Unilateral Lesions of the Globus Pallidus: Report of Four Patients Presenting with Focal Or Segmental Dystonia

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J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.69.4.494 on 1 October 2000. Downloaded from 494 J Neurol Neurosurg Psychiatry 2000;69:494–498 Unilateral lesions of the globus pallidus: report of four patients presenting with focal or segmental dystonia

A Münchau, D Mathen, T Cox, N P Quinn, C D Marsden,* K P Bhatia

Abstract basal ganglia in humans only 17 patients with Objectives—To interpret clinical features lesions restricted to the GP were identified but after unilateral lesions of the globus in only two was the lesion unilateral.1 Since pallidus on the basis of physiology of the then only nine additional patients with bilateral basal ganglia. pallidal lesion have been reported.2–4 Here we Methods—Four patients with unilateral describe four patients with discrete unilateral lesions in the globus pallidus (GP) were lesions of the GP (table). clinically examined and the literature on patients with pallidal lesions was re- viewed. Case reports Results—Three patients presented with CASE 1 contralateral dystonia largely confined to At the age of 19 this right handed man was one arm in one case and one leg in two involved in a road traYc accident while driving. cases. One patient had predominant con- He was struck on the right side of his head and tralateral hemiparkinsonism manifested was comatose for 24 hours. On regaining con- mainly as micrographia and mild dystonia sciousness he had both anterograde and retro- in one arm. The cause of the lesions was grade amnesia for about a day. He also had unknown in two patients. In the other two double vision which receded after a few days, symptoms had developed after head transient mild facial asymmetry on smiling, trauma and after anoxia. All lesions in- and diYculties in performing skilled move- volved the internal segment of the GP.Two ments with his left hand. Since his recovery he patients, including the patient with hemi- had experienced mild problems with short parkinsonism, had additional involvement term memory, but was able to retain his job as of the external segment of the GP. In the an engineer. Three years after the accident he literature reports on 26 patients with bilat- noted that his left arm started to involuntarily eral lesions restricted to the GP only two pull across his chest so that the fingers would University with unilateral lesions were found. The touch his right shoulder. These spasms initially Department of Clinical patients with bilateral pallidal lesions occurred for 5–10 seconds at a time and later Neurology, Institute of manifested with dystonia, parkinsonism, or became continuous. There was no alteration in Neurology, Queen the level of consciousness during these attacks Square, London abulia. One of the patients with unilateral

and they were not associated with pain or http://jnnp.bmj.com/ WC1N 3BG, UK GP lesions had contralateral hemidystonia, altered sensation in the arm. When the arm A Münchau the other contralateral arm tremor. hung loosely he felt the muscles tensing invol- D Mathen Conclusion—These cases emphasise the N P Quinn untarily. During spasms the ﬁngers ﬂexed at importance of the GP, particularly its C D Marsden* the metacarpophalangeal and extended at the internal segment, in the pathophysiology K P Bhatia interphalangeal joints. Occasionally he noted of dystonia. that his left big toe would claw independently. National Hospital for (J Neurol Neurosurg Psychiatry 2000;69:494–498) Neurology and He had no other medical history and had no

Neurosurgery Keywords: globus pallidus lesions; basal ganglia; dysto- familial or personal history of psychiatric or on September 24, 2021 by guest. Protected copyright. TCox nia movement disorders. There was no history of toxic exposure or treatment with neuroleptic Correspondence to: drugs. On examination 3 years after the onset Dr Kailash P Bhatia Motor and other eVects produced by selective [email protected] of his symptoms at the age of 25 he had some lesions aVecting the basal ganglia may give immediate recall problems but did not show Received 15 October 1999 clues to their function. Focal lesions restricted other neuropsychological deficits or behav- and in revised form to the globus pallidus (GP), particularly unilat- 13 March 2000 ioural abnormalities. His face was slightly Accepted 11 May 2000 eral, are rare. In a recent review of behavioural asymmetric at rest, but facial movements were *Died 29 September 1998 and motor consequences of focal lesions of the symmetric. He had recurrent dystonic spasms Case summaries of the reported patients of the left arm with internal rotation and adduction of the left arm, flexion of the elbow Age of and wrist, and extension of the fingers. Case onset Latency Clinical findings Lesion on MRI Cause Dystonic activity was found mainly in the left 1 22 y 3 y Dystonia L arm, clawing L toes R dorsal GP Head trauma pectoralis major, trapezius, biceps, triceps and 2 6 months Unknown Dystonia L leg R GPi Unknown brachioradialis muscles. Distal hand move- 3 22 y Unknown L hemiparkinsonism, dystonia L R GPe and GPi Unknown arm ments were well preserved. 4 5 y Several Dystonia R foot L GPi Anoxia He walked without swinging his left arm. months The neurological examination was otherwise GP=Globus pallidus; GPe=external segment of the globus pallidus; GPi=internal segment of the normal. Brain MRI (fig 1) done 7 years after gobus pallidus. his head injury showed a lesion in the dorsal

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Figure 1 Brain MRI of case 1. (A) On the T2 weighted image and (B) the proton density image a small focus of hyperintensity is visible in the right dorsal GP. part of the right GP. The lesion was hyperin- infections, head injury, drug exposure, or meta- tense on T2 weighted and proton density bolic abnormalities. He had developed involun- images. Tetrabenazine, baclofen, clobazam, tary inversion of the left foot and flexion of the carbamazepine, and sodium valproate had no left knee and hip at the age of 6 months. He eVect. His symptoms responded to higher crawled from 8 months, stood at 10 months, doses of clonazepam but he had to reduce the walked at 17 months, and his walking was its dose due to aggression and irritability. He best at about 2 years of age. His mental develop- responded well to botulinum toxin injections ment was normal. He was first examined at the into his left shoulder and upper arm muscles. age of 3 years when severe dystonia of the left leg CASE 2 below the knee was noted. On examination at This 3 year old boy was the product of a normal the age of 7 years the left foot was held in an pregnancy and delivery. There was no docu- equinovarus position and his leg was flexed at mented history of any perinatal problems, the hip and knee. He could straighten his leg to http://jnnp.bmj.com/ on September 24, 2021 by guest. Protected copyright.

Figure 2 Brain MRI of case 2. (A) A small lesion in the internal segment of the right GP that is hyperintense on the T2 weighted image and (B) the proton density image is shown.

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Figure 3 Brain MRI of case 3. An isolated lesion involving the internal and external segments of the right GP is shown. (A) The lesion is hypointense on the T2 weighted image and (B) hyperintense on the T1 weighted image. The coronal T1 weighted image (B) confirms the situation of the lesion and demonstrates patchy high signal consistent with microcalcification or mineralisation (blood degradation products): no evidence of calcification was seen at this site on CT.

bear weight. On passive manipulation the foot showed an isolated lesion in the right GP could be everted and inverted fully and involving both the internal and external dorsiﬂexed past 90 degrees. He could stand on segment. A repeat study done a year later did one leg and walked with the help of crutches. not show any change. The lesion was hyperin- The rest of the neurological examination was tense on T1 and hypointense on T2 weighted normal. He was of normal intelligence. Meta- images. Brain CT was normal. bolic screening was negative. Brain MRI (ﬁg 2) at the age of 7 years showed a small (4 mm) CASE 4 lesion in the internal segment of the right GP This patient had normal development until the that was hyperintense on T2 weighted and age of 5 years when he had an operation on his proton density images, probably representing a left hip for an abscess. Apparently his heart small vascular lesion. Repeat MRI at the ages of

stopped during this operation and he was in a http://jnnp.bmj.com/ 8, 9, and 12 years did not show any change. He coma for a few days. Several months after the was given adequate trials of levodopa, ben- operation he began to limp on his right leg. He zhexol, and baclofen without beneﬁt. was, however, able to walk reasonably well until the age of 15 years when he began to have CASE 3 cramps in the right calf associated with more This 27 year old left handed man presented intense spasms of the right foot with his toes for- witha5yearhistory of diYculties with cibly ﬂexing and the ankle twisting inwards.

handwriting. He had noted that his writing was Symptoms did not spread to other body regions. on September 24, 2021 by guest. Protected copyright. becoming progressively smaller. He had also Medical history was otherwise unremarkable noticed that his left ankle tended to invert on and there was no family history of movement walking and neck muscles on the left tended to disorders or other neurological disease. On tense on and oV, especially when writing. examination at the age of 25 the patient walked There was no significant medical history apart with his right foot in an abnormal position with from asthma, no exposure to medication, and abduction of the toes. When lying on the bed no family history of movement disorders. On any voluntary action of the left leg led to over- examination there was slight hyperpronation of flow dystonia in the right leg with the foot the left arm and some flexion and abduction of turning in and the toes plantar flexing. Tone the little finger, but no other evidence of dysto- was increased in the right leg. Tendon reflexes nia. He had marked micrographia and slowness were variable, sometimes being brisker on the of writing. In addition, there was akinesia and right leg than on the left which was interpreted fatiguing of alternating finger and wrist move- as the result of dystonia in the right leg leading ments on the left and also of ankle movements to reinforcement at the time of muscle on that side. Power and reflexes were normal contraction. Both plantar responses were apart from brisk knee jerks and crossed adduc- flexor. Neurological examination was other- tors. Plantars were flexor. His arm swing was wise normal. Brain CT did not show any diminished on the left. Neurological examina- abnormalities. However, brain MRI (fig 4) tion was otherwise normal. Brain MRI (fig 3) showed a small isolated lesion in the internal done 5 years after the onset of his symptoms segment of the left GP.

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Discussion associated with behavioural problems, particu- We have described four patients with unilateral larly abulia or disinhibition.1–4 14–16 18 19 lesions in the GP. Three presented with What is the pathophysiology of symptoms contralateral dystonia, largely confined to one occurring after unilateral or bilateral pallidal arm in one case and a leg in two cases. One lesions? On the basis of the current basal gan- patient had contralateral hemiparkinsonism glia model, data on animal studies, and clinical manifested mainly as micrographia and mild observations, Bhatia and Marsden1 concluded dystonia in one arm (case 3). In two cases the that lesions of the GPe might cause parkinson- cause was unknown. In the other two, symp- ism due to disinhibition of the subthalamic toms developed after head trauma and after nucleus and the GPi with subsequent overinhi- anoxia respectively. In these patients onset was bition of the ventroanterior and ventrolateral gradual and delayed which has also been thalamus and hence the premotor cortex. Sup- reported in other cases of symptomatic port for this comes from the finding of bilateral dystonia.5–8 The reason for this is not clear. It lesions confined to the GPe causing parkinso- has been suggested that a delayed onset is the nian symptoms.2 This could explain why the result of slowly evolving aberrant sprouting of pallidal lesions in case 3 that involved the GPe, surviving neurons adjacent to the lesion9 or gave rise to hemiparkinsonism in this patient. secondary retrograde degeneration or func- Involvement of the GPi seems to be crucial tional changes in deaVerented neurons.10–12 to the dystonia present in all our patients. In all Cases with isolated unilateral pallidal lesions these cases the pallidal lesions aVected the GPi, are rare. In a recent meta-analysis of conse- albeit not exclusively. Similarly, in their study quences of basal ganglia lesions1 only two such of patients with bilateral pallidal lesions Bucher cases513 were documented. Pettigrew and et al2 encountered dystonic symptoms, particu- Jankovic5 reported on a patient who developed larly in patients with lesions in the GPi. dystonia of his left foot with subsequent spread Based on functional imaging data, an under- to the entire left leg, left arm, and left hand 4 activity of the GPi releasing the ventral tier years after closed head injury. He presumably thalamic nuclei from their normal pallidofugal had a vascular lesion in the right GP. Maki et inhibition is also emphasised in current patho- al13 described the case ofa4yearoldboywho physiological models of primary dystonia.20 21 fell to the ground while playing on a swing and Recordings of neuronal activity in GP during developed a transient right hemiparesis that pallidotomy in patients with dystonia have was followed 1 month later by tremor of the recently shown lowered mean discharge rates, right arm that lasted for several weeks. On CT increased responses to peripheral manipulation he had a lesion in the left GP involving both the (proprioceptive stimulation), and irregularly internal and external segment. grouped discharges.22–25 Decreased discharge Bilateral lesions confined to the GP are more rates in both segments of the GP were common than unilateral lesions,1 which can be interpreted as being caused primarily by explained by the fact that the GP is vulnerable overactive inhibitory projections from the to systemic hypoxia and intoxications, espe- striatum to both the GPi and the GPe via the cially carbon monoxide poisoning.14–17 Patients direct and indirect pathway, respectively.23 24 with bilateral GP lesions can present with gen- Decreased activity in the GPe would lead to

eralised dystonia or parkinsonism, sometimes disinhibition of the subthalamic nucleus and http://jnnp.bmj.com/ on September 24, 2021 by guest. Protected copyright.

Figure 4 Brain MRI of case 4. (A) On the T2 weighted image and (B) the proton weighted image a small cleft like signal change is visible in the left Gpi. Part of this lesion does not have CSF signal intensity in the proton density image, which suggests that this area represents gliosis.

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thus to an increased drive from this nucleus to suggestive of cerebral damage extending be- the GPi which could explain the increased yond the basal ganglia in these patients. This response to proprioceptive stimuli in Gpi23 24 as might have contributed to the development of proprioceptive inputs reach the GPi probably symptoms. largely via the subthalamic nucleus.26 However, the irregularities in pallidal activity may be AM was supported by the Ernst Jung-Stiftung für Wissenschaft more critical in the pathophysiology of idio- und Forschung in Hamburg, Germany and the Eugene Brehm pathic dystonia than the change of mean Bequest, United Kingdom. discharge rate or increased response to peripheral stimuli.24 25 This may also apply to our 1 Bhatia KP, Marsden CD. Behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain cases of symptomatic dystonia due to pallidal 1994;117:859–76. lesions as these lesions are likely to disturb pal- 2 Bucher SF, Seelos KC, Dodel RC, et al. Pallidal lesions: structural and functional magnetic resonance imaging. lidal function, giving rise to irregular pallidal Arch Neurol 1996;53:682–6. output, rather than abolish pallidal activity. 3 Piccirilli M, Mazzi P, Luccioli R, et al. Selective bilateral lesion of the globus pallidus: 10 year follow up of memory This would explain the apparent paradox that a impairment and frontal symptomatology. Ital J Neurol Sci pallidal lesion in previously healthy subjects 1995;16:635–40. 4 Gruber Gikovate C, Zirretta JC, Ferreira Bezerra JM, et al. causes dystonia but GPi pallidotomy alleviates Transient globus pallidus T1 shortening associated with symptoms in patients with dystonia23–25 27–29 as polycythaemia and dystonia. Neuroradiology 1999;41:288– 91. the first makes the GPi “noisy”, the second, on 5 Pettigrew LC, Jankovic J. Hemidystonia: a report of 22 the other hand, removes this “noise” by patients and review of the literature. J Neurol Neurosurg Psychiatry 1985;48:650–7. abolishing the output of an abnormally active 6 Marsden CD, Obeso JA, Zarranz JJ, et al. The anatomical GPi and may thereby lead to a normalisation of basis of symptomatic hemidystonia. Brain 1985;108:463– 83. basal ganglia function. Alternatively, the conse- 7 Lehéricy S, Vidailhet M, Dormont D, et al. Striatopallidal quences of a lesion within the GPi, whether and thalamic dystonia. A magnetic resonance imaging anatomoclinical study. Arch Neurol 1996;53:241–50. pathological as in symptomatic dystonia or 8 Krystkowiak P, Martinat P, Defebvre L, et al. Dystonia after iatrogenic after pallidotomy, might be deter- striatopallidal and thalamic stroke: clinicoradiological cor- relations and pathophysiological mechanisms. J Neurol mined by the precise lesion location. For Neurosurg Psychiatry 1998;65:703–8. instance, apart from patient 1, who had a lesion 9 Burke RE, Fahn S, Gold AP. Delayed-onset dystonia in patients with ‘static’ encephalopathy. J Neurol Neurosurg in the dorsal GPi, pallidal lesions in our Psychiatry 1980;43:789–97. patients seemed to be located anteriorly, 10 Miwa H, Hatori K, Kondon T, et al. Thalamic tremor. Neu- rology 1996;46:75–9. whereas pallidotomy lesions in patients with 11 Martin JP. Hemichorea (hemiballism) without lesions in the dystonia are situated more dorsally.24 27 corpus luysii. Brain 1957; 80:101–5. 12 Dooling EC, Adams RD. The pathological anatomy of post- Symptomatic hemidystonia and also focal hemiplegic athetosis. Brain 1975;98:29–48. limb dystonia is most commonly associated 13 Maki Y, Akimoto H, Enomoto T. Injuries of basal ganglia 158 following head trauma in children. Childs Brain 1980;7: with lesions of the contralateral putamen, 113–23. perhaps because such lesions potentially aVect 14 Klawans HL,Stein RW, Tanner CM, et al. A pure parkinso- 1 nian syndrome following acute carbon monoxide intoxica- both direct and indirect pathways which seems tion. Arch Neurol 1982;39:302–4. to be relevant for the development of 15 Ali-Cherif A, Royere ML, Gosset A, et al. Behaviour and 20 mental activity disorders after carbon monoxide poisoning. dystonia. Although symptomatic hemidysto- Bilateral pallidal lesions. Rev Neurol 1984;140:401–5. nia is most commonly caused by putaminal 16 Grinker RR. Parkinsonism following carbon monoxide poisoning. JNervMentDis1926;64:18–28. lesions, the report of our four patients illus- 17 Hawker K, Lang AE. Hypoxic-ischemic damage of the basal ganglia. Case report and review of the literature. Mov Dis- trates that contralateral dystonia can also occur http://jnnp.bmj.com/ ord 1990;5:219–24. in patients with pallidal lesions and confirms 18 Laplane D, Levasseur M, Pillon B, et al. Obsessive- the notion that altered pallidal function, compulsive and other behavioral changes with bilateral basal ganglia lesions. Brain 1989;112:699–725. particularly the GPi, is an important element in 19 Jellinger K. Exogenous lesions of the pallidum. In:Vinken the pathophysiology of acquired dystonia. PJ, Bruyn GW, Klawans HL, eds. Handbook of clinical neurology. Amsterdam: Elsevier Science, 1986:465–91. Dystonia was largely restricted to one limb in 20 Crossman AR, Brotchie JM. Pathophysiology of dystonia. our patients, which may suggest a somatotopic Adv Neurol 1998;78:19–25. 21 Eidelberg D. Metabolic brain networks in idiopathic torsion representation within the GPi. In monkeys De dystonia. Adv Neurol 1998;78:127–33. 30 22 Lenz, FA, Suarez JI, Verhagen Metman L, . Pallidal Long et al could document some somatotopic et al on September 24, 2021 by guest. Protected copyright. activity during dystonia: somatosensory reorganisation and organisation of the GPi but were unable to changes with severity. J Neurol Neurosurg Psychiatry demonstrate any simple somatotopic represen- 1998;65:767–70. 23 Vitek JL, Zhang J, Evatt M, et al. GPi pallidotomy for tation of the diVerent portions of the limbs dystonia: clinical outcome and neuronal activity. Adv Neu- (proximal and distal) within the arm or leg rol 1998:78:211–9. 24 Vitek JL, Chockkan V, Zhang JY, et al. Neuronal activity in areas of the GPi. In a recent clinicoradiological the basal ganglia in patients with generalised dystonia and study of five patients with striatopallidal lesions hemiballismus. Ann Neurol 1999;46:22–35. 25 Lozano AM, Kumar R, Groass RE, et al. Globus pallidus the distribution of symptoms also implied internus pallidotomy for generalized dystonia. Mov Disord some somatotopy of the pallidum but precise 1997;12:865–70. 8 26 Hamada I, DeLong MR. Excitotoxic acid lesions of the pri- characterisation was not possible. As only lim- mate subthalamic nucleus result in reduced pallidal neuro- ited data on unilateral pallidal lesions in nal activity during active holding. J Neurorphysiol 1992;68: 1859–66. humans are available and localisation of lesions 27 Ondo WG, Desaloms JM, Jankovic J, et al. Pallidotomy for within the GP is still relatively imprecise, the generalised dystonia. Mov Disord 1998;13:693–8. 28 Lin JJ, Lin GY, Shih C, et al. Benefit of bilateral pallidotomy precise somatotopic organisation of the GP in in the treatment of generalised dystonia. Case report. J humans remains uncertain. Neurosurg 1999;90:974–6. 29 Iacono RP, Kuniyoshi SM, Lonser RR, et al.. 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