Surgical treatment of Parkinson’s Disease

Nick Hall

Parkinsons Disease

• 1817 - James Parkinson - “an essay on the shaking palsy”

• Movement disorder characterised by tremor, rigidity, bradykinesia & postural instability.

• Typical gait disturbances

• Mood disturbances

• Cognitive Disturbances

• Sleep, Sensory and Autonomic disturbances

• Clinical diagnosis - Unified Parkinson's Disease Rating Scale(1) Sir William Richard Gower 1886

(1) Martinez P et al: Unified Parkinson's Disease Rating Scale characteristics and structure. The Cooperative Multicentric GroupMov Disord. 1994 Jan;9(1):76-83.

Pathophysiology

• Loss of dopaminergic cells in pars compacta of substantia nigra

• Leads to alteration in activity of neural circuitry in basal ganglia:– Inhibition of direct pathway }– Excitation of indirect pathway } both nigrostriatal pathway,– lesser effects to mesocortical, mesolimbic, tuberoinfundibular pathways

• Mechanism secondary to accumulation of alpha-synuclein bound to ubiquitin, formation of Lewy bodies

• Aetiology: Idiopathic, Genetic, Toxic, Head Trauma, Drug Induced

Physiology

Conceptual model of activity in basal ganglia and associated thalamocortical systemsWichmann T, Vitek JL Neuroscientist 236 (1) 1995

Dopaminergic pathways of the human brain in normal condition (left) and Parkinson's disease (right). Red Arrows indicate suppression of the target, blue arrows indicate stimulation of target structure.

Anatomy

• Coronal section illustrating Sub Thalamic Nuclei

The STN is an ovoid nucleus that has a volume of 150-200mm3

What can we do?

Surgical localization of STN

• Historically by ventriculography and macrostimulation• Now co-registration CT and MRI together with micro-recording ie a

mixture of anatomical and physiological techniques• Anatomical:

– AC - PC line– X - Y- Z co-ordinates– MRI visualization– Track down internal capsule avoiding Globus Pallidus and Thalamus– Stereotactic frame

• Physiological:– Micro-recording and micro-stimulation electrode during passive movements– 10-20 micrometre electrode aiming to define sensorimotor region– Somatotopic arrangement

Anatomical localization

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X - 2-3 mm behind mid-commisural point

Y - 11-13mm lateral to inter-commisural line

Z - 4-6 mm below line.

Physiological localization - 1

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Physiological localization - 2

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Where to target?

• Cooper 40 yrs ago tied off anterior choroidal artery - improved tremor in Parkinson’s patient. Ischemic injury to ventralis lateralis.

• Hassler & Riechart: caudal VL for tremor, rostral VL for rigidity - further localized to ventralis intermedius nucleus (Vim)

• Long term caused akinetic rigid signs and leva-dopa induced dyskinesias

• MPTP monkey model(*) supported sectioning, intralesional glutamate injection or high frequency stimulation of STN or Gpi

• More recent studies have compared efficacy of STN vs Gpi(**)

(*) Smeyne RJ, Jackson Lewis V: The MTMP model of Parkinson’s Disease. Molecular Brain Research, 134 57-66, 2005

(**) Deep brain stimulation for Parkinsons Disease study group: Deep brain stimulation of the Sub-Thalamic Nucleus or the Pars Interna of the Globus Pallidus in treatment of Parkinson’s Disease. New Eng J Med 345(13)956-963

The Paper

• Deep-Brain Stimulation of the Subthalamic Nucleus or the Pars Interna of the Globus Pallidus in Parkinson's Disease - New Eng J Med 2001 345(13) 956-963

• Deep brain stimulation for Parkinsons Disease study Group.• Prospective, double blind, crossover STN vs. GPi• Multi-Centre collaboration. Groups 96 (STN) vs 38(GPi)bilateral

stimulators• Motor scores of UPDRS random “on-off” at 1,3 & 6 months

• Inclusion criteria: • 2 of 3 cardinal features of PD• Good response to Levadopa• UPDRS score >30• Failure to control Sx of Parkinson’s disease

• Exclusion criteria:• Psychiatric disease• Major cognitive impairment• Major medical co-morbidity

• Over 6 month period• 30-75 yrs included• Standardized electrodes but NOT insertion plans• Standardized scoring outcome measures

• UPDRS• Dyskinesia rating scale

• Blinding:– Meds off overnight then one of 2 schedules double blinded– Unblinded assessments in 4 sequences– Home diary

• 1o outcome measure difference in UPDRS motor scores

• 2o measures:

• effect of stimulation on the change between base line and six months in the UPDRS motor score in the off-medication and on-medication states

• the number of hours per day during which patients had good mobility without dyskinesia

• scores on subscales of the UPDRS (activities of daily living, tremor, rigidity, bradykinesia, gait, and postural stability), and levodopa dose equivalents

• 18 centers between July 1995 and July 1999• 143 pts total

• STN stimulation– 102 - STN, 96 bilateral, 91 completed follow up– significant treatment effect associated with stimulation (P<0.001)– Mean improvement 43%, median improvement 49% (P<0.001)

• GPi stimulators– 41 enrolled, 38 bilateral, 36 completed follow up

– evaluation performed at three months demonstrated a significant treatment effect in favor of stimulation (P<0.001)

– mean improvement of 32 percent and a median improvement of 37 percent in the UPDRS motor score (P<0.001)

• Adverse events:

Conclusions• Multicentre, double blind

controlled study• Clear benefit to both

treatment arms• STN gives greater benefit &

reduced L-Dopa requirement vs GPi.

• Only 141 pts in 18 centers over 5 yrs?

• Non-standardized localization

• Comparison to other treatments not made

•No long term follow up

Further reading

• Neurology Journal 55(12) Supplement - 6 Dec 2000