nus. Also the fact that the myoclonus presented immediately aftera single cannabis exposure would suggest a causal relation. Nev-ertheless, we have to consider the possibility of a contaminant thatwas ingested with the cannabis, but this is speculative.

Cannabinoids are known to cause sedation, hallucination,ataxia, muscle twitching and reduction in blood pressure.8These drugs act on endogenous cannabinoid receptors, locatedin the brain, spinal cord as well as the peripheral nervoussystem.9 By means of these receptors, cannabis may have atoxic effect on spinal neurons. Therefore, propriospinal myoc-lonus should be included amongst the toxic effects of cannabis,should this drug be accepted for clinical use in the future.

References

1. Chokroverty S. Propriospinal myoclonus. Clin Neurosci 1995–96;3:219–222.

2. Di Lazzaro V, Restuccia D, Nardone R, Oliviero A, Profice P, InsolaA, Tonali P, Rothwell JC. Changes in spinal cord excitability in apatient with rhythmic segmental myoclonus. J Neurol NeurosurgPsychiatry 1996;61:641–644.

3. Nogues M, Cammarota A, Sola C, Brown P. Propriospinal myoc-lonus in ischemic myelopathy secondary to a spinal dural arterio-venous fistula. Mov Disord 2000;15:355–358.

4. Brown P, Rothwell JC, Thompson PD, Marsden CD. Propriospinalmyoclonus: evidence for spinal “pattern” generators in humans.Mov Disord 1994;9:571–576.

5. Sugiyama-Oishi A, Arakawa K, Araki E, Yamada T, Tobimatsu S,Kira J. A case of chronic toluene intoxication presenting stimulus-sensitive segmental spinal myoclonus. No To Shinkei 2000;52:399–403.

6. Brown P, Thompson PD, Rothwell JC, Day BL, Marsden CD. Axialmyoclonus of propriospinal origin. Brain 1991;114:197–214.

7. Cartwright PD, Hesse C, Jackson AO. Myoclonic spasms followingintrathecal diamorphine. J Pain Symptom Manage 1993;8:492–495.

8. Campbell FA, Tramer MR, Carroll D, Reynolds DJ, Moore RA,McQuay HJ. Are cannabinoids an effective and safe treatmentoption in the management of pain? A qualitative systematic review.BMJ 2001;323:13–16.

9. Glass M, Dragunow M, Faull RL. Cannabinoid receptors in thehuman brain: a detailed anatomical and quantitative autoradio-graphic study in the fetal, neonatal and adult human brain. Neuro-science 1997;77:299–318.

Partial Lesion of Thalamic VentralIntermediate Nucleus After Chronic

High-Frequency Stimulation

Jasmine Henderson, PhD,1–3* Michael Rodriguez, FRCPA,4

Dudley O’Sullivan, FRACP,5 Malcolm Pell, FRACS,5

Victor Fung, PhD, FRACP,6

Alim Louis Benabid, MD, PhD,5,7

and Glenda Halliday, PhD2,3

1Department of Pharmacology, University of Sydney,Sydney, Australia

2Prince of Wales Medical Research Institute,Randwick, Australia

3University of New South Wales, Kensington, Australia4Department of Forensic Medicine, Central Sydney Area

Health Service, Glebe, Australia5Departments of Neurology and Neurosurgery, St. Vincent’s

Hospital, South Eastern Sydney Area Health Service,Darlinghurst, Australia

6Department of Neurology, Westmead Hospital,Westmead, Australia

7Neurosciences Department, Joseph Fourier University,Centre Hospitalier Universitaire, Grenoble, France

Abstract: A 73-year-old man with Parkinson’s disease under-went thalamic stimulation for disabling tremor with excellentresults only when stimulation on. Post-mortem neuropathology(7 years postoperatively) revealed 60% cell loss within 0.5 mmof the electrode tip. Tremor improvement was attributable tochronic stimulation, not microthalamotomy. © 2004 Move-ment Disorder Society

Key words: VIM stimulation; Parkinson’s disease

The ventral intermediate nucleus of the thalamus (VIM) hasbeen lesioned for decades for the amelioration of parkinsoniantremor1 until the advent of deep brain stimulation (DBS), whichis considered to provide limited tissue destruction.2,3 Manypatients with Parkinson’s disease (PD) have successfully re-ceived DBS for tremor, but 7 autopsy cases have been reportedwhere the patients died 1 to 5.75 years after electrode implan-tation.4,5 We report on a PD case who had successful chronicVIM DBS for 7 years. We found substantial but circumscribedneuronal loss in the vicinity of the electrode tip in this case,which did not contribute to tremor improvement.

Case Report

A 64-year-old man presented with a resting, action, andpostural tremor of the right upper limb. Cognition was

*Correspondence to: Dr. Jasmine Henderson, Department of Phar-macology, Room 211e, Bosch Building, University of Sydney, NSW2006, Australia. E-mail jasmine@med.usyd.edu.au

Received 12 June 2003; Revised 15 September 2003; Accepted 15October 2003

Published online 28 January 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mds.10709

FIG. 1. Multi-channel surface EMG recording of a propriospinal my-oclonus. Filled arrow indicates onset of jerk in the superior segment ofthe rectus abdominis muscle (SRA); empty arrow the delayed spread tosternocleidomastoid (SCM). PM, pectoralis major; IRA, inferior seg-ment of rectus abdominis; RF, rectus femoris.

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intact, neurological examination was otherwise unremark-able, and there was no family history of parkinsonism ortremor. He was diagnosed with PD and commenced onlevodopa (L-dopa) with some symptomatic improvement.Three years later he exhibited mild bradykinesia in the upperlimbs (right � left), right-sided rigidity, loss of arm swing,and hypomimia. Over the next several years, the right upperlimb tremor became severe, causing significant functionaldisability. Nine years after diagnosis, a high-frequencyquadripolar stimulation electrode (DBS 3387; Medtronic)was implanted into the left VIM. A pacemaker (Itrel 2Neuropacemaker) was implanted infraclavicularly on the leftside 5 days later.3 Initially, there was complete abolition ofthe tremor with DBS (2.5 V, 60 �sec, 135 Hz).

Two months after surgery, the tremor was evaluated in detailusing both clinical rating scales (modified Unified Parkinson’sDisease Rating Scale [UPDRS], New York University Parkin-son’s disease scale, and tremor severity ratings) and accelerom-etry. Overall, the tremor in the right upper limb was improvedmarkedly by high-frequency stimulation (from rating of 4 �severe, disabling �4-cm amplitude to 1 � slight, barely noticeablein the unmedicated state) and L-dopa dosage was halved. In theunmedicated state, there was evidence of a rebound effect in thefirst 15 minutes after stimulation was turned off; however, thetremor then decreased in amplitude toward preoperative off levels.

There was worsening of tremor in the right upper limb 6 monthsafter surgery and reprogramming the stimulation from monopolar(electrode 0) to bipolar (electrodes 0 positive and 1 negative;60–90-�sec pulse width and 170 Hz) had some benefit. Thepatient underwent further programming (3.2 V, 120 �sec, 170 Hz)1 year after surgery, after experiencing nocturnal awakenings dueto tremor, and propranolol was administered (120 mg/day) fortremor and mild hypertension. Recurrence of significant tremor onthe right 3 years postoperatively prompted replacement of a failedneuropacemaker battery. Tremor developed in the left upper limb.The stimulation was adjusted (electrode 0 negative and the casepositive, 2.5 V, 90-�sec pulse width, 145 Hz) with excellenttremor suppression on the right.

Over 5 years, VIM was stimulated for 62% of the time withstimulation at 145 Hz. By age 80 year there was almost con-tinuous, severe tremor in the left upper limb (contralateral tothe unoperated side). The patient developed severe constipationand weight loss and experienced difficulty walking, depressionand inability coping at home as well as mild cognitive impair-ment.6 He voluntarily entered a nursing home and L-dopa wasincreased (1 g/day). He developed acute confusion 4 monthslater and died of ischemic heart disease.

Neuropathology

The brain (fresh weight 1,500 g) was fixed in 20% bufferedformalin for 2 weeks. An electrode lead was noted emergingfrom the left superior frontal gyrus, which was removed afterthe position was marked with dye. There was mild bilateralfrontal atrophy. The entire cerebrum was cut coronally on arotary slicer into 3-mm sections. A 1-mm wide track extendedfrom the left superior frontal gyrus into the lateral angle of theleft frontal horn of the lateral ventricle immediately posterior tothe anterior commissure, and terminated in the ventrolateralposterior nucleus of the left thalamus at the level of the anteriorlateral geniculate nucleus (Fig. 1A). Examination of other brainregions found moderate dilatation of the lateral and third ven-tricles (Fig. 1A) and slightly enlarged temporal horns. In the

FIG. 1. A: Low power photomicrograph of hematoxylin/eosin-stainedsection through the thalamus showing the placement of the electrode tip(arrow) and microthalamotomy (asterisk). 3V, third ventricle; CM, cen-tromedian thalamic nucleus; MD, mediodorsal thalamic nucleus; VIM,ventral intermediate thalamic nucleus. B: Photomicrograph of hematoxy-lin/eosin stained section adjacent to the electrode tract (at left). Normalneurons can be seen at right (arrowheads). Remaining neurons close to theelectrode tract had abnormal morphology (arrows and inset, scale in inset25 �m). C: Photomicrograph of increased astrocytic reaction (at left ofinterrupted line) adjacent to the electrode tract (asterisk) identified usingGFAP immunohistochemistry. Cresyl violet counterstain.

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brainstem there was moderate bilateral pallor of the substantianigra, especially laterally.

Extensive tissue blocks were sampled, paraffin embedded,cut at 4 to 10 �m and stained using hematoxylin/eosin or cresylviolet/Luxol fast blue, impregnated with silver (Garvey-modi-fied Bielchowsky), or immunostained for ubiquitin (1:500,Z0458; Dako, Glostrup, Denmark), tau (1:10,000, T5530;Sigma, St. Louis, MO) and �-synuclein (1:2,000, 18-0215;Zymed, San Francisco, CA) and glial fibrillary acidic protein(GFAP) (1:3,000, Z0334; Dako). Rare, isolated neurofibrillarytangles and moderate numbers of neuritic and diffuse plaquesand �4 �-synuclein, ubiquitin-positive Lewy bodies per 200�field were noted in temporal association cortices and the hip-pocampus. In the brainstem, the substantia nigra showed mod-erate to severe depigmentation, cell loss, gliosis, Lewy body,Lewy neurite, and pale body formation. Mild neuronal loss,gliosis, and Lewy bodies were present in the locus coeruleusand dorsal motor nucleus of the vagus. The distribution anddensity of Lewy bodies were consistent with a clinicopatho-logical diagnosis of PD with late dementia.7

Microscopic examination revealed upregulated astrocytesand some hemosiderin deposition along the electrode track. Thetip and electrodes 0 and 1 were situated in the VIM (medial partof the ventrolateral posterior nucleus), close to the border of thecentromedian-parafascicular complex (Fig. 1A). Semiquantita-tive analysis was carried out on thalamic sections taken at thelevel of the electrode tip and in VIM on the unoperated side atthe same level (Fig. 1A).8 Neurons (containing nucleoli) werecounted at 200� magnification in 18 (0.49 � 0.49mm) evenly-spaced samples extending 1.5 mm each side of the electrode tipand electrode 0 (total sampled area, 4.3 mm2) and in a similarnumber of samples in the corresponding position in the con-tralateral VIM. There was approximately 60% neuronal loss(Fig. 1B) with astrocytosis (Fig. 1C) and myelin pallor within0.5 mm of the electrode tip and electrode 0 (the stimulatingelectrode). Many remaining neurons in this zone seemed py-knotic (Fig. 1C, inset); there was no significant neuronal loss0.5 to 1.5 mm from the electrode tip or electrode 0 and 1.Within 0.5 mm of electrodes 2 and 3 (not used for stimulation),there was mild gliosis and no significant neuronal loss.

Discussion

In a case of tremor-dominant PD, treated successfully for 7years with DBS of the left VIM, significant cell loss (60%)occurred around the electrode tip. Using the same quantitativeprocedures, analysis of an STN case with 4 months stimulation9

demonstrated approximately 30% neuronal loss within 0.5 mmof the electrode tract with preservation of surrounding neurons.In both cases, neuronal loss was noted adjacent to the stimu-lating (active) but not the inactive electrodes. It is possible thatneuronal loss was due to stimulation per se rather than totrauma associated with electrode insertion, as trauma wouldhave been similar in both cases whereas there was more stim-ulation over time in VIM. The absence of a microglial responsesuggests that the cell loss is long-standing rather than occurringas a terminal event. Previous case reports of chronic VIMstimulation in PD have demonstrated mild gliosis around theelectrode track without qualitative neuronal loss.4,5 Neuronalloss has been documented in the cat spinal cord,10 however, andin the thalamic centromedian-parafascicular complex in thehuman8 after chronic DBS. In the centromedian-parafascicularcomplex, chronic DBS did not provide symptomatic relief and

was associated with far greater and more widespread cell lossdue to neuronal vulnerability in this structure in PD.11

The size of the VIM lesion after DBS is much smaller (4.2mm3) than that estimated previously for successful thalamot-omy (40 mm3),1 or with centromedian-parafascicular complexDBS.8 DBS is thought to act by local inhibition of neuronalactivity.12 Our data suggest that although VIM DBS may resultin a microthalamotomy, this did not contribute to any markedimprovement in the tremor with the stimulation off. Furtherquantitative analysis of DBS electrode sites in more post-mortem cases is warranted.

Acknowledgments: We thank the patient and his family. We alsothank Mrs. H. Cartwright for work on the figure.

References

1. Hirai T, Miyazaki M, Nakajima H, Shibazaki T, Ohye C. Thecorrelation between tremor characteristics and the predicted vol-ume of effective lesions in stereotaxic nucleus ventralis interme-dius thalamotomy. Brain 1983;106:1001–1018.

2. Benabid AL, Pollak P, Louveau A, Henry S, de RougemontJ. Combined (thalamotomy and stimulation) stereotaxic surgery ofthe VIM thalamic nucleus for bilateral Parkinson disease. ApplNeurophysiol 1987;50:344–346.

3. Benabid AL, Pollak P, Gervason C, et al. Long-term suppression oftremor by chronic stimulation of the ventral intermediate thalamicnucleus. Lancet 1991;337:403–406.

4. Caparros-Lefebvre D, Ruchoux MM, Blond S, Petit H, PercheronG. Long-term thalamic stimulation in Parkinson’s disease: post-mortem anatomoclinical study. Neurology 1994;44:1856–1860.

5. Haberler C, Alesch F, Mazal PR, et al. No tissue damage bychronic deep brain stimulation in Parkinson’s disease. Ann Neurol2000;48:372–376.

6. Hughes CP, Berg L, Danzinger WL, Coben LA, Martin RL. A newclinical scale for the staging of dementia. Br J Psychiatry 1982;140:566–572.

7. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines forthe clinical and pathologic diagnosis of dementia with Lewy bodies(DLB): report of the consortium on DLB international workshop.Neurology 1996;47:1113–1124.

8. Henderson JM, O’Sullivan DJ, Pell M, Fung VS, Hely MA, MorrisJG, Halliday GM.. Lesion of thalamic centromedian-parafascicularcomplex after chronic deep brain stimulation. Neurology 2001;56:1576–1579.

9. Henderson JM, Pell M, O’Sullivan DJ, McCusker EA, Fung VSC,Hedges P, Halliday GM. Postmortem analysis of bilateral subtha-lamic electrode implants in Parkinson’s disease. Mov Disord 2002;17:133–137.

10. Woodford BJ, Carter RR, McCreery D, Bullara LA, Agnew WF.Histopathologic and physiologic effects of chronic implantation ofmicroelectrodes in sacral spinal cord of the cat. J Neuropathol ExpNeurol 1996;55:982–991.

11. Henderson JM, Carpenter K, Cartwright H, Halliday GM. Degen-eration of the centre median-parafasciular complex in Parkinson’sdisease. Ann Neurol 2000;47:345–352.

12. Benabid AL, Benazzouz A, Pollack P. Mechanisms of deep brainstimulation. Mov Disord 2002;17(Suppl.):73–74.

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