of attentional mechanisms with basic sensory processes through the selection of stimuli and tasks involving different sensory modalities [14].
This work was supported by grant PG-41 from the Medical Research Council of Canada, the Isaac Walton Killam Fellowship Fund of the Montreal Neurological Institute, and the Fonds de la Recherche en SantG du Quebec. The numerous stimulating discussions contributed by Dr R.W. Dykes, Centre de Recherches en Sciences Neurologiques, Universite de Montr6al; Dr E. Hamel, McConnell Brain Imaging Centre; and Dr D. Bub, Director, Neurolinguistics, McGill University, are gratefully acknowledged. We thank the technical staff of the McConnell Brain Imaging Centre, the Medical Cyclotron Unit, and the Neurophotography Department for their assistance.
References 1. Hyvixinen J, Pocanen A, Jokinen Y . Influence of attentive behavior on neuronal response to vibration in primary somatosensory cortex of the monkey. .J Neurophysiol 1980;43:870-882 2. Roland PE. Metabolic measurements of the working frontal cortex in man. TINS November 1984:430-435 3. Goldberg ME, Wurrz RH. Activity of superior colliculus in behaving monkeys. 11. Effect of attention on neuronal responses. J Neurophysiol 1972;35:560-574 4.Roland PE. Cortical regulation of selective attention in man. A regional cerebral blood flow study. J Neurophysiol 1982;48: 1059-1078 5. Herscovitch P, Markham J, Raichle ME. Brain blood flow measured with intravenous 0-15 H 2 0 . l. Theory and error analysis. J Nucl Med 1983;24:782-789 6. Raichle ME, Martin WRW, Herscovitch P, et al. Brain blood flow measured with intravenous 0 - 1 5 H20.11. Implementation and validation. J Nucl Med 1983;24:?90-798 7 . Thompson CJ, Dagher A, Meyer E, et al. Imaging performance of a dynamic positron emission tomograph: Positomr Illp. IEEE Trans Med Imaging 1986;5:183-198 8. Meyer E. Simultaneous correction for tracer arrival delay and dispersion in CBF measurements by the H,”O autoradiographic method and dynamic PET. J Nucl Med 1989;30:1060-1078 9. Bergstr6m M,Litton J, Eriksson L, et al. Determination of ohject contour from projections for atrenuation correction in cranial positron emission tomography. J Comput Assist Tomogr 1982;6:365-372 10. Evans AC, Beil C, Marretr S, et al. Anatomical-functional correlation using an adjustable MRI-based region of interest atlas with positron emission tomography. J Cereb Blood Flow Metab 1988;8:j13-530 11. Fox PT,Perlmutter JS, Raichle ME. A stereotactic method of andtomicd locahzation for positron emission tomography. J Comput Assist Tornogr 1985;9:14 1- 153 12. Zar JH. Biostatistical analysis, 2nd ecl. Englewood Cliffs, NJ: Prentice-Hall, 1984 13. Fox FT, Burton H , h c h l e ME. Mapping human somatosensory cortex with positron emission tomography. J Neurosurg 1987;67:34-43 14. Corbetta M, Miezin FM, Dobmcyer S, et al. Attentional modulation of neural processing of shape, color, and velocity in humans. Science 1990;248:1556-1559 15. Talairdch J. Tournoux P. Co-planar stereotaxic atlas of the human brain. Stuttgart: Thieme Medical Publishers, 1988
Selective Impairment of Smooth-Pursuit Eye Movements Due to an Ischemic Lesion of the Basal Pons Peter Thier, MD, Alexander Bachor, Jiirgen Faiss, MD,* Johannes Dichgans, MD, and Eberhard Koenig, M D
Voluntary and reflex-like eye movements were measured in a patient with an ischemic lesion of the right basal pons. Ipsilateral smooth-pursuit eye movements were predominantly impaired and interrupted by saccades. This profound smooth-pursuit deficit contrasted with only minor abnormalities of visually guided saccades and the vestibulo-ocular reflex. A selective disturbance of smooth-pursuit eye movements due to a lesion of the basal pons in this patient concurs with recent work in monkeys suggesting that smooth-pursuit eye movements are mediated by a parietooccipito-ponto-cerebellarpathway. Thier P, Bachor A, Fass J, Dichgans J, Koenig E. Selective impairment of smooth-pursuit e y e movements due t o a n ischemic lesion of t h e basal pons. Ann Neurol 1991;29:443-448
In contrast to the well defined tegmental brainstem centers for saccades and eye reflexes, the brainstem centers mediating smooth-pursuit eye movements have been poorly understood. Recent experiments in monkeys indicate the importance of brainstem sites not in the tegmentum for the organization of smooth-pursuit eye movements. Single cell recordings 11-41, microstimulation studies [ S ] , and experimental lesions [GI all suggest that the dorsolateral pontine nucleus in the basal pons of monkeys is the major link in a descending pathway from the parieto-occipital lobe to the cerebellum, communicating signals relevant for smoothpursuit eye movements. In the present study, we describe the oculomotor consequences of an ischemic lesion of the human basal pons, and we present the
From the Departments of Neurology and Neuroradtology, University of Tubingen, Hoppe-Seyler-Str&e 3, 7400 Tubingen, German1 Received Apr 26, 1090, and in revised form Jul 2 3 and Oct 8 Accepted for publication Oct 9, 1990 Address correspondence to Dr Thier, Department of Bran and Cognitive Scienres, Massachusetts Institute of Technology, E25-236, Cambridge, MA 02139 ‘Present addresc Department of Neurology, University of Essen, Hufelandstrde 55, 4300 Essen, Germany
Copyright
0 1991 by t h e American Neurological Association 443
first evidence for a similar role in the control of smooth-pursuit eye movements in humans.
Case Report A 61-year-old, right-handed man awoke with tingling and prickling of the tongue and cheek, impaired balance, and weakness of his left side. S i x days after onset of symptoms, examination disclosed hemihypesthesia and weakness on the left, including an inability to stand straight without support. Biceps and knee reflexes were slightly brisker on the left side, the right ankle reflex was absent, and the left one was reduced. Plantar reflexes were flexor. Rapid alternating movements of the left hand were slower. Hearing was impaired on the right. Oculomotor anomalies will be described in detail. The remainder of the neurological examination was normal. Magnetic resonance imaging (MRI) scans (Fig 1) obtained 16 days after the onset of symptoms demonstrated a circular zone of altered signal intensity, presumably representing a new postischemic defect in the right pontine base abutting the right crus cerebri rostrally but sparing the caudaI pons. Although the available MRI scans did not allow discrimination of the nuclear zones from the fibers of the cerebral peduncle, it may safely be assumed that the extent and the location of the lesion had destroyed large parts of the pontine nuclei. Neither the X-ray computed tomographic scans nor the MRI images revealed any brain pathology outside the basal pons. In view of the clinical syndrome with left-sided weakness, pyramidal tract involvement might have been expected. Transcranial magnetic stimulation of the motor cortex C7, 81, however, led to contractions of hand and foot muscles with normal latency and amplitude. In contrast, involvement of the medial lemniscus, ascending in close vicinity of the basal pons, was suggested by an analysis of cortically evoked somatosensory potentials. The P40 complex, elicited by stimulation of the left tibial nerve, was significantly delayed, compatible with a lesion of this fiber tract upward of its decussation at the level of the right basal pons. At the time of discharge, 18 days after the onset of symptoms, the initial neurological deficit had receded except for a residual mild left side hemiparesis and gait ataxia.
Material and Methods Eye movements were recorded using direct current electrooculography (EOG)both monocularly and bitemporally. Saccadic eye movements were induced by instructing the patient always to look at that member of a pair of red light-emitting diodes (LED) that was switched on (the other one being switched off). The two LEDs were positioned 20 degrees to the left and 20 degrees to the right with respect to the patient’s primary position at a viewing distance of l.l m. Each LED subtended a visual angle of 0.25 degrees. The visual target used to elicit smooth-pursuit eye movements was a red laser spot (visual angle, 0.25 degrees), projected onto a screen 1.1 m in front of the patient and which could be moved along the horizontal meridian according to a triangular velocity profile (amplitude, 20 degrees; velocity, 25 or 40 degreesisec). The patient was instructed to fixate the laser target as accurately as possible. Tests of saccadic and smoothpursuit eye movements were performed at a background lu-
444 Annals of Neurology Vol 29 N o 4 April 1991
minance of 0.6 cd/m2. Horizontal optokinetic reflexes (Om) were elicited with a whole-field stimulus consisting of vertical black and white stripes (period, 15 degrees; contrast, 0.5; mean background luminance, 4 cd/m2) moving horizontally at 60 degreesisec. This stimulus was created by rotating a small drum with vertical slits of appropriate spacing around a light source coaxial with the patient. Horizontal vestibuloocular reflexes (VOR) were induced by seating the patient on a motorized platform that was sinusoidally rotated (maximum velocity, 80 degreesisec, 0.2 Hz). VOR was studied with eyes closed. Suppression of the horizontal VOR was tested by asking the patient to fixate an LED target 0.7 m in front of him (background luminance, 0.6 cd/m2) and moving in synchrony with him. Owing to limitations of instrumentation, no attempt was made to study vertical eye movements. EOG records were calibrated under the assumption that the eyes were on target during maintained fixation of the two LEDs used to elicit saccades.
Results Eye movements were conjugate, and there was n o gaze-evoked nystagmus. Occasionally, a slight leftward beating spontaneous nystagmus with slow-phase velocity of about 1 to 2 degreedsec could be observed when the patient’s eyes were closed and he was asked to perform mental arithmetic. Saccades elicited by the periodic, predictable steps of the target from right to left and back were performed with normal latency and velocity. O n 50% of all saccades to the right and on 22% of all saccades to the left, however, the eyes undershot the target by a few degrees (Fig 2A). Such hypometric saccades were always corrected by o n e additional saccade of appropriate amplitude. Smooth-pursuit eye movements to the right, elicited by t h e periodic and predictable movement of the fixation spot, were dramatically impaired. With the target moving at 25 degreesisec (Fig 2B), the velocity of the eyes during slow phases of the saccade-interrupted visual-tracking eye movements to the ipsilateral (right) side comprised only 3 to 30% of t h e target velocity and many catch-up saccades were needed to keep the eyes o n target. At higher target velocities (40 degrees/ sec, Fig 2C), smooth-pursuit eye movements of reduced velocity were entirely absent for target movement to the ipsilateral (right) side. Occasionally, slow drifts of the eyes to the contralateral (left) side occurred, which were interrupted by large amplitude catch-up saccades into the direction of target movement. I n contrast, smooth-pursuit eye movements to
b
Fig 1 . Magnetic resonance imaging scam, cut in horizontal (A, B), coronal (C, 0) and parasagittal (EJ planes illustrating the localization and extent of the ischemic lesion affecting the right basal pons. The orientation of the respective planes of sectioning is illutruted in F . A, C , and E depict TI -weighted scans and B and D, T2-weighted scans. Rder t o the text for further descrip~
tion.
I-t
tion of the horizontal VOR, however, did not reveal a substantial deviation from normal. Maximal slow eye velocity amounted to 59% of head velocity for rotation to the right and 66% for rotation to the left, which is within the normal range. The ability of the patient to suppress his horizontal VOR by visual fixation of a target oscillated in synchrony with head and body was impaired. For both orientations of rotation, only 25% of slow eye velocity elicited by the same stimulus with eyes closed could be suppressed, that is, no right-left asymmetry was apparent.
2 sec
A
2 scc
C Fig 2. Samples of the patient’s eye-movement recordings. (A)Saccades, elicited Sy predictable and periodic steps of a small target from l4t t o right and back again. Note occasional hypometric saccades (the arrow mar& an example). (B. C) Visual-tracking eye mwements elicited by horizontal movement of a laser target from ldt to right and back again, according t o a triangular waveform.Target velocity was 25 degreeslsec in B and 40 degreeslsec in C. 1, 2, and 3 are lines indicating mean smooth-pur.ruit eye velocity. Occurrence of target steps in A and turning points of the h e r target in B and C are marked by small, filled triangles. Note that the samples of the target trajectories (t) in A, B, and C are plotted displaced with respect t o the eye-position curues le) for the sake of clarity. The electro-oculogram was recorded bitemparally.
the contralateral side were less affected; at the lower of the two velocities of target movement used, periods of normal-gain smooth-pursuit e y e movement alternated with periods of saccadic smooth-pursuit eye movement, with slow-phase velocity amounting to approximately 50 to 60% of target velocity (Fig 2B). A more consistent smooth-pursuit deficit was present only at the higher target velocity, with slow-phase velocity amounting to approximately 45% of target velocity (Fig 2C). A pronounced reduction of response amplitude combined with an asymmetry of responses was also visible in the OKR records. Whereas slow-phase velocity for drum rotation to the contralateral side amounted to up to 30% of pattern velocity, slow-phase velocity for drum rotation to the ipsilateral side attained only up to 15% of pattern angular velocity with considerable fluctuation and without clear, slow build-up. Investiga-
446 Annals of Neurology Vol 29 No 4 April 1991
Discussion The human basal pons contributes to the generation of smooth-pursuit eye movements to the ipsilateral side. This is the major conclusion to be drawn from our observation that a patient suffering from an acute ischemic lesion on one side of the basal pons, but without any indication of additional brain pathology, presented with grossly disturbed smooth-pursuit eye movements to the ipsilateral side. According to prevailing concepts, two other types of eye movements, the optokinetic reflex and the suppression of the vestibulo-ocular reflex by visual fixation, are thought to be functionally related to smooth-pursuit eye movements. It is therefore interesting to consider whether they showed related patterns of disturbances. This was clearly the case with respect to the OKR, which also showed reduced slow-phase velocity toward the side of the lesion. This is what would be expected if a signal derived from the system generating foveal-pursuit eye movements is used to supplement the OKR proper, as suggested by well established models of the OKR t91. In contrast to the clear asymmetry in the performance of smooth-pursuit eye movements and the OKR, suppression of the VOR by fixation of a visual target, the other type of eye movement suggested to be related to smooth-pursuit eye movement, did not show this asymmetry and was impaired for rotation to both sides. An interpretation of this finding requires a brief look at the question of how suppression of the VOR by visual fixation is achieved. One of the two mechanisms suggested, the “addition” mechanism [lo], assumes a linear summation of two independent signals, a smooth-pursuit eye movement command and a vestibular command. The other mechanism, called the “parametric adjustment” mechanism t111, proposes immediate adjustment of transmission in the VOR pathway. Obviously, the lack of asymmetry of fixationsuppression of the VOR in a patient with normal VOR but asymmetric smooth pursuit eye movement cannot be explained by the addition mechanism. Usage of parametric adjustment in fixation-suppression of this patient’s VOR is indicated. This is not to say that the addition mechanism might not play a role under other
conditions not tested by us. Actually, recent work in monkeys [12) suggests that the two mechanisms, rather than being mutually exclusive, are both available to the brain. The one more profitable with respect to gaze accuracy will be favored, depending on the condition prevailing. Although fixation-suppression of the VOR in the present patient was not asymmetric, it was far from being sufficient to guarantee accurate tracking of the target. Whether this was simply due to insufficient attention to the target or was attributable to other factors cannot be decided on the basis of the limited data available on fixation-suppression of this patient’s VOR. In contrast to the oculomotor functions related to smooth-pursuit eye movements, the other types of eye movements, namely the VOR and visually guided saccades, were only marginally or not at all affected by the basal pons lesion. Although more sophisticated methods than the ones available for investigation of this patient might have revealed additional subtle abnormalities of VOR or saccades, this would not substantially diminish our conclusion that the lesion mainly affected a pathway for smooth-pursuit eye movements. A rather selective disturbance of smooth-pursuit eye movements due to a lesion of the basal pons is consistent with the concept, as yet mainly based on experimental work on animals, of an anatomical segregation of the brainstem pathways for smooth-pursuit eye movements, saccades, and vestibular and optokinetic reflexes. Whereas the brainstem tegmentum subserves saccades and reflex-like eye movements [l31, smoothpursuit eye movements are mediated by the basal pons, the major anatomical link between the cortices of cerebrum and cerebellum [14]. In the monkey, signals related to smooth-pursuit eye movements are confined to the dorsolateral parts of the pontine nuclei [1-4}, which are the major constituents of the basal pons. Unilateral lesions of the dorsolateral pontine nucleus in monkeys cause an eye movement deficit that resembles the one observed in the patient described here [GI. In monkeys, the major source of afferents to the dorsolateral pontine nucleus are large parts of the socalled superior temporal sulcus [ 15-18], which houses the middle temporal (MT), fundal superior temporal (FST), and middle superior temporal (MST) areas. Whereas area MT seems to contribute to the organization of smooth-pursuit eye movements by processing retinal target slip velocity [19), other areas such as MST and FST contain nonretinal signals related to smooth-pursuit eye movements reminiscent of those also found in the dorsolateral pontine nucleus t20-2 31. Lesioning the latter areas causes a disturbance of smooth-pursuit eye movement directed to the side ipsilateral to the lesion C24, 251. These observations are
compatible with the notion that the functional contribution of the dorsolateral pontine nucleus to smoothpursuit eye movements is highly dependent on its cortical input. The dorsolateral pontine nucleus, however, may be considered the major gateway for smoothpursuit-related signals to the cerebellum because, in the monkey, it has been shown to project [26-29) to all parts of the cerebellum known relevant for smoothpursuit eye movements, for example, the flocculus [30, 31) and the posterior vermis {32-35). The present observation of a selective disturbance of smoothpursuit eye movements after a lesion of the human basal pons therefore suggests that the concept of a parietooccipito-ponto-cerebellar pathway for smoothpursuit eye movements, previously established only for monkeys, may be extended to humans. This work was supported by DFG SFB 307-A1 and -A2 We are grateful to D. Tweed for helpful comments on earlier versions of the manuscript.
References 1. Suzuki DA, Keller EL. Visual signals in the dorsolateral pontine
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nucleus of the alert monkey: their relationship to smoothpursuit eye movements. Exp Brain Res 1984;53:473-478 Mustari MI, Fuchs AF, Wallman J. Response properties of dorsolateral pontine units during smooth pursuit in the rhesus macaque. J Neurophysiol 1988;60:664-686 Thier P, Koehler W, Buettner UW. Neuronal activiry in the dorsolateral pontine nucleus ol the alert monkey modulated by visual stimuli and eye movements. Exp Brain Res 1988;70: 496-512 Thier P, Koehler W, Buettner UW, Dichgans J. Does the system for smooth pursuit eye movements rely on a neuronal representation of target motion in space? In: Deeke L, Mountcastle V, Eccles J. eds. From neuron to action. Berlin: Springer-Verlag, 1991 (in press) May JG, Keller EL, Crandall WF. Changes in eye velocity during smooth pursuit tracking induced by microsrimulation in the dorsolateral pontine nucleus of the macaque. Soc Neurosci Abstr 1985;11:79 (Abstract) May JG, Keller EK, Suzuki DA. Smooth pursuit eye movement deficits with chemical lesions in the dorsolateral pontine nucleus of the monkey. J Neurophysiol 1988;59:952-977 Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet 1985;1:1106-1107 Hess CW, Mills KR, Murray NMF. Responses in small hand muscles from magnetic stirnulation of the human brain.J Physiol (Lond) 1987;388:397-419 Robinson DA. Control of eye movements. In: Brookhart JM, Mountcastle VB, eds. Handbook of physiology. The nervous system. Bethesda: American Physiology Society, 1981:12751320 Lanman J, Bizzi E, Allum J. The coordination of eye and head movement during smooth pursuit. Brain Res 1978;153:39-55 Robinson DA. A model of cancellation of the vestibular-ocular reflex. In: Lennerstrand G, Zee DS, Keller EL, eds. Functional basis of ocular motility disorders. Oxford, UK: Pergamon, 1982~5-13 Lisberger SG. Visual tracking in monkeys: evidence for short-
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latency suppression of the vestibuloocular reflex. J Neurophysio! 1990;63:676-688 Wurtz RH, Goldberg M, eds. The neurobiology of saccadic eye movements. Amsterdam: Elsevier Science Publishing BV (Biomedical Division), 1989 Brodal A. Neurological anatomy in relation to clinical medicine, 3rd ed. New York: Oxford University Press, 1981 Glickstein M, Cohen JL, Dixon B, et al. Corticopontine visual projections in macaque monkeys. J Comp Neurol 1980;190: 209-229 Leichnetz GR, Smith DJ, Spencer RF. Cortical projections to the paramedian tegmental and basilar pons in the monkey. J Comp Neurol 1984;228:388-408 Tusa RJ, Ungerleider LG. Fiber pathways of cortical areas mediating smooth pursuit eye movements in monkey. Ann Neurol 1988;23: 174- 183 Fries W. The projection from striate and prestriate visual cortex onto the pontine nuclei of the macaque. Soc Neurosci Absrr 1981;7:762 (Abstract) Newsome WT, Wurtz RH, Diirsteler MR, Mikami A. Deficits in visual motion processing following ibotenic acid lesions of the middle temporal visual area of the macaque monkey. J Neurosci 1985;5:825-840 Komatsu H, Wurtz RH. Relation of cortical areas MT and MST to pursuit eye movements. I. Localization and visual properties of neurons. J Neurophysiol 1988;60:580-603 Newsome WT, Wura RH, Komatsu KH. Relation of cortical areas MT and MST to pursuit eye movements. 11. Differentiation of retinal from extraretinal inputs. J Neurophysiol 1988; 60~604-620 Komatsu H , Wurtz RH. Relation of cortical areas MT and MST to pursuit eye movements. 111. Interaction with full-field visual stimulation. J Neurophysiol 1388;60:62 1-644 Erickson RG, Dow B. Foveal tracking cells in the superior temporal sulcus of the macaque monkey. Exp Brain Res 1989;78: 113-131 Diirsteler MR, Wurtz RH, Newsome WT. Directional pursuit deficits following lesions of the foveal representation within the superior temporal sulcus of the macaque monkey. J Neurophysiol 1987;57:1262-1287 Diirsteler MR, Wurtz RH. Pursuit and optokinetic deficits following chemical lesions of cortical areas hiT and MST. J Neurophysiol 1988;60:940-965 Brodal P. Further observations on the cerebellar projections from the pontine nuclei and the nucleus reticularis tegmenti pontis in the rhesus monkey. J Comp Neurol 1982;204:44-55 Langer T, Fuchs AF, Scudder CA, Chubb MC. Afferents to the flocculus of the cerebellum in the rhesus macaque as revealed by retrograde transport of horseradish peroxidase. J Comp Neurol 1985;235:1-25 Yamada J, Noda 13. Afferent and efferent connecrions of the oculomotor vermis in the macaque monkey. J Cornp Neurol 1987;265:224-241 Glickstein M, Mercier B, Baizer J. Visual input to the cerebellum of macaques. SOCNeurosci Abstr 1988;14:495 (Abstract) Miles FA, Fuller JH. Visual tracking and the primate flocculus. Science 1975 ;189:1000- 1002 Lisberger SG, Fuchs AF. Role of primate flocculus during rapid behavioral modification of vestibuloocular reflex. 1. Purkinje cell activity during visually guided horizontal smooth-pursuit eye movements and passive head rotation. J Neurophysiol 1978;41: 733-763 Kase M, Noda H , Suzuki DA, Miller DC. Target velocity signals of visual tracking in verrnal Purkinje cells of the monkey. Science 1979;203:717-720 Suzuki DA, Noda H, Kase M. Visual and pursuit eye
movement-related activity in posterior vermis of monkey cerebellum. J Neurophysiol 1981;46:1120-1139 34. Suzuki DA, Keller EL. The role of the posterior vermis of monkey cerebellum in smooth-pursuit eye movement control. I. Eye and head movement-related activity. J Neurophysiol 1988; 59:1- 17 35. Suzuki DA, Keller EL. The role of the posterior vermis of monkey cerebellum in smooth-pursuit eye movement control. 11. Target velocity-related Purkinje cell activity. J Neurophysiol 1988;59:19-40
Adult Polyglucosan Body Disease: The Diagnostic Value of h l l a Skin Biopsy H. L. S. M. Busard, MD," A. A. W. M. Gabreels-Festen, MD,* W. 0. Renier, MD, PhD,* F. J. M. Gabreels, MD, PhD,* E. M. G. Joosten, MD, PhD,* M. A. van 't Hof, MS,? and J. B. M. Rensing, MDS
The diagnostic value of axilla skin biopsy has been investigated in a patient with adult polyglucosan body disease. The biopsy data have been compared with those of control subjects and with those from previously reported patients with Lafora's disease. In a patient with adult polyglucosan body disease and in patients with Lafora's disease, an abundance of polyglutosan bodies was found in the myoepithelial cells of the axillary apocrine glands. In the control group of subjects, polyglucosan bodies were only sporadically seen. Axilla skin biopsy is, therefore, an easy and reliable method for confirming the diagnosis of adult polyglucosan body disease. Busard HLSM, Gabreels-Festen AAWM, Renier WO, Gabreels FJM, Joosten EMG, van 't Hof MA, Rensing JBM. Adult polyglucosan body disease: the diagnostic value of axilla skin biopsy. Ann Neurol 1991;29.448-451
Adult polyglucosan body disease (APBD) is characterized by a variable association of progressive upper and lower motor neuron dysfunction, pronounced sensory
From the *Institute of Neurology and iDepartment of Medical Statistics, University Hospital Nijmegen, and the $Department of Pathology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands. Received Jun 6, 1990, and in revised form Aug 21 and Oct 5. Accepted for publication Oct 5 , 1990. Address correspondence to Dr Renicr, Institute of Neurology, University Hospital Nijmegen, PO Box 9101, NL-6500 H B Nijmegen, The Netherlands.
Copyright 8 1971 by the American Neurological Association
This work was supported by grant PG-41 from the Medical Research Council of Canada, the Isaac Walton Killam Fellowship Fund of the Montreal Neurological Institute, and the Fonds de la Recherche en SantG du Quebec. The numerous stimulating discussions contributed by Dr R.W. Dykes, Centre de Recherches en Sciences Neurologiques, Universite de Montr6al; Dr E. Hamel, McConnell Brain Imaging Centre; and Dr D. Bub, Director, Neurolinguistics, McGill University, are gratefully acknowledged. We thank the technical staff of the McConnell Brain Imaging Centre, the Medical Cyclotron Unit, and the Neurophotography Department for their assistance.
References 1. Hyvixinen J, Pocanen A, Jokinen Y . Influence of attentive behavior on neuronal response to vibration in primary somatosensory cortex of the monkey. .J Neurophysiol 1980;43:870-882 2. Roland PE. Metabolic measurements of the working frontal cortex in man. TINS November 1984:430-435 3. Goldberg ME, Wurrz RH. Activity of superior colliculus in behaving monkeys. 11. Effect of attention on neuronal responses. J Neurophysiol 1972;35:560-574 4.Roland PE. Cortical regulation of selective attention in man. A regional cerebral blood flow study. J Neurophysiol 1982;48: 1059-1078 5. Herscovitch P, Markham J, Raichle ME. Brain blood flow measured with intravenous 0-15 H 2 0 . l. Theory and error analysis. J Nucl Med 1983;24:782-789 6. Raichle ME, Martin WRW, Herscovitch P, et al. Brain blood flow measured with intravenous 0 - 1 5 H20.11. Implementation and validation. J Nucl Med 1983;24:?90-798 7 . Thompson CJ, Dagher A, Meyer E, et al. Imaging performance of a dynamic positron emission tomograph: Positomr Illp. IEEE Trans Med Imaging 1986;5:183-198 8. Meyer E. Simultaneous correction for tracer arrival delay and dispersion in CBF measurements by the H,”O autoradiographic method and dynamic PET. J Nucl Med 1989;30:1060-1078 9. Bergstr6m M,Litton J, Eriksson L, et al. Determination of ohject contour from projections for atrenuation correction in cranial positron emission tomography. J Comput Assist Tomogr 1982;6:365-372 10. Evans AC, Beil C, Marretr S, et al. Anatomical-functional correlation using an adjustable MRI-based region of interest atlas with positron emission tomography. J Cereb Blood Flow Metab 1988;8:j13-530 11. Fox PT,Perlmutter JS, Raichle ME. A stereotactic method of andtomicd locahzation for positron emission tomography. J Comput Assist Tornogr 1985;9:14 1- 153 12. Zar JH. Biostatistical analysis, 2nd ecl. Englewood Cliffs, NJ: Prentice-Hall, 1984 13. Fox FT, Burton H , h c h l e ME. Mapping human somatosensory cortex with positron emission tomography. J Neurosurg 1987;67:34-43 14. Corbetta M, Miezin FM, Dobmcyer S, et al. Attentional modulation of neural processing of shape, color, and velocity in humans. Science 1990;248:1556-1559 15. Talairdch J. Tournoux P. Co-planar stereotaxic atlas of the human brain. Stuttgart: Thieme Medical Publishers, 1988
Selective Impairment of Smooth-Pursuit Eye Movements Due to an Ischemic Lesion of the Basal Pons Peter Thier, MD, Alexander Bachor, Jiirgen Faiss, MD,* Johannes Dichgans, MD, and Eberhard Koenig, M D
Voluntary and reflex-like eye movements were measured in a patient with an ischemic lesion of the right basal pons. Ipsilateral smooth-pursuit eye movements were predominantly impaired and interrupted by saccades. This profound smooth-pursuit deficit contrasted with only minor abnormalities of visually guided saccades and the vestibulo-ocular reflex. A selective disturbance of smooth-pursuit eye movements due to a lesion of the basal pons in this patient concurs with recent work in monkeys suggesting that smooth-pursuit eye movements are mediated by a parietooccipito-ponto-cerebellarpathway. Thier P, Bachor A, Fass J, Dichgans J, Koenig E. Selective impairment of smooth-pursuit e y e movements due t o a n ischemic lesion of t h e basal pons. Ann Neurol 1991;29:443-448
In contrast to the well defined tegmental brainstem centers for saccades and eye reflexes, the brainstem centers mediating smooth-pursuit eye movements have been poorly understood. Recent experiments in monkeys indicate the importance of brainstem sites not in the tegmentum for the organization of smooth-pursuit eye movements. Single cell recordings 11-41, microstimulation studies [ S ] , and experimental lesions [GI all suggest that the dorsolateral pontine nucleus in the basal pons of monkeys is the major link in a descending pathway from the parieto-occipital lobe to the cerebellum, communicating signals relevant for smoothpursuit eye movements. In the present study, we describe the oculomotor consequences of an ischemic lesion of the human basal pons, and we present the
From the Departments of Neurology and Neuroradtology, University of Tubingen, Hoppe-Seyler-Str&e 3, 7400 Tubingen, German1 Received Apr 26, 1090, and in revised form Jul 2 3 and Oct 8 Accepted for publication Oct 9, 1990 Address correspondence to Dr Thier, Department of Bran and Cognitive Scienres, Massachusetts Institute of Technology, E25-236, Cambridge, MA 02139 ‘Present addresc Department of Neurology, University of Essen, Hufelandstrde 55, 4300 Essen, Germany
Copyright
0 1991 by t h e American Neurological Association 443
first evidence for a similar role in the control of smooth-pursuit eye movements in humans.
Case Report A 61-year-old, right-handed man awoke with tingling and prickling of the tongue and cheek, impaired balance, and weakness of his left side. S i x days after onset of symptoms, examination disclosed hemihypesthesia and weakness on the left, including an inability to stand straight without support. Biceps and knee reflexes were slightly brisker on the left side, the right ankle reflex was absent, and the left one was reduced. Plantar reflexes were flexor. Rapid alternating movements of the left hand were slower. Hearing was impaired on the right. Oculomotor anomalies will be described in detail. The remainder of the neurological examination was normal. Magnetic resonance imaging (MRI) scans (Fig 1) obtained 16 days after the onset of symptoms demonstrated a circular zone of altered signal intensity, presumably representing a new postischemic defect in the right pontine base abutting the right crus cerebri rostrally but sparing the caudaI pons. Although the available MRI scans did not allow discrimination of the nuclear zones from the fibers of the cerebral peduncle, it may safely be assumed that the extent and the location of the lesion had destroyed large parts of the pontine nuclei. Neither the X-ray computed tomographic scans nor the MRI images revealed any brain pathology outside the basal pons. In view of the clinical syndrome with left-sided weakness, pyramidal tract involvement might have been expected. Transcranial magnetic stimulation of the motor cortex C7, 81, however, led to contractions of hand and foot muscles with normal latency and amplitude. In contrast, involvement of the medial lemniscus, ascending in close vicinity of the basal pons, was suggested by an analysis of cortically evoked somatosensory potentials. The P40 complex, elicited by stimulation of the left tibial nerve, was significantly delayed, compatible with a lesion of this fiber tract upward of its decussation at the level of the right basal pons. At the time of discharge, 18 days after the onset of symptoms, the initial neurological deficit had receded except for a residual mild left side hemiparesis and gait ataxia.
Material and Methods Eye movements were recorded using direct current electrooculography (EOG)both monocularly and bitemporally. Saccadic eye movements were induced by instructing the patient always to look at that member of a pair of red light-emitting diodes (LED) that was switched on (the other one being switched off). The two LEDs were positioned 20 degrees to the left and 20 degrees to the right with respect to the patient’s primary position at a viewing distance of l.l m. Each LED subtended a visual angle of 0.25 degrees. The visual target used to elicit smooth-pursuit eye movements was a red laser spot (visual angle, 0.25 degrees), projected onto a screen 1.1 m in front of the patient and which could be moved along the horizontal meridian according to a triangular velocity profile (amplitude, 20 degrees; velocity, 25 or 40 degreesisec). The patient was instructed to fixate the laser target as accurately as possible. Tests of saccadic and smoothpursuit eye movements were performed at a background lu-
444 Annals of Neurology Vol 29 N o 4 April 1991
minance of 0.6 cd/m2. Horizontal optokinetic reflexes (Om) were elicited with a whole-field stimulus consisting of vertical black and white stripes (period, 15 degrees; contrast, 0.5; mean background luminance, 4 cd/m2) moving horizontally at 60 degreesisec. This stimulus was created by rotating a small drum with vertical slits of appropriate spacing around a light source coaxial with the patient. Horizontal vestibuloocular reflexes (VOR) were induced by seating the patient on a motorized platform that was sinusoidally rotated (maximum velocity, 80 degreesisec, 0.2 Hz). VOR was studied with eyes closed. Suppression of the horizontal VOR was tested by asking the patient to fixate an LED target 0.7 m in front of him (background luminance, 0.6 cd/m2) and moving in synchrony with him. Owing to limitations of instrumentation, no attempt was made to study vertical eye movements. EOG records were calibrated under the assumption that the eyes were on target during maintained fixation of the two LEDs used to elicit saccades.
Results Eye movements were conjugate, and there was n o gaze-evoked nystagmus. Occasionally, a slight leftward beating spontaneous nystagmus with slow-phase velocity of about 1 to 2 degreedsec could be observed when the patient’s eyes were closed and he was asked to perform mental arithmetic. Saccades elicited by the periodic, predictable steps of the target from right to left and back were performed with normal latency and velocity. O n 50% of all saccades to the right and on 22% of all saccades to the left, however, the eyes undershot the target by a few degrees (Fig 2A). Such hypometric saccades were always corrected by o n e additional saccade of appropriate amplitude. Smooth-pursuit eye movements to the right, elicited by t h e periodic and predictable movement of the fixation spot, were dramatically impaired. With the target moving at 25 degreesisec (Fig 2B), the velocity of the eyes during slow phases of the saccade-interrupted visual-tracking eye movements to the ipsilateral (right) side comprised only 3 to 30% of t h e target velocity and many catch-up saccades were needed to keep the eyes o n target. At higher target velocities (40 degrees/ sec, Fig 2C), smooth-pursuit eye movements of reduced velocity were entirely absent for target movement to the ipsilateral (right) side. Occasionally, slow drifts of the eyes to the contralateral (left) side occurred, which were interrupted by large amplitude catch-up saccades into the direction of target movement. I n contrast, smooth-pursuit eye movements to
b
Fig 1 . Magnetic resonance imaging scam, cut in horizontal (A, B), coronal (C, 0) and parasagittal (EJ planes illustrating the localization and extent of the ischemic lesion affecting the right basal pons. The orientation of the respective planes of sectioning is illutruted in F . A, C , and E depict TI -weighted scans and B and D, T2-weighted scans. Rder t o the text for further descrip~
tion.
I-t
tion of the horizontal VOR, however, did not reveal a substantial deviation from normal. Maximal slow eye velocity amounted to 59% of head velocity for rotation to the right and 66% for rotation to the left, which is within the normal range. The ability of the patient to suppress his horizontal VOR by visual fixation of a target oscillated in synchrony with head and body was impaired. For both orientations of rotation, only 25% of slow eye velocity elicited by the same stimulus with eyes closed could be suppressed, that is, no right-left asymmetry was apparent.
2 sec
A
2 scc
C Fig 2. Samples of the patient’s eye-movement recordings. (A)Saccades, elicited Sy predictable and periodic steps of a small target from l4t t o right and back again. Note occasional hypometric saccades (the arrow mar& an example). (B. C) Visual-tracking eye mwements elicited by horizontal movement of a laser target from ldt to right and back again, according t o a triangular waveform.Target velocity was 25 degreeslsec in B and 40 degreeslsec in C. 1, 2, and 3 are lines indicating mean smooth-pur.ruit eye velocity. Occurrence of target steps in A and turning points of the h e r target in B and C are marked by small, filled triangles. Note that the samples of the target trajectories (t) in A, B, and C are plotted displaced with respect t o the eye-position curues le) for the sake of clarity. The electro-oculogram was recorded bitemparally.
the contralateral side were less affected; at the lower of the two velocities of target movement used, periods of normal-gain smooth-pursuit e y e movement alternated with periods of saccadic smooth-pursuit eye movement, with slow-phase velocity amounting to approximately 50 to 60% of target velocity (Fig 2B). A more consistent smooth-pursuit deficit was present only at the higher target velocity, with slow-phase velocity amounting to approximately 45% of target velocity (Fig 2C). A pronounced reduction of response amplitude combined with an asymmetry of responses was also visible in the OKR records. Whereas slow-phase velocity for drum rotation to the contralateral side amounted to up to 30% of pattern velocity, slow-phase velocity for drum rotation to the ipsilateral side attained only up to 15% of pattern angular velocity with considerable fluctuation and without clear, slow build-up. Investiga-
446 Annals of Neurology Vol 29 No 4 April 1991
Discussion The human basal pons contributes to the generation of smooth-pursuit eye movements to the ipsilateral side. This is the major conclusion to be drawn from our observation that a patient suffering from an acute ischemic lesion on one side of the basal pons, but without any indication of additional brain pathology, presented with grossly disturbed smooth-pursuit eye movements to the ipsilateral side. According to prevailing concepts, two other types of eye movements, the optokinetic reflex and the suppression of the vestibulo-ocular reflex by visual fixation, are thought to be functionally related to smooth-pursuit eye movements. It is therefore interesting to consider whether they showed related patterns of disturbances. This was clearly the case with respect to the OKR, which also showed reduced slow-phase velocity toward the side of the lesion. This is what would be expected if a signal derived from the system generating foveal-pursuit eye movements is used to supplement the OKR proper, as suggested by well established models of the OKR t91. In contrast to the clear asymmetry in the performance of smooth-pursuit eye movements and the OKR, suppression of the VOR by fixation of a visual target, the other type of eye movement suggested to be related to smooth-pursuit eye movement, did not show this asymmetry and was impaired for rotation to both sides. An interpretation of this finding requires a brief look at the question of how suppression of the VOR by visual fixation is achieved. One of the two mechanisms suggested, the “addition” mechanism [lo], assumes a linear summation of two independent signals, a smooth-pursuit eye movement command and a vestibular command. The other mechanism, called the “parametric adjustment” mechanism t111, proposes immediate adjustment of transmission in the VOR pathway. Obviously, the lack of asymmetry of fixationsuppression of the VOR in a patient with normal VOR but asymmetric smooth pursuit eye movement cannot be explained by the addition mechanism. Usage of parametric adjustment in fixation-suppression of this patient’s VOR is indicated. This is not to say that the addition mechanism might not play a role under other
conditions not tested by us. Actually, recent work in monkeys [12) suggests that the two mechanisms, rather than being mutually exclusive, are both available to the brain. The one more profitable with respect to gaze accuracy will be favored, depending on the condition prevailing. Although fixation-suppression of the VOR in the present patient was not asymmetric, it was far from being sufficient to guarantee accurate tracking of the target. Whether this was simply due to insufficient attention to the target or was attributable to other factors cannot be decided on the basis of the limited data available on fixation-suppression of this patient’s VOR. In contrast to the oculomotor functions related to smooth-pursuit eye movements, the other types of eye movements, namely the VOR and visually guided saccades, were only marginally or not at all affected by the basal pons lesion. Although more sophisticated methods than the ones available for investigation of this patient might have revealed additional subtle abnormalities of VOR or saccades, this would not substantially diminish our conclusion that the lesion mainly affected a pathway for smooth-pursuit eye movements. A rather selective disturbance of smooth-pursuit eye movements due to a lesion of the basal pons is consistent with the concept, as yet mainly based on experimental work on animals, of an anatomical segregation of the brainstem pathways for smooth-pursuit eye movements, saccades, and vestibular and optokinetic reflexes. Whereas the brainstem tegmentum subserves saccades and reflex-like eye movements [l31, smoothpursuit eye movements are mediated by the basal pons, the major anatomical link between the cortices of cerebrum and cerebellum [14]. In the monkey, signals related to smooth-pursuit eye movements are confined to the dorsolateral parts of the pontine nuclei [1-4}, which are the major constituents of the basal pons. Unilateral lesions of the dorsolateral pontine nucleus in monkeys cause an eye movement deficit that resembles the one observed in the patient described here [GI. In monkeys, the major source of afferents to the dorsolateral pontine nucleus are large parts of the socalled superior temporal sulcus [ 15-18], which houses the middle temporal (MT), fundal superior temporal (FST), and middle superior temporal (MST) areas. Whereas area MT seems to contribute to the organization of smooth-pursuit eye movements by processing retinal target slip velocity [19), other areas such as MST and FST contain nonretinal signals related to smooth-pursuit eye movements reminiscent of those also found in the dorsolateral pontine nucleus t20-2 31. Lesioning the latter areas causes a disturbance of smooth-pursuit eye movement directed to the side ipsilateral to the lesion C24, 251. These observations are
compatible with the notion that the functional contribution of the dorsolateral pontine nucleus to smoothpursuit eye movements is highly dependent on its cortical input. The dorsolateral pontine nucleus, however, may be considered the major gateway for smoothpursuit-related signals to the cerebellum because, in the monkey, it has been shown to project [26-29) to all parts of the cerebellum known relevant for smoothpursuit eye movements, for example, the flocculus [30, 31) and the posterior vermis {32-35). The present observation of a selective disturbance of smoothpursuit eye movements after a lesion of the human basal pons therefore suggests that the concept of a parietooccipito-ponto-cerebellar pathway for smoothpursuit eye movements, previously established only for monkeys, may be extended to humans. This work was supported by DFG SFB 307-A1 and -A2 We are grateful to D. Tweed for helpful comments on earlier versions of the manuscript.
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Adult Polyglucosan Body Disease: The Diagnostic Value of h l l a Skin Biopsy H. L. S. M. Busard, MD," A. A. W. M. Gabreels-Festen, MD,* W. 0. Renier, MD, PhD,* F. J. M. Gabreels, MD, PhD,* E. M. G. Joosten, MD, PhD,* M. A. van 't Hof, MS,? and J. B. M. Rensing, MDS
The diagnostic value of axilla skin biopsy has been investigated in a patient with adult polyglucosan body disease. The biopsy data have been compared with those of control subjects and with those from previously reported patients with Lafora's disease. In a patient with adult polyglucosan body disease and in patients with Lafora's disease, an abundance of polyglutosan bodies was found in the myoepithelial cells of the axillary apocrine glands. In the control group of subjects, polyglucosan bodies were only sporadically seen. Axilla skin biopsy is, therefore, an easy and reliable method for confirming the diagnosis of adult polyglucosan body disease. Busard HLSM, Gabreels-Festen AAWM, Renier WO, Gabreels FJM, Joosten EMG, van 't Hof MA, Rensing JBM. Adult polyglucosan body disease: the diagnostic value of axilla skin biopsy. Ann Neurol 1991;29.448-451
Adult polyglucosan body disease (APBD) is characterized by a variable association of progressive upper and lower motor neuron dysfunction, pronounced sensory
From the *Institute of Neurology and iDepartment of Medical Statistics, University Hospital Nijmegen, and the $Department of Pathology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands. Received Jun 6, 1990, and in revised form Aug 21 and Oct 5. Accepted for publication Oct 5 , 1990. Address correspondence to Dr Renicr, Institute of Neurology, University Hospital Nijmegen, PO Box 9101, NL-6500 H B Nijmegen, The Netherlands.
Copyright 8 1971 by the American Neurological Association
