Parkinson treatment

See DBS for Parkinson disease

Issues

Motor fluctuations

Wearing off with re-emergence of worse Parkinson's symptoms
Dyskinesias

Can occur in both ON and OFF period.
Dyskinesia are sometimes mistaken for manifestations of progressive PD or confused with tremor by patients and their families, rather than recognized as reversible consequences of levodopa treatment.
Dyskinesia occurs in 30-40% of patients treated with levodopa during the first 5 years of use and nearly 60% or more by 10 years.
Management usually involves

Adjusting the levodopa doses and dosing schedule OR
Adding an additional anti-Parkinsonian medication OR
Manipulating dietary protein intake.

Simplified and schematic representation of motor complications in Parkinson’s disease in relation to disease progression

Definitions for motor complications of Dopamine treatment

ON periods

Patient experiences a positive response to medication

Peak dose Dyskinesia

Is usually choreiform in type:

Appearance of restlessness and continuous jerky,
Involuntary movements of the extremities, head, face, trunk, or respiratory muscles

Chorea, dystonia, ballism, and myoclonus.

Typically starting 30-90 min after a dose of levodopa.
Remarkably well tolerated by most patients as prefer being “on” with dyskinesia to being “off,”
Severe dyskinesia may take the form of large amplitude, ballistic movements that interfere with function and become very disturbing to patients and their families

OFF periods

Patient experiences a re-emergence of the Parkinson’s symptoms.

Dyskinesia in the “off” state is more commonly dystonic

Early morning dystonic inversion of a foot (usually on the side of greater Parkinsonian involvement) occurs as a withdrawal reaction because of the long interval without medication overnight.

Dystonia in OFF period as below

Akathisia

Diphasic dyskinesia

Uncommon form where dyskinesia peaks twice after each dose

First when patients turn “on” and again when they begin to turn “off.”
In the second phase, dyskinesia (often involving the legs) in one body part may coexist with the emergence elsewhere in the body of Parkinsonian signs such as tremor and bradykinesia

Between the fluctuation there are a few phases

Wearing off phenomenon

Re-emergence of Parkinsonian motor problems as the effect of levodopa diminishes near the end of the dose interval (i.e., usually before 4 h)

Unpredictable off periods

Transitions from being “on” to being “off” bearing no obvious relationship with the time of levodopa administration.
May be due to

Erratic absorption of levodopa from the gut
Pharmacodynamic changes in the brain

Freezing of Gait

Occurs as a transient “off” phenomenon or randomly at variable frequency in patients with advanced PD.

Patients suddenly become immobilized for seconds to minutes at a time, usually when initiating walking, in a confined space such as a doorway or a closet, or when getting on or off an elevator and may cause falls.

Random freezing is poorly responsive to anti-Parkinson’s medications and DBS

Treatment:

Possible treatment target DBS targeting pedunculopontine nucleus area being investigated

No-on phenomenon

Lack of an “on” response following a dose of levodopa.

May be due to delayed gastric motility, especially when no-on preceded by an excessively prolonged or severe “off” period

Acute akinesia

Sudden severe exacerbation of PD including an akinetic state that lasts for several days and does not respond to treatment with anti-Parkinson’s medication.

Commonly due to systemic infection or other intercurrent medical problem

Dystonia in PD can occur in the following form

Dystonia in untreated PD

Dystonia as a complication of levodopa treatment.

Dystonia due to levodopa can occur either as a peak levodopa effect or during “off” periods due to levodopa withdrawal. Withdrawal dystonia most commonly occurs in the early morning when it produces painful flexion and inversion postures of the feet and toes

Dystonia in young-onset PD

Most commonly involves the foot,
Typically taking onset as exercise-induced cramp-like discomfort, first noticed in the toes and later evolving into inversion of the affected foot, sometimes bringing the person to a halt (kinesigenic foot dystonia).

Dystonia in non-medicated patients with Parkinson’s plus syndromes (e.g., retrocollis, blepharospasm).

Akathisia

Aka motor restlessness

A form of levodopa withdrawal

Resemble restless legs syndrome, and usually occurs at night, several hours after the last dose of levodopa.

Management

Providing slow release levodopa or a dopamine agonist before retiring

Camptocormia

Is an apparently fixed truncal flexion deformity that disappears in recumbent position

Medical management

General

Drugs may improve symptoms, but do not alter the natural course of the disease.

Should be given start when a patient becomes functionally impaired

Use the UPDRS to assess disability.

Current opinion is divided about when to start therapy with levodopa-carbidopa.

Delay starting benefits:

Minimize the risks of motor complications
Theoretical progression of disease by oxidant radical formation from the metabolism of levodopa.
Most specialists delay

Giving less potent medications a trial first, especially in younger patients.

Goal

Restore normal dopamine
dec. ACh activity at muscarinic receptors in the striatum

PD Pathology: degeneration of nigrostriatal dopamine tracts with imbalance between dopamine (dec.) and ACh (inc.)

1st line drug

Levodopa-carbidopa

First-choice medication for most elderly patients
Almost universally effective.
Combination therapy begins with the addition of a COMT inhibitor to levodopa-carbidopa.

2nd line

Dopamine agonists + levodopa-carbidopa
Parkinson’s related depression is the most common nonmotor symptom in Parkinson’s disease, affecting 40% of patients.

Drugs increasing dopamine function

Levodopa

Prodrug converted to dopamine by aromatic amino acid decarboxylase (AA)
Usually given with carbidopa
Side effects:

Dyskinesias
"On-off" effects

'On' time is when levodopa is working well and your symptoms are controlled.
'Off' time is when levodopa is no longer working well and symptoms such as tremor, rigidity and slow movement re-emerge.
Due to

Sudden desensitization block of dopamine receptors, due to some conformational change of the receptor protein

Psychosis
Hypotension
Vomiting

What pitfall must be avoided in treating a patient with Parkinson disease and malignant melanoma?

Levodopa should not be given because dopamine is a precursor of melanin; giving levodopa may stimulate tumor growth.

Drugs that prevent breakdown of Dopamine

Carbidopa

Inhibits aromatic L-amino-acid decarboxylase (DOPA decarboxylase or DDC) → inhibit peripheral metabolism of levodopa

Tolcapone and entacapone

COMT (catechol-O-methyltransferase) inhibitors → enhance levodopa uptake and efficacy.

COMT converts L-dopa to 3-0-methyldopa, a partial agonist at dopamine receptors.

Can reduce on and off effects
Tolcapone is hepatotoxic.

Selegiline

MAOB-selective inhibitor (no tyramine interactions)
Initial treatment and adjunct to levodopa
Side effects:

Dyskinesias
Psychosis
Insomnia (metabolized to amphetamine)

Dopamine-receptor agonists

Bromocriptine

Use: hyperprolactinemia and acromegaly
Side effects:

Psychosis
Extrapyramidal dysfunction

Akathisia ( inability to remain still.)
Acute dystonic reaction
Dyskinesias

Endocrine dysfunction such as prolactinemia

Pramipexole and ropinirole

Drugs decreasing ACh function

Muscarinic blockers

Include

Benztropine
Trihexyphenidyl

An anticholinergic drug which is used to manage chorea, dystonia and dyskinesias (by correcting the imbalance between dopamine and acetylcholine in the basal ganglia).

Diphenhydramine,

Actions:

dec. tremor and rigidity
Have little effects on bradykinesia

Side effects:

Atropine-like

Procyclidine is an anticholinergic (same class as atropine, benztropine) drug principally used for the treatment of drug-induced parkinsonism, akathisia and acute dystonia;

Amantadine

Antiviral
Mechanism

Block muscarinic receptors
Inc. dopamine release
NMDA antagonist

Side effects: atropine-like and livedo reticularis

Summary

Drug Class	Example	Role
MAOI-B	Selegiline, Rasagiline	May have neuroprotective effect hence given early in disease. Selegiline blocks free radical formation during dopamine oxidation
Levodopa	Levodopa-carbidopa	Usually first line in elderly patients; can lead to motor complications with prolonged treatment. Conversion of l-dopa to dopamine occurs outside the CNS in a wide variety of tissues, but once converted to dopamine in the periphery, the drug becomes inaccessible to the brain. Peripheral conversion of l-dopa to dopamine is routinely inhibited by adding a dopa decarboxylase inhibitor (carbidopa). Because it cannot cross the blood-brain barrier, carbidopa cannot inhibit the conversion of l-dopa to dopamine in the brain
Dopamine agonists	Pramipexole, Ropinirole, Rotigotine (transdermal)	Usually first line in young patients (early onset PD). For elderly patients, dopamine agonists are often a second-line option. The effects of these agents are independent of degenerating dopaminergic neurons. Therefore, the use of dopamine agonists may avoid problems associated with levodopa-carbidopa. The dopamine agonists do not, however, improve all types of symptoms and have specific dopaminergic adverse effects. Rotigotine is a dopamine agonist that is administered transdermally and offers continuous dopaminergic stimulation. It is approved by the FDA for early-stage idiopathic Parkinson’s disease
ㅤ	Apomorphine	For the treatment of acute, intermittent hypomobility and “off” episodes
NMDA antagonist	Amantadine	Potentiates dopaminergic response with a mild anticholinergic effect and can be used for early Parkinsonism, as well as for reduction of levodopa-induced dyskinesias associated with later-stage Parkinson’s disease
Anticholinergic	Benztropine	Treatment of isolated tremor
COMT inhibitor	Entacapone	Reduce motor fluctuation by extending the duration of action of levodopa pa-carbidopa, thus having a dose-sparing effect and reducing “off-time”
Antidepressant	SSRI and TCA	TCAs are contraindicated in patients taking MAOI
Cholinesterase inhibitor	Rivastigmine	Treatment of mild to moderate dementia includes improved cognition and activities of daily living in about 15% of patients

Complex therapies for PD

None are better than the other due to

Lack of head to head studies
Decision is usually based on patient preference or other symptoms that may exclude them from one therapy (eg cognitive), or ease of access

Subcutaneous apomorphine pen/pump

General

Only dopamine analogue with an equivalent efficacy to levodopa

NICE:

Apomorphine should be considered as part of ‘best medical therapy’ before options that involve surgical interventions, such as DBS and gastro-jejunostomy used to deliver levodopa infusion

Evidence

Katzenschlager 2018

First randomized, placebo-controlled, double-blind, multicentre trial
Apomorphine vs placebo in PD patients with persistent motor fluctuations despite optimized oral/transdermal medication
Outcome

Clinically meaningful OFF-time reduction
Increase in ‘good quality’ ON time.
These outcomes were sustained at even 1 year

1	Initiation setting	Can be undertaken in a hospital outpatient or day-case setting, usually over 5–10 days. Subsequent adaptations may take several weeks, especially if several oral drugs are reduced in a step-wise manner.
2	Anti-emetic medication	Should be administered according to local guidelines, if available. ECG monitoring, for the QTc interval, is recommended prior to and during the initiation of domperidone. It is recommended to commence the anti-emetic domperidone at least 2 days prior to initiating apomorphine, at a dose of 10 mg three times/day. Due to the risk of QTc prolongation, domperidone should be used at the lowest effective dose and for the shortest possible duration.
3	Establishing a stable apomorphine dose	Starting dose: a starting dose of up to 1 mg/hour on day 1, with daily rate increases of 0.5–1 mg/hour, until the patient is stabilized on an effective, tolerated dose with individually adjusted concomitant oral medication. Each patient’s stable apomorphine dose will depend on individual efficacy and tolerability.
4	Reducing or discontinuing concomitant anti-PD medications	Patients treated with apomorphine continuous infusion can substantially reduce their concomitant oral PD medication, and in some cases discontinue them. This is a specific treatment goal in patients with troublesome dyskinesias. Once a patient is established on apomorphine, the suggested procedure is to reduce oral PD medications in the following order: • Dopamine agonists • Monoamine oxidase type B (MAOB) inhibitors • Catechol-O-methyl transferase (COMT) inhibitors • Oral levodopa dose, then frequency
5	Infusion hours	Usually during daytime, i.e., around 16 h/day. In patients with troublesome nocturnal OFF symptoms, 24-h use may helpful.
6	Bolus dose function	Provides flexibility to give additional medication if needed but without increasing the overall dose per hour. Frequent use of the bolus dose function suggests that the hourly flow rate may need to be increased.

Close-up of a person's stomach with an infusion needle AI-generated content may be incorrect.

Maintain patients in the ON state while minimizing dyskinesia

Side effect

Nausea: treatment with Domperidone

Intestinal gel

Duodopa

Via Jejunostomy
Done as there is Gut paralysis in PD

Levodopa
Carbidopa

Indication

Usually not done earlier than 5 years post symptom onset
In patients who have

Refractory motor complications
Or severe refractory tremor

In people who are otherwise medically well

Pros

DBS may be better at reducing dyskinesia and has best evidence for longevity
Price — highest lifetime cost for duodopa>DBS>apomorphine

Overall costs are offset by less disability and nursing home placement

Aim of the selection process for DBS

No evidence of significant cognitive vulnerabilities (as can decompensate post-op, and will have reduced verbal fluency post-op)
No severe neuropsychiatric problems

Depression/anxiety can worsen
Impulse control disorders are an exception and may improve with reduction in PD meds

Lack of axial symptoms
Appropriate expectations
Good levodopa response

When we should consider DBS for parkinson's?

Aim of DBS

DBS unlikely to improve symptoms beyond "current best" (apart from severe dyskinesia and medication-resistant tremor)
Most patients are able to reduce PD drugs post-surgery
DBS aims to

Reduce OFF time
Increase ON time / reduce ON with troublesome dyskinesia
Improve Quality of life / Activities of Daily Living

Pre op work up

MRI under General Anesthetic
Neuropsychology assessment (mood and cognition and expectations)
Levodopa Challenge Test (>30-40% improvement predicts a good DBS response)

Complications

Risks of general anesthesia
Risks of surgical procedure

Hemorrhage
Infection

DBS system risks

Technical device failure
Movement/ snapping of wires

DBS side effects depend on target nucleus

STN:

Pins and needles
Double vision, slurred speech, dizziness
Increased dyskinesias
Weight gain
Gait and balance difficulties
Psychiatric

Depression, psychosis, suicidality

Deterioration in some aspects of cognition such as verbal fluency

Lesioning

Cannot be done for STN can lead to hemiballismus

Pallidotomy

Indication

For End stage PD not suitable for DBS

Thalamotomy and thalamic VIM stimulation have only a small role in current PD tremor management because GPi and STN stimulation provides better control of symptoms other than tremor (hence even patients who are tremor dominant will develop other symptoms with time which will not benefit from thalamic stimulation).