Extra-Pyramidal Disorders

• PD is a progressive neurodegenerative disorder associated with a loss of dopaminergic nigrostriatal neurons.
• It is one of the best characterized diseases of the BG.
• It is named in honour of James Parkinson, whose monograph entitled "An essay on the Shaking Palsy", written in 1817, provided an insight into the clinical features of the disease.

• PD is the 2nd most common neurodegenerative disorder.
• It affects approximately 0.3% of the population and 1-2% of those >60 years.
• An estimated 5 million people throughout the world have the disease.
• Average age at onset is about 60 years.
• With the aging of the population and the substantial increase in the number of at-risk individuals older than 60 years, it is anticipated that the prevalence of PD will increase considerably in the coming decades.
• It is 1.5 times more common in males vs females.
• Lifetime risk of developing PD is 4.4% in males and 3.7% in females.

• Symptoms of PD result from loss of dopaminergic neurons in the nigrostriatal pathway.
• The loss of dopaminergic neurons occurs most prominently in the ventral lateral substantia nigra.
• Approximately 60-80% of dopaminergic neurons are lost before the motor signs of PD emerge.
• The major neuropathologic findings in PD are a loss of pigmented dopaminergic neurons in the substantia nigra and the presence of Lewy bodies.
• NB: Presence of Lewy bodies within pigmented neurons of the substantia nigra is characteristic, but not pathognomonic of idiopathic PD.

Neuropathologic findings

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Neuropathologic findings

• Most cases of idiopathic PD are believed to be due to a combination of genetic and environmental factors.
• At both ends of the spectrum are rare cases that appear to be due solely to one or the other.
• Double hit hypothesis: This suggests that patients might develop PD if they are exposed to a particular toxin and carry a susceptibility gene.

Genetic factors

• Approximately 5-10% of patients with PD have a familial pattern of inheritance.
• To date, linkage has been reported to 11 different genes, with several specific gene mutations having been identified.

Environmental factors

• Epidemiologic studies have suggested that a variety of environmental factors might be risk factors for developing PD.
• The most consistent findings have been:

• Rural living, and exposure to well water, pesticides, herbicides, and wood pulp mills.

Paradox!

• There is an inverse relationship between the risk of developing PD and;

1. Coffee/caffeine consumption
2. Smoking

• The mechanism of this apparent neuroprotection is not known.

Parkinsonism could be from;

1. Parkinson’s disease
2. Primary Degenerative Parkinsonism
1. PSP
2. MSA
1. Striatonigral degeneration (MSA-Parkinsonism)
2. Shy Drager syndrome
3. Oculopontocerebellar atrophy (MSA- C)
3. Corticobasal ganglionic degeneration
3. Secondary parkinsonism
1. Stroke
2. Tumor
3. CO
4. Manganese
5. Neuroleptics
6. Wilson’s disease

Benign essential tremor is also a differential diagnosis.

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History

• Parkinson disease may have a long premotor phase.
• Mid-life risk factors for the later development of Parkinson disease include constipation, anosmia, daytime sleepiness, and REM behavior disorder (RBD).
• REM behavior disorder is a sleep disorder in which there is a loss of normal atonia during REM sleep.

Motor manifestations

• Onset of motor signs in Parkinson disease is typically asymmetric, with the most common initial finding being an asymmetric resting tremor in an upper extremity.
• About 20% of patients first experience clumsiness in one hand.
• Over time, patients notice symptoms related to progressive bradykinesia, rigidity, and gait difficulty.
• Tremor usually begins in one upper extremity and initially may be intermittent.
• After several months or years, the tremor may affect the extremities on the other side, but asymmetry is usually maintained.
• Tremors may also involve the lower extremities, tongue, lips, or chin.
• The first affected arm may not swing fully when walking, and the foot on the same side may scrape the floor.
• Over time, axial posture becomes progressively flexed and strides become shorter.
• Decreased swallowing may lead to excess saliva in the mouth and ultimately drooling.
• Symptoms of autonomic dysfunction are common and include constipation, sweating abnormalities, sexual dysfunction, and seborrheic dermatitis.

Physical signs

• The 3 cardinal signs of PD are resting tremor, rigidity, and bradykinesia.
• Of these cardinal features, 2 out of 3 are required to make a clinical diagnosis and of the 2, bradykinesia must be present.
• Postural instability (balance dysfunction) is the fourth cardinal sign, but it emerges late in the disease, usually after 8 years or more.

Resting Tremor

• The characteristic PD tremor is present and most prominent with the limb at rest.
• The usual frequency is 4-6 Hz.
• The tremor may appear as a pill-rolling motion of the hand or a simple oscillation of the hand or arm.
• The same tremor may be observed with the arms outstretched (position of postural maintenance) and a less prominent, higher frequency kinetic tremor is also common.

Rigidity

• Rigidity refers to an increase in resistance to passive movement across a joint.
• The resistance can be either smooth (lead pipe) or oscillating (cogwheeling).
• Cogwheeling is thought to reflect tremor rather than rigidity and may be present with tremors not associated with an increase in tone (i.e., essential tremor).
• Rigidity is tested by flexing and extending the patient's relaxed wrist.
• It (rigidity) can be made more obvious with voluntary movement in the contralateral limb.

Bradykinesia

• This refers to slowness of movement but also includes paucity of spontaneous movements and decreased amplitude of movement.
• Bradykinesia is also expressed as;
• micrographia (small handwriting)
• hypomimia (decreased facial expression)
• decreased blink rate
• hypophonia (soft speech)

Postural instability

• Postural instability refers to imbalance and loss of righting reflexes.
• Its emergence is an important milestone, because it is poorly amenable to treatment and is a common source of disability in late disease.
• Patients may experience freezing when starting to walk (start-hesitation), during turning, or while crossing a threshold, such as going through a doorway.
• They also have propulsion and retropulsion.

• There is no specific laboratory or neuroradiological investigation for the diagnosis of PD.
• Pathological confirmation is done at post mortem.
• If secondary parkinsonism is suspected, investigation of the primary cause should be done, e.g., serum ceruloplasmin concentration is obtained as a screening test for Wilson disease.

The various forms of treatment are;

1. Medical treatment
2. Surgical treatment
3. Supportive care

MEDICAL TREATMENT

Goal of medical treatment;

• To provide control of signs and symptoms for as long as possible while minimizing adverse effects.

Symptomatic therapy

1. Levodopa + peripheral decarboxylase inhibitor (PDI): This remains the standard of symptomatic treatment for PD
• It provides the greatest antiparkinsonian benefit with the fewest adverse effects in the short term.
• However, its chronic use is associated with the development of fluctuations and dyskinesias.
• Example: Sinemet® (L-DOPA + Carbidopa).
2. Dopamine agonists (e.g., Bromocriptine, Cabergoline, Pergolide, Pramipexole, Ropinirole)
• Provide symptomatic benefit comparable to levodopa/PDI in early disease.
• They lack sufficient efficacy to control signs and symptoms by themselves in more advanced disease.
• They can be used as initial symptomatic therapy in early disease, rather than levodopa/PDI, to delay the onset of motor fluctuations and dyskinesia. This strategy is usually reserved for younger individuals (<65-70 yrs) who are cognitively intact.
3. MAO-B inhibitors:
• E.g., Selegiline and Rasagiline
• These provide mild symptomatic benefit, have excellent side effect profiles, and may improve long-term outcomes.
• When the MAO-B inhibitor alone is not sufficient to provide good control of motor symptoms, another medication (e.g., dopamine agonist or levodopa) is added.
4. Anticholinergics e.g., Trihexyphenidyl (Artane®)
• These have moderate effects on symptom control.
• Their effect may be more felt in those with younger onset, tremor-predominant PD.
• Side effects include dry mouth, constipation, somnolence, and memory impairment. Higher doses may also result in visual hallucinations.
5. Amantadine
• This has a mild antiparkinsonian effect.
• Its mechanism of action is unclear.
• Adverse effects include constipation, confusion, and hallucinations.
6. COMT inhibitors
• Entacapone
• Tolcapone

Putative neuroprotective therapy

• Neuroprotective therapies are defined as those that slow the underlying loss of dopamine neurons.
• Currently, there are no proven neuroprotective agents.
• Examples of agents that have (and are being) tried are Selegiline and Rasagiline.

SURGICAL THERAPY

Brain stimulation

• Deep Brain stimulation (DBS)
• Thalamic stimulation
• Pallidal stimulation
• Subthalamic stimulation

Lesion surgery

• This involves the destruction of targeted areas of the brain to control the symptoms of PD.
• They have largely been replaced by DBS.
• Examples are Thalamotomy, pallidotomy.

Transplantation

• Fetal nigral cells, sympathetic ganglia, carotid body glomus cells, and neuroblastoma cells, have been studied with varying results.
• Some studies have shown that gene therapy could be effective in modifying the genes involved in PD.
• The role of stem cells in the management is undergoing laboratory trials.