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PostPosted: 08 Oct 2013 03:01 
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Parkinson Disease

Parkinson disease (PD) is one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years and causing progressive disability that can be slowed, but not halted, by treatment. The 2 major neuropathologic findings in Parkinson disease are loss of pigmented dopaminergic neurons of the substantia nigra pars compacta and the presence of Lewy bodies and Lewy neurites.

Essential update: Biomarkers in CSF may diagnose and predict progression of Parkinson disease
In the "Parkinson's Progression Markers Initiative" cross-sectional study of 63 drug-naive patients with early-stage PD and 39 healthy controls, the combination of the Alzheimer's biomarkers β-amyloid 1-42 (Aβ1-42), total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and α-synuclein — all measured in the CSF — were lower in the drug-naive patients than in the controls. Aβ1-42 and P-tau 181 were significant predictors of Parkinson's disease, and T-tau and α-synuclein were associated with the severity of motor dysfunction. In particular, lower Aβ1-42 and P-tau181 concentrations were associated with the postural instability–gait disturbance–dominant PD phenotype, but were not associated with the tremor-dominant or intermediatephenotypes.[1, 2]

Signs and symptoms.
Initial clinical symptoms of Parkinson disease include the following:

Tremor
Subtle decrease in dexterity
Decreased arm swing on the first-involved side
Soft voice
Decreased facial expression
Sleep disturbances
Rapid eye movement (REM) behavior disorder (RBD; a loss of normal atonia during REM sleep)
Decreased sense of smell
Symptoms of autonomic dysfunction (eg, constipation, sweating abnormalities, sexual dysfunction, seborrheic dermatitis)
A general feeling of weakness, malaise, or lassitude
Depression or anhedonia
Slowness in thinking
Onset of motor signs include the following:

Typically asymmetric
The most common initial finding is a resting tremor in an upper extremity
Over time, patients experience progressive bradykinesia, rigidity, and gait difficulty
Axial posture becomes progressively flexed and strides become shorter
Postural instability (balance impairment) is a late phenomenon
Nonmotor symptoms
Nonmotor symptoms are common in early Parkinson disease. Recognition of the combination of nonmotor and motor symptoms can promote early diagnosis and thus early intervention, which often results in a better quality of life.

Diagnosis
Parkinson disease is a clinical diagnosis. No laboratory biomarkers exist for the condition, and findings on routine magnetic resonance imaging and computed tomography scans are unremarkable.

Clinical diagnosis requires the presence of 2 of 3 cardinal signs:

Resting tremor
Rigidity
Bradykinesia

Management.

The goal of medical management of Parkinson disease is to provide control of signs and symptoms for as long as possible while minimizing adverse effects.

Symptomatic drug therapy

Usually provides good control of motor signs of Parkinson disease for 4-6 years
Levodopa/carbidopa: The gold standard of symptomatic treatment
Monoamine oxidase (MAO)–B inhibitors: Can be considered for initial treatment of early disease
Other dopamine agonists (eg, ropinirole, pramipexole): Monotherapy in early disease and adjunctive therapy in moderate to advanced disease
Anticholinergic agents (eg, trihexyphenidyl, benztropine): Second-line drugs for tremor only
Treatment for nonmotor symptoms

Sildenafil citrate (Viagra): For erectile dysfunction
Polyethylene glycol: For constipation
Modafinil: For excessive daytime somnolence
Methylphenidate: For fatigue (potential for abuse and addiction)
Deep brain stimulation

Surgical procedure of choice for Parkinson disease
Does not involve destruction of brain tissue
Reversible
Can be adjusted as the disease progresses or adverse events occur
Bilateral procedures can be performed without a significant increase in adverse events
See Treatment and Medication for more detail.

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PostPosted: 28 Oct 2013 03:03 
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Excellant summary read.
Thank you ,Raghu.

G Mohan.


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PostPosted: 12 Dec 2013 23:35 
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Hello Raghu
I am sorry I am late. I missed this excellent piece when it was published about two months ago. Thank you very much.

As you have rightly said, this is one of a few major diseases which are purely clinical entities. It is a child's play to diagnose this condition in an advanced stage. You are fortunate if you pick this malady in the initial period. So it becomes the responsibility of primary care physicians to be on the look out. We must keep in the mind that we will see only what we know. Before you physically examine, you make the diagnosis. The way he enters your room. His walk, posture and how he greets you and the way he articulates are some of the findings which will lead to you think of this entity. But if you see him only after he sits next you, you are most likely missing it. Another important clue you get when you hold his forearm. The early setting in of the so called cogwheel rigidity in the most subtle form will be perceptible to you while holding his forearm.

All over the world it is claimed that stereotactic surgery is fairly successful. It is not very common in these parts. I expect some light on the role of surgery in PD.

UA Mohammed


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PostPosted: 25 Dec 2013 12:03 
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Raghu, your very interesting article stirred me in to reading further about PD, particularly about the surgical treatment in PD, I did not realise that it is a huge topic where doctors have been spending their whole life researching in to it. It took me more than a weeks reading to have some understanding on the topic. I shall try and present it in 2 sections. In the 1st section I shall try and analyse briefly the anatomy and pathology of PD and in the 2nd section write a brief note on surgery. I hope the neurologists won't find too many faults in my presentation.


Symptoms of Parkinsons Disease:

The type and severity of symptoms vary from patient to patient and with the stage of the disease. Symptoms usually start between 50 and 60 years of age.

The most common symptoms include: Resting tremor as against essential tremor, rigid muscles that may affect the arm swing when walking and Bradykinesia (slowness of movement). Rigidity of facial muscles can cause “mask like” face with a vacant expression. Difficulty with walking (shuffling gait) and balance (postural instability). Balance and posture problems may result in frequent falls.

Tremor is often the first symptom. Initially, the tremor may appear in just one arm or leg or only on one side of the body. The tremor also may affect the chin, lips, and tongue. As the disease progresses, the tremor may spread to both sides of the body. But in some cases the tremor remains on just one side. Emotional and physical stress tend to make the tremor more noticeable. Sleep, complete relaxation, and intentional movement or action usually reduce or stop the tremor.

Pathology in Parkinson’s:

Before considering treatment we must have some knowledge of the circuits in the brain. We all know that brain is a complex structure, a super computer controlling all functions of the body. It will be many more years of research to fully understand the workings of the brain. To understand Parkinson’s disease it is necessary for us to have some basic knowledge of the complex coordinated movement that occurs in the human body. It happens through an interaction between the cerebral cortex, basal ganglia and cerebellum.

The basal ganglia and cerebellum are large collections of nuclei that modify movement continuously. Motor cortex sends information to both, and both structures send information right back to cortex via the thalamus. The output of the cerebellum is excitatory, while the basal ganglia are inhibitory. The balance between these two systems allows for smooth, coordinated movement, and a disturbance in either system will cause movement disorders.

The basal ganglia are a collection of nuclei that include caudate, putamen, nucleus accumbens, globus pallidus, substantia nigra and subthalamic nucleus. The relationships between these nuclei are complex and difficult to understand. There are many different neuraltransmitters within the basal ganglia (ACh, GABA, and dopamine) their overall effect on thalamus is inhibitory. Lesions in specific nuclei tend to produce characteristic deficits. Substantia Nigra produces dopamine. In Parkinson's disease, symptoms are caused by the slow and steady loss of dopaminergic neurons in Substantia Nigra.

Overall the basal ganglia acts as a kind of brake controlling the movements. It is either applying the brake or releasing it. A small disturbance in the pathway can throw the whole system out of balance, often in unpredictable ways. It can result in either unwanted movements or an absence or difficulty with intended movements -
tremor, rigidity, and bradykinesia. The tremor is most apparent at rest. Rigidity is a result of simultaneous contraction of flexors and extensors, which tends to lock up the limbs. Bradykinesia, or "slow movement", is a difficulty initiating voluntary movement, as though the brake cannot be released.

The cerebellum is involved in the coordination of movement through proprioceptive feedback and normally corrects the movement if there is a problem.

Tremor: Neurologists are unable to explain the exact cause for resting tremor. Clinically, tremor is seen in only three out of four patients with Parkinson's disease, and tremor-dominant patients generally follow a more benign disease course than non-tremor patients. Pathophysiologically, tremor is linked to altered activity in not one, but two distinct circuits: the basal ganglia, which are primarily affected by dopamine depletion, and the cerebello-thalamo-cortical circuit (which is also involved in many other tremors).

When the brain cannot get accurate sensory feedback about how well movements are proceeding, it can no longer effectively correct bad movements or adjust slow movements. The most complex movements, such as movements of the fingers and hands, are the first to be affected, and the most affected.

(Treatment -Surgical Options continued in the next section)


Last edited by Badri on 25 Dec 2013 12:39, edited 1 time in total.

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PostPosted: 25 Dec 2013 12:24 
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Treatment available for Parkinson's:

Drug therapy
Ablative Neurosurgery
Deep Brain Stimulation


Drug therapy
Dopaminergic Drugs: Because the loss of dopamine-producing cells is what causes the symptoms of Parkinson's, restoring dopamine levels can provide some relief. The first medication prescribed for Parkinson's will therefore be a dopaminergic drug which is converted to dopamine within the brain.

COMT inhibitors: These reduce the breakdown of dopaminergic drugs. They will therefore extend the duration and positive effects of each dopaminergic dose.

Surgical Treatment:

Surgery is not a cure for Parkinson's disease. It can reduce the amount of drugs required to control symptoms.

Ablative techniques
• Deep brain stimulation


Any surgery for Parkinson's disease is a major procedure. The risks during and immediately after surgery include infection, haemorrhage, and even death. Complications from surgery may include cognitive impairment, swallowing difficulty, visual impairment, seizures, headache and difficulty communicating.

Neuroablative lesion surgeries involve the destruction of targeted areas of the brain to control some of the symptoms of Parkinson disease (PD). They are irreversible and non-adjustable; they have largely been replaced by deep brain stimulation (DBS).

The 2 most commonly performed neuroablative procedures are thalamotomy – lesion created in ventro lateral thalamic nucleus (VL) and pallidotomy, in which lesions are created in the internal segment of the globus pallidus.

Ventrolateral thalamotomy
The VL receives afferent innervation from 2 primary sources: the GPi via the ansa lenticularis and thalamic fasciculus and the contralateral cerebellum via the superior cerebellar peduncle. These cerebellar fibers synapse primarily in the ventral intermediate (VIM) and ventral oral posterior (VOP) segments, the most posterior segments of the VL.

Oscillating excitatory input from the cerebellum may be responsible for the tremor and hence lesions placed within the VL (and specifically within the VIM or VOP) arrest parkinsonian and essential tremors.

• VL Thalamotomy:
In this procedure, a part of the thalamus, generally the VIM, is destroyed to relieve tremor. The VIM is almost unanimously considered the best target for tremor suppression, with excellent short- and long-term results in 80-90% of patients with PD. Thalamotomy has little effect on bradykinesia, rigidity, motor fluctuations, or dyskinesia. When rigidity and akinesia are prominent, other targets, including the GPi and the subthalamic nucleus (STN), are preferred.

The negative symptoms of PD (ie, rigidity and bradykinesia) are caused, in part, by excessive inhibitory output from the GPi to the VL thalamic nucleus.

• Pallidotomy:
In a pallidotomy, the surgeon destroys a tiny part of the globus pallidus. This reduces the brain activity in that area, which may help relieve the negative symptoms such as rigidity and bradykinesia. There is a higher risk of visual problems with Pallidotomy.

• Deep Brain Stimulation – DBS is now replacing Neuroablative Surgery

Deep brain stimulation (DBS) uses an implantable medical device similar to a cardiac pacemaker, which treats the main symptoms of advanced Parkinson's disease by delivering electrical stimulation to a precisely targeted area deep within the brain. It is fully reversible and helps to control the main symptoms of Parkinson's Disease.
It is most suitable for patients whose symptoms are not well controlled by drug treatment, or who cannot tolerate the side-effects of medication.

The electrical signals delivered by DBS de-activate the target site within the brain without destroying any tissue. The goal is to restore the balance of electrical activity within brain, to offset the progressive loss of cells caused by Parkinson's. The electrical signals are also adjustable, allowing more precise calibration and targeting of the effect. This can help improve the control of symptoms and reduce the risks of accidental damage to neighbouring areas.

The surgery is conducted under local, rather than general, anaesthesia, because the patient needs to provide feedback to help the neurosurgeon locate the exact target. The use of a rigid metal frame attached to the head ensures precise guidance of the instruments during surgery.

Hardware includes electrodes in the brain, a battery-powered pulse generator in the chest, and a wire connecting them under the skin

DBS requires repeated visits to the neurologist so that the electrodes can be programmed to deliver the maximum benefit to the patient.

Any type of surgery here requires precision and need to locate the area to treat accurately. With MRI and localising frames stereotactic surgery has now become more precise. Stereotactic headframe is applied at start of surgery. MRI-localizing box is attached to frame only during targeting MRI. Localizer defines working volume of frame and provides reference coordinate system from which target coordinates are derived. CT-guided stereotaxis provides direct imaging of brain parenchyma without image distortion; however, its gray-white resolution is inferior to that of MRI, and it can provide only axial imaging. MRI provides superior target resolution and triplanar imaging; however, some smaller targets may not be visualizable, and MRI is prone to image distortion. Although these distortions are usually small, they can affect targeting for functional neurosurgery.


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PostPosted: 25 Dec 2013 16:05 
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Hello Raghu,Badri,

A Masterclass in Parkinsons. Who needs textbooks!?.
Surely a reference text, and up to date.


Thank you,

G Mohan.


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PostPosted: 29 Dec 2013 12:40 
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Yes Mohan

I fully agree with you.

UA Mohammed


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PostPosted: 30 Dec 2013 11:17 
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Hi Badri,

Comprehensive and very informative, Thank you very much.

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