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Parkinson’s Disease (PD)
is the most common degenerative movement disorder, but as of yet there is no
cure. The cardinal features of PD are bradykinesia, rigidity, tremor and
postural instability, but more recently focus has also been given to the
non-motor symptoms of the disease which include depression, psychosis and sleep
disturbances; studies have shown these have a greater significance when
assessed by quality-of-life measures, institutionalisation rates, or health
economics (Chaudri et al.,
2006). The disease is pathologically defined by ‘degeneration of the
dopaminergic neurons in the substantia nigra and development of Lewy bodies in
the residual dopaminergic neurons’ (Gazewood et al., 2013: 1), which lead to complex
brain-signalling disturbances in multiple motor and non-motor neural circuits
in the basal ganglia (Okun,
2012).

 

More on pathology of parkinsons

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Medical therapy is
advised once patients develop functional disability, and is aimed at increasing
dopamine levels in the substantia nigra. Levodopa treatment (in combination
with carbidopa to prevent the peripheral metabolism of levodopa) is the most
effective agent to reduce motor symptoms, but its early use is associated with
earlier development of dyskinesias. Dopamine therapies, including dopamine
agonists, dopamine reuptake inhibitors and MAO-B inhibitors, are less effective
at treating motor symptoms but cause less dyskinesia. These therapies are also
associated with additional unwanted side effects including sleepiness, edema,
nausea and hallucinations (Gazewood
et al., 2013). For these reasons, patients are often prescribed dopamine
agonists early in the disease progression but eventually require the more
effective symptomatic control of levodopa, and the risk of dyskinesia that comes
with it.

 

Motor complications from
levodopa can emerge as early as 5 to 6 months after treatment initiation with
doses ³600mg/day. Evidence suggests that these
complications are a result of high dosage and the non-continuous delivery of
levodopa to the brain; levodopa has a short plasma half-life of ~60-90 minutes
due to rapid metabolization in the periphery. In the early stages of the
disease, motor complications are rare as surviving dopamine neurons are able to
store the exogenous dopamine generated from levodopa, keeping dopamine levels
high enough before the next dose is administered. However, as the disease
progresses and further neurodegeneration occurs, the levodopa-buffering
capacity is lost and motor complications occur. If levodopa is continuously
infused enterally, its bioavailability is significantly increased and this is
associated with dramatic improvements in dyskinesia, but this method of
delivering the drug is impractical. Administering levodopa more regularly in
smaller doses, or combining it with carbidopa/entactpone to reduce peripheral
metabolism and increase the half-life of by up to 85% can help prevent troughs
in striatal dopamine providing more consistent delivery of levodopa to the
brain and reducing motor complications (Brooks, 2008). Nevertheless, as the disease
progresses into later stages, patients will experience more “off-time” when
disease symptoms recur and most patients will eventually develop disabling
symptoms despite optimal medical therapy, making them candidates for Deep Brain
Stimulation (DBS) (Gazewood
et al., 2013)

 

L-dopa dna methylation??

 

DBS is a neurosurgical
technique in which one or more electrodes are implanted within subcortical structures
of the brain, and are able to deliver electrical impulses to specific targets. A
lead connects the electrode to the battery-powered implanted pulse generator
(IPG), which is located subcutaneously below the clavicle, and delivers the electrical
stimuli to brain tissue in order to modulate or disrupt neural signalling within
the targeted region.

 

DBS of the thalamus
was first approved by the Food and Drug Administration (FDA) in the USA as a
treatment for tremors in 1997, and has since become a highly effective surgical
option for patients with medically refractory movement disorders, including
essential tremor, dystonia and Parkinson’s Disease, with over 100,000 patients
implanted worldwide. DBS targeting the subthalamic nucleus (STN) and global pallidus
interna (GPi) as treatment for Parkinson’s disease were approved by the FDA in
2002 and 2003 respectively, and over the past 15 years’ additional targets have
also been identified including the ventralis intermedius (VIM) nucleus and the pedunculo?pontine
nucleus (PPN) (Rezai &
Sharma, 2014).

 

Dueschl et al. (2006) conducted a
randomized controlled trial (RCT) in 156 patients with advanced PD and severe
motor symptoms, to compare the effectiveness of neurostimulation of the STN and
medical management alone over a six-month period. The primary outcome measures
were changes in the quality of life and motor function; the secondary outcome
measures included changes in a dyskinesia scale and in the activities of daily
living, as measured by the Unified Parkinson’s Disease Rating Scale, Part II
(UPDRS-II). The study concluded that neurostimulation of the STN was more
effective than medical management alone. Another RCT conducted by Weaver et al. (2009) compared
six-month outcomes in 255 patients who received DBS of the STN (n=60) or GPi
(n=134) with those who received best medical therapy (n=134).  They found DBS to be more effective than best
medical therapy in improving “on” time without troubling dyskinesias (an
average increase of 4.6 hours per day of on time), as well as an increase in
motor function and quality of life, but was associated with a significant increased
risk of serious adverse events, including those related to surgery as well as
neurobehavioral effects such as depression, confused state and anxiety. This study
also differentiated between patients younger and older than 70 years of age,
and found DBS to be a more effective treatment in both cases. Weaver et al. (2012)
investigated the 36-month outcomes of DBS targeting the GPi or STN in 159
patients, and found that the beneficial effect of DBS on motor function was
stable and comparable by target over 36 months, but improvement in motor
control, as well as quality of life, diminished over time which likely reflects
underlying disease progression. Further studies have also reached similar conclusions,
including Williams et al.
(2010) who found that at one year, surgery and best medical therapy
improved patient self-reported quality of life more than best medical therapy
alone in patients with advanced PD. Generally, levodopa-responsive symptoms,
tremor, on off fluctuations and dyskinesia are most likely to improve with DBS,
whereas impairments in gait, balance and speech are less likely to improve nd
may in some cases worsen (Okun,
2012).

 

Despite its clinical
success, the therapeutic mechanism of how DBS relieves Parkinsonian motor symptoms
remains elusive.

 

 

 

 

The targets of DBS are
in the basal ganglia and related structures, which is where most of the
degenerative change associated with PD occurs. Stimulation influences the local
brain environment, affecting the cells and fibres located closest to the
implanted electrode, and tending to inhibit the neuronal cell-bodies and excite
the axons.

 

 Astrocytes are also stimulated to release
calcium. (Okun, 2012)

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