwards) deviation of the eyes while PIN inactivation led to an eso (inward) tone of the eyes. The authors suggested that in esotropia the cFN/PIN-supraoculomotor area-medial rectus motoneuron circuit provides a convergence bias signal to the medial rectus muscle. The abducens nucleus must also receive these signals to allow for relaxation of the lateral rectus [19]. The reason for these erroneous signals remained unclear in the aforementioned studies. Experimental removal of the oculomotor vermis in monkeys led to, among other oculomotor disturbances, esodeviation of the eyes and disturbances in phoria adaptation [38]. This could be related to a disruption of the cFN-supraoculomotor areamedial rectus motoneuron circuit described above, since, in animal experiments, the oculomotor vermis has been shown to project to and inhibit the cFN [44], while the PIN is anatomically connected to the flocculus [39]. In agreement with these findings, patients with cerebellar lesions exhibit reduced divergence but not convergence velocity to ramp targets. These defects were particularly evident in patients with vermal lesions [36]. Functional imaging studies in humans have shown activation of the cerebellar vermis and hemispheres during the near response [35]. Esotropia with greater esodeviation at distance was described in patients with lesions to the dorsal cerebellar vermis [30]. The pathogenetic significance of the vestibulo-cerebellum in maintaining correct ocular alignment is underscored by case reports describing periodic alternating nystagmus, attributed to lesions in the vestibulo-cerebellum, in combination with alternating vertical misalignment of the eyes [33]. Both the floccular and also the vermal pathways possibly play a role in maintaining the correct static binocular alignment. It has been proposed that the floccular/PIN pathway may be involved in the control of divergence eye movements, while the dorsal vermis/cFN pathway may be more related to convergence, but such compartmentalization of functions remains a hypothesis [21]. These findings fit well with the results of our present study, which identified the reduced ocular abduction and associated horizontal gaze-evoked nystagmus as the probable mechanism of esophoria/esotropia in patients with cerebellar syndrome. Many types of oculomotor adaptation require an intact cerebellum for their normal performance [17, 24]. Patients with cerebellar lesions were shown to have significantly reduced horizontal phoria adaptation [27]. However, this could not be confirmed in a different study [11]. This
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discrepancy might be explained by the fact that in the latter study base-out prisms were used, which elicited a convergence response. The convergence reaction is not impaired in patients with cerebellar lesions. These patients, on the contrary, show ‘‘too much’’ convergence and thus esotropia/esophoria. This might explain why patients with cerebellar lesions can be found to have disturbed horizontal phoria adaptation when base-in prisms are used and intact adaptation when base-out prisms are used. Phoria adaptation to vertical binocular disparity is frequently impaired in patients with cerebellar dysfunction [23]. Unfortunately, fusional abilities were not measured in the current study. Also vertical misalignment was observed in patients with cerebellar lesions. It was previously termed ‘‘incomitant skew’’ or ‘‘abducting hypertropia’’. We prefer the latter term, since a true skew deviation is usually part of the ocular tilt reaction, which was not present in our patients. It has, however, been observed that true skew deviation, including SVV deviation, cyclorotation, and vertical deviation can be observed in patients with localized cerebellar lesions, which mainly include the dentate nucleus [2]. In our patients, the vertical misalignment changed with the direction of view, i.e., the deviations often showed a characteristic pattern of alternating skew deviation on right and left lateral gaze with the abducting eye higher (described before [40]). It is possible that otolith influences and their cerebellar processing play a role in the ocular misalignment observed in cerebellar patients. Lesions to the uvula, nodulus and flocculus influence the processing of vestibular information. Especially the otolith influences might be important for the observed effects [4]. However, not all cases of adult onset esophoria/esotropia during gaze in the distance are related to cerebellar disease. The term ‘‘divergence insufficiency esotropia’’ has been used to describe idiopathic cases in older adults as well as cases associated with neurological disorders such as pseudotumor cerebri or progressive supranuclear palsy [16, 34], while ‘‘age-related distance esotropia’’ or ‘‘sagging eye syndrome’’ describe cases caused by an involutional effect of orbital connective tissue degeneration [5, 29]. In our opinion these different terms describe the identical clinical syndrome which can be caused by a variety of underlying pathologies, one of which we propose to be cerebellar dysfunction. The present study has inherent limits which are due to the retrospective and cross-sectional approach. The study design did not allow for a follow-up of patients. Until prospective, longitudinal data are available we would like to propose a practical clinical approach: In patients with a newly diagnosed esotropia/esophoria during gaze only in the distance, a further neurological evaluation for a cerebellar dysfunction should be performed.
J Neurol Acknowledgments This study was not industry sponsored. The study was supported by the German Federal Ministry of Education and Research (BMBF 01EO0901). We thank Judy Benson and Katie Ogston for carefully copy-editing the manuscript. Conflicts of interest
None declared.
Ethical standard The study was approved by the ethics committee of the Ludwig-Maximilians University, Munich, Germany and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained for the videooculography recordings.
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