Lateral pallidotomy exacerbates akinesia in the Parkinsonian patient

Journal of Clinical Neuroscience (1999) 6(6), 474-476

© 1999 Harcourt Publishers Ltd

Clinical study

Lateral pallidotomy e x a c e r b a t e s akinesia in the Parkinsonian patient Lisa E. Munro-Davies 1 FRCS, Ralph Gregory 2 MRCP, Waney Squires 3 FRCPATH,Mateus Radatz 1 MD, Peter Silburn s FRACP, Richard Scott 6 PHD, Tipu Aziz 1 FRCS(SN),John F. Stein s MRCP 1Departmentof Neurosurgery 2Departmentof Neurology 3Departmentof Neuropathoiogy 4Russell-Cairns Unit, Radcliffe Infirmary, Oxford, UK 2Departmentof Neurology, Princess Alexandra Hospital, Brisbane, Australia 6University Laboratory of Physiology, Parks Road, Oxford, UK

Summary Despite the recent resurgence of interest in the use of pallidotomy for the treatment of Parkinson's disease, there remains considerable debate about the optimal lesion site. Although the current understanding of the neural mechanisms underlying Parkinsonism would suggest that the medial pallidum is the logical site for alleviation of symptoms, some surgeons still advocate lesions in the lateral pallidum. We report the case of such a lesion placement verified pathologically, which resulted in exacerbation of akinesia postoperatively. This demonstrates that accurate targeting in the pallidum is critical to avoid exacerbation of symptoms by lesioning the lateral pallidum. © 1999 Harcourt Publishers Ltd Keywords: adverse affects, pallidotomy, Parkinson's disease

INTRODUCTION

The past two decades have seen great advances in our understanding of the way in which the basal ganglia contribute to the control of movement. Many of these have come from experimental work in animals, in particular from studying primates treated with methyl phenyl tetra hydropyridine (MPTP) as a model of Parldnson's disease (PD) ]'2. These experiments have established that there are distinct 'direct' and 'indirect' pathways through the basal ganglia (Fig. 1A).3 In PD it appears that the loss of dopaminergic input to the striatum, particularly the putamen, leads to overactivity of the indirect pathway at the expense of the direct pathway, so that the motor programmes which they control are overinhibited. These programmes are generated by thalamocortical and upper brain stem circuits. In PD lack of D2 receptor inhibition of the indirect pathway from the striatum to the lateral globus pallidus (GP) disinhibits the subthalamic nucleus (STN), which therefore excites the medial pallidum to overinhibit its targets in the motor thalamus and upper brain stem (Fig. lB.). 3 At the same time lack of D1 excitation to the direct inhibitory pathway to the medial GP further disinhibits it, adding to medial GP inhibition of these targets. Thus lack of dopamine facilitates the medial pallidum in two ways to cause the akinesia of PD. 4-7 Symptom alleviation should, therefore, follow lesions of the STN or the medial pallidum. Ibotenic acid and radio-frequency lesions of the STN cause dramatic symptom reversal in the MPTP induced Parkinsonian primate. Muscimol micro-injections into the medial pallidum were also found to alleviate experimental parkinsonism.8 Empirical studies in man suggested that lesions in the posteroventral pallidum could significantly alleviate Parkinsonian signs, 9 Received 20 February 1998 Accepted 30 July 1998 Correspondence to: T.Z. Aziz, Department of Neurosurgery, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK. Tel.: +44 (0) 1865 311188; Fax: +44 (0) 1865 224898.

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but such studies did not help clarify the exact pallidal segment that was lesioned. From animal studies, it seemed logical to assume that the lesions were in the medial pallidum, and that if the lateral pallidum were deliberately lesioned, the symptoms should be worsened.I° This issue however remains unresolved. We report the case of a patient with advanced idiopathic PD, whose akinesia was exacerbated by a lateral pallidotomy. CASE REPORT

A 48-year-old right-handed male developed PD at the age of 30 years with right-sided tremor, rigidity and bradykinesia. These symptoms improved considerably on levo-dopa and he remained in active employment as an engineer. After 12 years of excellent control, he began to develop peak dose dyskinesias, early wearing off of medication, and unpredictable freezing episodes with frequent falling. In the year prior to his presentation at this unit, his condition was that of being rigid, tremulous and akinetic when 'off', and wildly dysldnetic, right more than left, when 'on'. There were no atypical signs. He was Hoehn and Yahr stage 5 when 'off' and stage 3 when 'on'. He had a total UPDRS score of 142, with grade 3-4 predominantlyright-sided dysldnesias for at least 50% of the day. His medication consisted of 400 mg of levo-dopa, 10 mg of Sergeline, 8 mg of benztropine, and 1.25 mg of pergolide per day. Apomorphine had exacerbated the dysldnesias. Detailed neuropsychological assessment revealed no significant cognitive impairment or psychiatric disorder. After counselling of the patient and his wife, he consented to a left postero-ventral pallidotomy. Surgery was performed with the patient off all medication over night, using Image Fusion and Stereoplan (Radionics Inc, Boston, MA, USA) to target the postero-ventral pallidum with coordinates of 3 mm anterior, 23 mm lateral, and 2-7 mm below the midcommissural point. Intra-operative stimulation was used to confirm the target and the lesion was made with a 2 mm diameter, 5 mm exposed tip radio-frequency electrode. There was dramatic and immediate improvement in his right-sided rigidity and tremor. On restarting his medication the right-sided dyskinesias had been

Lateral pallidotomy 475

A

B

Fig. 1 (A) A simplified diagram of normal basal ganglia function in the control of movement in which the GLU arrows are excitatory and glutamatergic, and the GABA arrows are inhibitory and GABAergic, and the DA arrow indicates the probably largely inhibitory nature of the dopaminergic nigrostriatal projections. (B) In the Parkinsonian state, decreased activity in the inhibitory dopaminergic projections leads to a selectively increased activity in the putaminolatera[ projection as indicated by the heavier arrow. This leads to disinhibition of the STN which then exerts an excessive excitatory drive to the medial pallidum (GPM)with excessive thalamic and PPN inhibition.

abolished. He was discharged home 2 days postoperatively, much improved still taking his original medication. Eight days later he was readmitted as his 'off-state' had become virtually continuous and he had taken extra levo-dopa until hallucinosis and confusion had ensued, and the left-sided dykinesias were distressing. Magnetic resonance imaging of his brain showed the lesion with no evidence of haemorrhage (Figs 2 and 3). Various therapeutic manipulations were tried, but it was only possible to induce short periods where he appeared 'on'. During these times, even with only mild bradykinesia and rigidity clinically, he felt he was subjectively 'off'. He became depressed and resentful, and difficult to manage because of behaviourai problems. His overall condition deteriorated and he had a large haemorrhage from a rectal ulcer. He was successfully resuscitated but then developed bronchopneumoniaand septicemia, and died 30 days after surgery. Consent for a postmortem examination was obtained from the family and was performed the following day.

Fig. 2 Postoperative axial MRI of patient demonstrating pallidal lesion.

Fig. 3 Postoperative coronal MRI of patient demonstrating pa[lidal lesion.

DISCUSSION POSTMORTEM

FINDINGS

General autopsy examination revealed a left pleural empyama, bilateral bronchopneumonia and pyelonephrifis. The fresh brain weighed 1551 g. After fixation the brain showed no external abnormality. Slices through the brain demonstrated a well demarcated lesion, 0.5 cm in diameter, in the left lateral globus pallidus (Fig. 4). No other macroscopic lesion was seen. Histology showed the lateral pallidal lesion to have central necrosis with a mild lymphocyte and macrophage infiltration at the edge. There was no evidence of involvement of the medial pallidum or putamen, and no degeneration in the subthalamic or pedunculopontine nucleus. In the substantia nigra the diagnosis of PD was confirmed with neuronal loss, pigmentary incontinence and occasional Lewy bodies in the remaining neurons. © 1999 Harcourt Publishers Ltd

This case is consistent with the proposed pathophysiology of Parkinson's disease as inferred from animal models. Ideally, the lesion should be placed in the medial pallidum and ansa lenficularis, and lesions confined to the lateral pallidum will exacerbate rather than improve Parkinsonism. The initial short- lived improvement in our patient's condition was probably due to oedema and a reversible de-activation of the medial pallidum as histologically it was entirely intact. By lesioning the lateral pallidum, the excessive activity of the STN would increase further and exacerbate the Parkinsonian symptoms. It is of interest to note that akinesia was exacerbated, while contralateral rigidity, tremor and dopa induced dyskinesias were alleviated. The apparent disassociation between motor bradykinesia and cognitive bradyptn-enia also deserves further comment. Although Journal of Clinical Neuroscience (1999) 6(6), 474-476

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at 2 Hz and up to 2 volts causes contralateral visual phosphenes. Having thus identified the antero-posterior and ventro-medial limits of the target, sequential lesions are made until neurological improvement is satisfactory. This is the technique we use now rather than stimulation effects alone. Using the program of Image Fusion and Stereoplan, it has become clear that proportional correction of atlas coordinates by the ratio of the atlas A C - P C distance, to that of the patient is not accurate enough for neuroanatomical localisation and further correction in the lateral dimension must be performed. We believe that this case demonstrates that accurate targeting in the pallidum is critical to avoid exacerbation of symptoms by lesioning the lateral pallidum.

ACKOWLEDGEMENTS The authors wish to acknowledge the generous support received from the Norman Collinson Foundation with respect to the work of Miss L. Munro-Davies and the Oxford Movement Disorder Group.

REFERENCES

Fig. 4 Photomicrograph of postmortem specimen demonstrating lesion in lateral patlidum, p - putamen, I - lesion in lateral pallidum, m - medial pallidum, o - optic tract, c - internal capsule.

the concept of bradyphrenia is long standing, n the existence of primary 'cognitive' slowing as distinct from motoric expression in psychometric tasks or the psychomotor retardation associated with depression, has been called into question. 12 This patient's experience of 'feeling off' may, therefore, have been secondary to his depression. Alternatively, his report of 'feeling off', despite being able to execute and coordinate movements appropriately when prompted, may have referred to a deficit in the initiation of movement, rather than its execution. We may have, therefore, observed the abulic phenomenon that has been reported following lesions of the globus pallidus.~3 The case also raises the issue of target localisation. Physiological confu'mation of the target can be performed by micro-electrode recording or by stimulation. In the medial pallidum, stimulation and observation o f functional changes are too variable to be accurate. However, the indirect effects of stimulation and impedance monitoring can help to confirm accurate lesion localisation. We have since found that stimulation at 2 Hz and 2 volts to elicit contraction of the contralateral face and hand, localises the electrode tip to the posterior half of the medial pallidum with an impedance of 500-700 ohms. As the electrode is advanced more ventro-medially, the impedance rises to 900-1100 ohms on entering the ansa lenticulafis. On stimulation at this point

Journal of Clinical Neuroscience (1999) 6(6), 474-476

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© 1999 Harcourt Publishers Ltd