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Specific L-threo-DOPS-responsive locomotor dysfunction in two patients with multiple cerebral infarcts
Elsevier
PII: S1353-8020(96)00012
ELSEVIER
Parkinmnism 6 Related LIisordmsVol. 2, No. 3, pp. 161-163,1596 Copyright 0 19% Elswier Science Ltd. AU rights reserved Printed in Great Britain 1353-8020/% $15.00 + 0.00
Letter to the Editor Specific L-threo-DO&responsive Locomotor Dysfunction in Two Patients with Multiple Cerebral Infarcts SUSUMU CHIBA, YASUKO YONEZAWA, MANABU MATSUYA, MOT01 KASHIWAGI AND HIROYUKI MATiUMOTO Accepted 12 Jmmy
1996
L-threo-DOPS, a norepinephrine precursor, has been found to be effective on orthostatic hypotension associated with Shy-Drager syndrome and familial amyloid neuropathy. The clinical effects of L-threoDOPS on the freezing phenomenon in some patients with Parkinson’s disease was recently reported [l]. In this paper two cases of atypical gait disturbance who responded to L-threo-DOPS administration are reported. Case 1 was a 73-year-old female who had an unstable gait for 2 years. She visited the hospital because of gradual aggravation of the gait disturbance. Neurological examination showed clear consciousness without dementia or other higher brain dysfunction. Slight dysarthria without bulbar signs was noted. The finger-nose test showed hypermetria in the left upper limb. No symptoms suggestive of parkinsonism other than Myerson’s sign and a slightly impaired postural reflex were observed. The deep tendon reflexes (DTR) were slightly hyperactive without pathological reflexes. Multiple small infarcts were detected in the deep cerebral white matter on T2 weighted MRI (Fig. 1). A SPECT showed low perfusion areas in the left fronto-temporal lobes. When she was asked to walk while holding on to a rail with her right hand, she extended the right leg antero-laterally and to an exaggerated distance with the right knee and left arm extended. Her left arm showed no natural swing, and the four limbs lacked co-ordination. Her left step was slightly shorter than normal (Fig. 2A). No freezing phenomenon was seen. Without any support, she could not maintain a stable posture. With a cane in the right hand, she showed a more stable posture but no improvement in walking rhythm or pattern. The
landing of the cane was not co-ordinated with the legs. These were not corrected by rhythmic calls, transverse lines on the floor or a mirror. Curiously, her right knee showed normal flexion and extension while sitting, standing or crawling. A 100 mg dose of Lthreo-DOPS/day was given initially. At 300 mg/day, she regained a stable posture, freedom from overextension of the right knee and the anterolateral swing of the right leg recovered. She had a shorter right step and her walking rhythm was nearly normal. At 800 mg/day, the abnormalities in the right knee and leg completely disappeared. Her arms showed a slight unnatural lateral swing but were well co-ordinated with leg movements (Fig. 28). Case 2 was a 68-year-old female who had gait disturbance for approximately 6 years and had used a cane for 2 years. She visited the hospital because her gait had deteriorated such that she could no longer use stairs. Neurological examination showed clear
Department of Neurology, School of Medicine, Sapporo Medical University, Japan. Address correspondence to: Susumu Chiba, MD, PhD, Department of Neurology, School of Medicine, Sapporo Medical University, Minami 1 jo, Nishi 16 chome, Chuo-ku, Sapporo 060, Japan.
FIGURE 1. 161
LETTER TO THE EDITOR
162
FIGURE 2.
FIGURE 3.
consciousness without any higher brain dysfunction. Mild right hemiparesis was noted together with slightly hyperactive DTR and pathological reflexes. No symptoms suggestive of parkinsonism except for Myerson’s sign were observed. Multiple small infarcts were detected in the deep cerebral white matter and the left ventral pons on T2 weighted MRI (Fig. 3). A SPECT showed low perfusion areas in the right fronto-parieto-temporal lobe and bilateral basal ganglia. When she was asked to walk, she pushed out the right shoulder unnaturally and took a larger step with the left than with the right leg. The swing of the left arm was wide and diagonal in the anteromedialposterolateral direction. Small steps formed a mild festinating gait (Fig. 4A). When changing direction, she showed freezing. She could crawl normally. With 500 mglday of L-threo-DOPS, her step became symmetrical and was associated with normal swing of the right arm. The peculiar swing of the left arm was reduced, although the direction was uncorrected. With 600 mg/day of L-threo-DOPS combined with 300 mgl day of amantadine hydrochloride, much improvement was obtained in co-ordination between the upper and lower limbs and in the walking pattern and rhythm (Fig. 4B). No difference in cerebral blood perfusion on SPECT during L-threo-DOPS therapy was found. In both patients, motor dysfunction was not associated with dementia, agnosia, apraxia or even parkinsonism, and was restricted to ‘walking’. This can probably be explained by motor into-ordination between the limbs and the trunk. L-threo-DOPS remains unchanged or is converted to norepinephrine before it exerts its biological action. Norepinephrine-mediated projection from the locus ceruleus extends over the various nuclei except for the striatum, the cerebral cortex, white matter and spinal cord [2]. In both cases, multiple infarcts and reduced regional cerebral perfusion were indicated by MRI and
LElTER
TO THE EDITOR
163
FIGURE 4.
SPECT. Small foci in the paralemniscal pontine reticular formation disrupt the walking rhythm [3], and the crossed extension or interlimb reflexes necessary for the co-ordination of four limbs during walking [4], though no such lesions were found in the brainstems of the present patients, In addition, recent studies show that descending adrenergic motor nerve fibers in the spinal cord play a role in the initiation and control of walking in animal models [5]. However, the marked unto-ordination of the four limbs observed exclusively while walking implies concomitant higher cerebral dysfunction rather than brainstem or spinal cord involvement. Recently, Zornetzer found both cholinergic and noradrenergic neurotransmitter systems are important for regulatory memory-related functions including walking [6]. The present cases suggest that L-thero-DOPS has potential effects on some types of gait disturbance based on the dysregulation of memory-related function.
REFERENCES 1. Narabayashi H, Kondo T, Hayashi A, Suzuki T, Nagatsu T.
2.
3.
4.
5.
6.
L-three-3,4dihydroxyphenylseline treatment for akinesia and freezing of parkinsonism. Proc. ]pn. Acad. 1981; 57 (B): 351-354. Loughlin SE, Foote SO, Bloom FE. Efferent projections of nucleus locus ceruleus: topographic organization of cells of origin demonstrated by three-dimensional reconstruction. Neuroscience1986; 18: 291-306. Shimamura M, Kogure T, Fuwa T. The role of the paralemniscal pontine reticular formation in four limb stepping of thalamic cats. Neurosci.Res. 1984; 1: 393-410. Shimamura M, Tanaka I, Fuwa T. Supraspinal central mechanisms of coordinated movements among four limbs in cat during stepping. In: Shimamura M et al. eds. Neurobiological Basis of Human Locomotion. Tokyo: JSSP; 1991: 175-185. Hino M, Ono H, Fukuda H. Involvement of noradrenergic systems in the effects of conditioning stimulation of the lower brain stem on the lumbar spinal reflexes in rats. Gen. Pharmac. 1987; 18: 41-45. Zornetzer SF. Catecholamine system involvement in agerelated memory dysfunction. Ann. NY Acad. Sci. 1985; 444: 242-253.
PII: S1353-8020(96)00012
ELSEVIER
Parkinmnism 6 Related LIisordmsVol. 2, No. 3, pp. 161-163,1596 Copyright 0 19% Elswier Science Ltd. AU rights reserved Printed in Great Britain 1353-8020/% $15.00 + 0.00
Letter to the Editor Specific L-threo-DO&responsive Locomotor Dysfunction in Two Patients with Multiple Cerebral Infarcts SUSUMU CHIBA, YASUKO YONEZAWA, MANABU MATSUYA, MOT01 KASHIWAGI AND HIROYUKI MATiUMOTO Accepted 12 Jmmy
1996
L-threo-DOPS, a norepinephrine precursor, has been found to be effective on orthostatic hypotension associated with Shy-Drager syndrome and familial amyloid neuropathy. The clinical effects of L-threoDOPS on the freezing phenomenon in some patients with Parkinson’s disease was recently reported [l]. In this paper two cases of atypical gait disturbance who responded to L-threo-DOPS administration are reported. Case 1 was a 73-year-old female who had an unstable gait for 2 years. She visited the hospital because of gradual aggravation of the gait disturbance. Neurological examination showed clear consciousness without dementia or other higher brain dysfunction. Slight dysarthria without bulbar signs was noted. The finger-nose test showed hypermetria in the left upper limb. No symptoms suggestive of parkinsonism other than Myerson’s sign and a slightly impaired postural reflex were observed. The deep tendon reflexes (DTR) were slightly hyperactive without pathological reflexes. Multiple small infarcts were detected in the deep cerebral white matter on T2 weighted MRI (Fig. 1). A SPECT showed low perfusion areas in the left fronto-temporal lobes. When she was asked to walk while holding on to a rail with her right hand, she extended the right leg antero-laterally and to an exaggerated distance with the right knee and left arm extended. Her left arm showed no natural swing, and the four limbs lacked co-ordination. Her left step was slightly shorter than normal (Fig. 2A). No freezing phenomenon was seen. Without any support, she could not maintain a stable posture. With a cane in the right hand, she showed a more stable posture but no improvement in walking rhythm or pattern. The
landing of the cane was not co-ordinated with the legs. These were not corrected by rhythmic calls, transverse lines on the floor or a mirror. Curiously, her right knee showed normal flexion and extension while sitting, standing or crawling. A 100 mg dose of Lthreo-DOPS/day was given initially. At 300 mg/day, she regained a stable posture, freedom from overextension of the right knee and the anterolateral swing of the right leg recovered. She had a shorter right step and her walking rhythm was nearly normal. At 800 mg/day, the abnormalities in the right knee and leg completely disappeared. Her arms showed a slight unnatural lateral swing but were well co-ordinated with leg movements (Fig. 28). Case 2 was a 68-year-old female who had gait disturbance for approximately 6 years and had used a cane for 2 years. She visited the hospital because her gait had deteriorated such that she could no longer use stairs. Neurological examination showed clear
Department of Neurology, School of Medicine, Sapporo Medical University, Japan. Address correspondence to: Susumu Chiba, MD, PhD, Department of Neurology, School of Medicine, Sapporo Medical University, Minami 1 jo, Nishi 16 chome, Chuo-ku, Sapporo 060, Japan.
FIGURE 1. 161
LETTER TO THE EDITOR
162
FIGURE 2.
FIGURE 3.
consciousness without any higher brain dysfunction. Mild right hemiparesis was noted together with slightly hyperactive DTR and pathological reflexes. No symptoms suggestive of parkinsonism except for Myerson’s sign were observed. Multiple small infarcts were detected in the deep cerebral white matter and the left ventral pons on T2 weighted MRI (Fig. 3). A SPECT showed low perfusion areas in the right fronto-parieto-temporal lobe and bilateral basal ganglia. When she was asked to walk, she pushed out the right shoulder unnaturally and took a larger step with the left than with the right leg. The swing of the left arm was wide and diagonal in the anteromedialposterolateral direction. Small steps formed a mild festinating gait (Fig. 4A). When changing direction, she showed freezing. She could crawl normally. With 500 mglday of L-threo-DOPS, her step became symmetrical and was associated with normal swing of the right arm. The peculiar swing of the left arm was reduced, although the direction was uncorrected. With 600 mg/day of L-threo-DOPS combined with 300 mgl day of amantadine hydrochloride, much improvement was obtained in co-ordination between the upper and lower limbs and in the walking pattern and rhythm (Fig. 4B). No difference in cerebral blood perfusion on SPECT during L-threo-DOPS therapy was found. In both patients, motor dysfunction was not associated with dementia, agnosia, apraxia or even parkinsonism, and was restricted to ‘walking’. This can probably be explained by motor into-ordination between the limbs and the trunk. L-threo-DOPS remains unchanged or is converted to norepinephrine before it exerts its biological action. Norepinephrine-mediated projection from the locus ceruleus extends over the various nuclei except for the striatum, the cerebral cortex, white matter and spinal cord [2]. In both cases, multiple infarcts and reduced regional cerebral perfusion were indicated by MRI and
LElTER
TO THE EDITOR
163
FIGURE 4.
SPECT. Small foci in the paralemniscal pontine reticular formation disrupt the walking rhythm [3], and the crossed extension or interlimb reflexes necessary for the co-ordination of four limbs during walking [4], though no such lesions were found in the brainstems of the present patients, In addition, recent studies show that descending adrenergic motor nerve fibers in the spinal cord play a role in the initiation and control of walking in animal models [5]. However, the marked unto-ordination of the four limbs observed exclusively while walking implies concomitant higher cerebral dysfunction rather than brainstem or spinal cord involvement. Recently, Zornetzer found both cholinergic and noradrenergic neurotransmitter systems are important for regulatory memory-related functions including walking [6]. The present cases suggest that L-thero-DOPS has potential effects on some types of gait disturbance based on the dysregulation of memory-related function.
REFERENCES 1. Narabayashi H, Kondo T, Hayashi A, Suzuki T, Nagatsu T.
2.
3.
4.
5.
6.
L-three-3,4dihydroxyphenylseline treatment for akinesia and freezing of parkinsonism. Proc. ]pn. Acad. 1981; 57 (B): 351-354. Loughlin SE, Foote SO, Bloom FE. Efferent projections of nucleus locus ceruleus: topographic organization of cells of origin demonstrated by three-dimensional reconstruction. Neuroscience1986; 18: 291-306. Shimamura M, Kogure T, Fuwa T. The role of the paralemniscal pontine reticular formation in four limb stepping of thalamic cats. Neurosci.Res. 1984; 1: 393-410. Shimamura M, Tanaka I, Fuwa T. Supraspinal central mechanisms of coordinated movements among four limbs in cat during stepping. In: Shimamura M et al. eds. Neurobiological Basis of Human Locomotion. Tokyo: JSSP; 1991: 175-185. Hino M, Ono H, Fukuda H. Involvement of noradrenergic systems in the effects of conditioning stimulation of the lower brain stem on the lumbar spinal reflexes in rats. Gen. Pharmac. 1987; 18: 41-45. Zornetzer SF. Catecholamine system involvement in agerelated memory dysfunction. Ann. NY Acad. Sci. 1985; 444: 242-253.