Tremor: normally 4-7 Hz tremor, maximal when the limb is at rest, and decreased with voluntary movement. It is typically unilateral at onset Rigidity: cogwheeel from increased tone combined with resting tremor Rapid repetitive movements cause loss of amplitude Postural instability secondary to failure of postural reflexes Gait - shuffling short teps hardly leaving ground, decreased arm swing, turning en-bloc, Festination, Freezing Speech - hypophonia, festinating speech, dysphagia and aspiration Mood - depression 20-80%, 70% anxiety Cognitive - slowed reaction time, executive dysfunction (differential allocation of attention, impulse control, set shifting, prioritizing, evaluating the salience of ambient data, interpreting social cues, and subjective time awareness), dementia 20-40% patients Sleep - daytime somnelescence Symptoms of Parkinson's disease have been known and treated since ancient times.  However, it was not formally recognized and its symptoms were not documented until 1817 in An Essay on the Shaking Palsy  by the British physician James Parkinson . Parkinson's disease was then known as paralysis agitans , the term &quot;Parkinson's disease&quot; being coined later by Jean-Martin Charcot . The underlying biochemical changes in the brain were identified in the 1950s due largely to the work of Swedish scientist Arvid Carlsson , who later went on to win a Nobel Prize . L-dopa entered clinical practice in 1967,  and the first study reporting improvements in patients with Parkinson's disease resulting from treatment with L-dopa was published in 1968.  Diagnosis - -Unified Parkinsons Disease Rating Scale
These pathways are associated with, respectively: volition and emotional responsiveness; desire, initiative, and reward; and sensory processes and maternal behavior. Disruption of dopamine along the non-striatal pathways likely explains much of the neuropsychiatric pathology associated with Parkinson's disease. The mechanism by which the brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. The alpha-synuclein -ubiquitin complex cannot be directed to the proteosome. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies . Latest research on pathogenesis of disease has shown that the death of dopaminergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles ﾑ the endoplasmic reticulum (ER) and the Golgi apparatus In recent years, a number of specific genetic mutations causing Parkinson's disease have been discovered, including in certain populations ( Contursi , Italy). These account for a small minority of cases of Parkinson's disease. Somebody who has Parkinson's disease is more likely to have relatives that also have Parkinson's disease. However, this does not mean that the disorder has been passed on genetically The toxins most strongly suspected at present are certain pesticides and transition-series metals such as manganese or iron, especially those that generate reactive oxygen species ,   and or bind to neuromelanin , as originally suggested by G.C. Cotzias.   . In the Cancer Prevention Study II Nutrition Cohort, a longitudinal investigation, individuals who were exposed to pesticides had a 70% higher incidence of PD than individuals who were not exposed  . MPTP is used as a model for Parkinson's as it can rapidly induce parkinsonian symptoms in human beings and other animals, of any age. MPTP was notorious for a string of Parkinson's disease cases in California in 1982 when it contaminated the illicit production of the synthetic opiate MPPP . Its toxicity likely comes from generation of reactive oxygen species through tyrosine hydroxylation.  Other toxin-based models employ PCBs,  paraquat  (a herbicide) in combination with maneb (a fungicide)  rotenone  (an insecticide), and specific organochlorine pesticides including dieldrin  and lindane.  Numerous studies have found an increase in Parkinson disease in persons who consume rural well water; researchers theorize that water consumption is a proxy measure of pesticide exposure. In agreement with this hypothesis are studies which have found a dose-dependent an increase in PD in persons exposed to agricultural chemicals. Head trauma Past episodes of head trauma are reported more frequently by sufferers than by others in the population.    A methodologically strong recent study  found that those who have experienced a head injury are four times more likely to develop Parkinson ﾕ s disease than those who have never suffered a head injury. The risk of developing Parkinson ﾕ s increases eightfold for patients who have had head trauma requiring hospitalization, and it increases 11-fold for patients who have experienced severe head injury. The authors comment that since head trauma is a rare event, the contribution to PD incidence is slight. They express further concern that their results may be biased by recall, i.e., the PD patients because they reflect upon the causes of their illness, may remember head trauma better than the non-ill control subjects. These limitations were overcome recently by Tanner and colleagues,  who found a similar risk of 3.8, with increasing risk associated with more severe injury and hospitalization. Drug-induced Antipsychotics , which are used to treat schizophrenia and psychosis, can induce the symptoms of Parkinson's disease (or parkinsonism) by lowering dopaminergic activity. Due to feedback inhibition, L-dopa can also eventually cause the symptoms of Parkinson's disease that it initially relieves. Dopamine agonists can also eventually contribute to Parkinson's disease symptoms by decreasing the sensitivity of dopamine receptors.
Dark arrows illustrate inhibitory connections, open excitatory connections As a result of degenerative changes in the pars compacts of substantia nigra differential changes occur in the striatopallidal projections including Increased output from the Gpi to the thalamus
BSTN are part of extrapyramidal motor system. Consisting of corpus striatum (caudate nucleus, putamen, and globus paiildus) STN, substantia nigra, red nucleus and reticular formation, Form a complex series of feedback loops which
STN and Gpi somatotopic arm and face more lateral leg medial Vim reverse true
Methods of evaluation included the UPDRS, which incorporates assessments of motor function and activities of daily living,  and a dyskinesia-rating scale.  The dyskinesia score has a range of 0 (no dyskinesia) to 4 (severe dyskinesia). The double-blind, crossover study was performed after both medication and stimulation had been discontinued overnight. The patients were randomly assigned to undergo motor assessments in one of two treatment sequences. In sequence 1, the first evaluation was performed after stimulation had remained off for two additional hours and the second was performed after stimulation had been turned on for two hours; in sequence 2, the order was reversed. The investigators and patients were unaware of whether stimulation had been on or off. Permuted-block randomization was used to ensure uniform assignment of treatments to patients within each participating center and within each target site of implantation.Unblinded base-line assessments were performed in the off-medication state (after overnight withdrawal of antiparkinsonian medication) and in the on-medication state (when the patient had his or her best response to the morning dose of antiparkinsonian medication). Unblinded postoperative evaluations were performed sequentially in four conditions (off medication, without stimulation; off medication, with stimulation; on medication, without stimulation; on medication, with stimulation). Evaluations with stimulation were performed after the stimulator had been turned on for approximately 30 minutes. Within each center, all assessments were performed by the same investigator.
134 received bilateral implants in the subthalamic nucleus or the pars interna of the globus pallidus and were included in the efficacy analysis. Nine patients did not receive bilateral implants. One hundred two patients were enrolled in the subthalamic-nucleus group. Electrodes were bilaterally implanted in 96 patients, and 91 participated in the double-blind crossover evaluation and completed six months of follow-up The results of the unblinded evaluations are provided in Table 3 . In comparison with base line, stimulation in the off-medication state was associated with significant improvement in the UPDRS motor score at each visit. Smaller, but significant, benefits were also noted with stimulation in the on-medication state. Stimulation status was significantly associated with the motor score in a repeated-measures analysis of variance (P<0.001). Significant interaction effects between medication and stimulation were observed, suggesting that stimulation and medication act synergistically in predicting motor scores. Follow-up visits did not predict motor score (P=0.58), indicating that the beneficial effect of stimulation was stable over time. Stimulation in the off-medication state was also associated with significant improvement in tremor, rigidity, bradykinesia, gait, postural stability, and activities of daily living ( Table 4 ). Home-diary assessments of the percentage of time with good mobility and without dyskinesia during the waking day increased from 27 percent to 74 percent between base line and six months (P<0.001); this was paralleled by a decrease in the percentage of time with poor mobility, from 49 percent to 19 percent (P<0.001) ( Figure 1 ). The mean (+/-SD) dyskinesia score improved from 1.9+/-1.1 at base line to 0.8+/-0.8 at six months (P<0.001). Global assessments by physicians and patients noted severe disability at base line in 74 percent and 77 percent, respectively, as compared with 15 percent and 23 percent at six months. Daily levodopa dose equivalents were reduced from a mean of 1218.8+/-575 mg at base line to 764.0+/-507 mg at six months (P<0.001).
The effects of pallidal stimulation on activities of daily living and the cardinal features of Parkinson's disease are shown in Table 4 . Significant benefits were observed, particularly in the off-medication state. Home-diary assessments indicated that between base line and six months, the percentage of time with good mobility and without dyskinesia during the waking day increased from 28 percent to 64 percent (P<0.001); the percentage of time with poor mobility was correspondingly reduced from 37 percent to 24 percent (P=0.01) ( Figure 1 ). The dyskinesia score improved from a mean of 2.1+/-1.5 at base line to 0.7+/-0.8 at six months (P<0.01). Physician and patient global estimates of severe disability improved from 76 percent and 82 percent, respectively, at base line to 11 percent and 14 percent at six months. The mean daily dose in levodopa equivalents was unchanged between base line (1090.9+/-543 mg) and six months (1120+/-537 mg).
The mechanism of action of deep-brain stimulation remains to be defined.  Possible mechanisms include depolarization blockade, release of local inhibitory neurotransmitters, antidromic activation of inhibitory neurons, and jamming of abnormal neuronal firing patterns. By whatever mechanism, stimulation mirrors the effects of a destructive lesion.In conclusion, bilateral stimulation of the subthalamic nucleus or pars interna of the globus pallidus provides significant motor benefits for patients with advanced Parkinson's disease, while reducing dyskinesia and motor fluctuations. Although we did not conduct a direct comparison, these benefits are of greater magnitude than has been achieved with thalamotomy,  unilateral pallidotomy, [11,12,30,35] thalamic stimulation, [17,36] or fetal nigral transplantation. [37,38] Serious adverse events appear to be less frequent with bilateral stimulation than with bilateral ablative procedures. [13,31] Patients were not randomly assigned to a target site of implantation, and the study was therefore not designed to compare subthalamic and pallidal stimulation. Nonetheless, subthalamic stimulation appears to be associated with a greater benefit and permitted a reduction in the consumption of levodopa or its equivalents. These observations suggest that stimulation of the subthalamic nucleus might be superior to pallidal stimulation, but further studies are required to determine whether one target is preferable to the other.
Surgical treatment of parkinsons
Surgical treatment ofParkinson’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 Parkinsons Disease Rating Scale(1) Sir William Richard Gower 1886 (1) Martinez P et al: Unified Parkinsons Disease Rating Scale characteristics and structure. The Cooperative Multicentric Group Mov 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 systems Wichmann T, Vitek JL Neuroscientist 236 (1) 1995
Dopaminergic pathways of the human brain in normal condition (left) and Parkinsons disease(right). Red Arrows indicate suppression of the target, blue arrows indicate stimulation of targetstructure.
Anatomy The STN is an ovoid nucleus that has a volume of 150-200mm3• Coronal section illustrating Sub Thalamic Nuclei
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 QuickTimeª and a TIFF (Uncompressed) decompressor are needed to see this picture. QuickTimeª and a TIFF (Uncompressed) decompressor are needed to see this picture. QuickTimeª see a are needed to and this picture.TIFF (Uncompressed) decompressor X - 2-3 mm behind mid-commisural point Y - 11-13mm lateral to inter-commisural line Z - 4-6 mm below line.
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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 Parkinsons 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 • Only 141 pts in 18 centers controlled study over 5 yrs?• Clear benefit to both • Non-standardized treatment arms localization• STN gives greater benefit & reduced L-Dopa requirement • Comparison to other vs GPi. treatments not made •No long term follow up
Further reading• Neurology Journal 55(12) Supplement - 6 Dec 2000