Parkinson's Disease (PD)

Primer

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by a loss of dopaminergic innervation in the basal ganglia leading to motor and non-motor symptoms. Although historically considered a motor disorder, there are many neuropsychiatric symptoms associated with the disease, and the majority of diagnoses will progress to Parkinsons's Disease Dementia (PDD).

Epidemiology

Parkinson's disease affects 1 to 2% of individuals over 60 years of age.
PD is more common in men than women (1.4:1 ratio).
It is uncommon among in those younger than age 50 years and increases in prevalence with age, with a peak between ages 85 and 89 years.^[1]

Prognosis

Parkinson's disease has different variants with different prognoses.
- Individuals with the diffuse malignant subtype (between 10-15%) have prominent early motor and non-motor symptoms, poor response to medication, and fast disease progression.
- Individuals with mild motor-predominant PD (approximately 50%) have mild symptoms, a good response to dopaminergic medications, and slower disease progression.
Most individuals with PD die from the same causes as individuals without Parkinson disease. However, some may die from PD–related causes, such as aspiration pneumonia or complications (e.g. - fractures) from a fall.

Comorbidity

The most common comorbidities for the PD patients include cerebrovascular disease, hypertension, diabetes, and chronic pulmonary diseases.^[2]

Risk Factors

Major gene mutations cause only a small proportion of all PD cases, and in the majority of cases, non-genetic factors play a part, in interaction with susceptibility genes.
Pesticide, herbicide, and heavy metal exposures are linked to an increased risk for PD, whereas smoking and caffeine use are associated with decreased risk.^[3]

Diagnostic Criteria

To diagnose Parkinson's Disease, the patient must present first with features of parkinsonism. However, this only means the have parkinsonism, and not Parkinson's Disease itself (for example they could have other neurodegnerative disorders such as progressive supranuclear palsy [PSP] or multisystem atrophy [MSA]). In order for Parkinson's Disease to be confirmed, at the vey least there needs to be an improvement/resolution of symptoms when patients are put on a trial of Sinemet (carbidopa-levodopa). The latest diagnostic criteria is based on the 2015 Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease.^[4]

If the patient meets the absolute exclusion criteria, this immediately argues against the diagnosis of PD.

Diagnostic Criteria for PD

Postuma, Ronald B., et al. MDS clinical diagnostic criteria for Parkinson's disease. Movement Disorders 30.12 (2015): 1591-1601.

Essential Criterion
Must have parkinsonism, which is deﬁned as bradykinesia, in combination with at least `1` of rest tremor or rigidity. Examination of all cardinal manifestations should be carried out as described in the MDS–Uniﬁed Parkinson Disease Rating Scale
Clinically established PD requires
1. Absence of absolute exclusion criteria 2. At least two supportive criteria 3. No red flags
Clinically probable PD requires
1. Absence of absolute exclusion criteria 2. Presence of red flags counterbalanced by supportive criteria (i.e. - if one red flag is present there must also be at least one supportive criterion; if two red flags, at least two supportive criteria are needed. If there are more than two red flags, clinically probable PD cannot be diagnosed).

Supportive Criteria for PD

Supportive Criteria
1. Clear and dramatic beneficial response to dopaminergic therapy. During initial treatment, patient returned to normal or near-normal level of function. 2. Presence of levodopa-induced dyskinesia 3. Resting tremor of a limb, documented on clinical examination (in past, or on current examination) 4. The presence of either olfactory loss or cardiac sympathetic denervation on MIBG scintigraphy

Mnemonic

The mnemonic TRAP can be used to remember the physical symptoms of Parkinson's

T - Tremor
R - Rigidity
A - Akinesia (lack of, or slow movement)
P - Postural instability

Absolute Exclusion Criteria

The presence of any of these features rules out PD
1. Unequivocal cerebellar abnormalities, such as cerebellar gait, limb ataxia, or cerebellar oculomotor abnormalities (e.g. - sustained gaze evoked nystagmus, macro square wave jerks, hypermetric saccades) 2. Downward vertical supranuclear gaze palsy, or selective slowing of downward vertical saccades 3. Diagnosis of probable behavioral variant frontotemporal dementia or primary progressive aphasia, defined according to consensus criteria within the first 5 years of disease 4. Parkinsonian features restricted to the lower limbs for more than 3 years 5. Treatment with a dopamine receptor blocker (e.g. - antipsychotic) or a dopamine-depleting agent in a dose and time-course consistent with drug-induced parkinsonism 6. Absence of observable response to high-dose levodopa despite at least moderate severity of disease 7. Unequivocal cortical sensory loss (i.e. - graphesthesia, stereognosis with intact primary sensory modalities), clear limb ideomotor apraxia, or progressive aphasia 8. Normal functional neuroimaging of the presynaptic dopaminergic system 9. Documentation of an alternative condition known to produce parkinsonism and plausibly connected to the patient’s symptoms, or, the expert evaluating physician, based on the full diagnostic assessment feels that an alternative syndrome is more likely than PD

The presence of any of these features rules out PD

1. Unequivocal cerebellar abnormalities, such as cerebellar gait, limb ataxia, or cerebellar oculomotor abnormalities (e.g. - sustained gaze evoked nystagmus, macro square wave jerks, hypermetric saccades)

2. Downward vertical supranuclear gaze palsy, or selective slowing of downward vertical saccades

3. Diagnosis of probable behavioral variant frontotemporal dementia or primary progressive aphasia, defined according to consensus criteria within the first 5 years of disease

4. Parkinsonian features restricted to the lower limbs for more than 3 years

5. Treatment with a dopamine receptor blocker (e.g. - antipsychotic) or a dopamine-depleting agent in a dose and time-course consistent with drug-induced parkinsonism

6. Absence of observable response to high-dose levodopa despite at least moderate severity of disease

7. Unequivocal cortical sensory loss (i.e. - graphesthesia, stereognosis with intact primary sensory modalities), clear limb ideomotor apraxia, or progressive aphasia

8. Normal functional neuroimaging of the presynaptic dopaminergic system

9. Documentation of an alternative condition known to produce parkinsonism and plausibly connected to the patient’s symptoms, or, the expert evaluating physician, based on the full diagnostic assessment feels that an alternative syndrome is more likely than PD

Red Flags

Red flags rule out probable PD diagnosis only when they cannot be counterbalanced by supportive criteria.
1. Rapid progression of gait impairment requiring regular use of wheelchair within 5 years of onset 2. A complete absence of progression of motor symptoms or signs over 5 or more years unless stability is related to treatment 3. Early bulbar dysfunction: severe dysphonia or dysarthria (speech unintelligible most of the time) or severe dysphagia (requiring soft food, NG tube, or gastrostomy feeding) within first 5 years 4. Inspiratory respiratory dysfunction: either diurnal or nocturnal inspiratory stridor or frequent inspiratory sighs 5. Severe autonomic failure in the first 5 y of disease. 6. Recurrent (> 1 per year) falls because of impaired balance within 3 years of onset 7. Disproportionate anterocollis (dystonic) or contractures of hand or feet within the first 10 years 8. Absence of any of the common nonmotor features of disease despite 5 years of disease duration. These include sleep dysfunction (sleep-maintenance insomnia, excessive daytime somnolence, symptoms of REM sleep behavior disorder), autonomic dysfunction (constipation, daytime urinary urgency, symptomatic orthostasis), hyposmia, or psychiatric dysfunction (depression, anxiety, or hallucinations) 9. Otherwise-unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic hyperreflexia (excluding mild reflex asymmetry and isolated extensor plantar response) 10. Bilateral symmetric parkinsonism. The patient or caregiver reports bilateral symptom onset with no side predominance, and no side predominance is observed on objective examination

Red flags rule out probable PD diagnosis only when they cannot be counterbalanced by supportive criteria.

1. Rapid progression of gait impairment requiring regular use of wheelchair within 5 years of onset

2. A complete absence of progression of motor symptoms or signs over 5 or more years unless stability is related to treatment

3. Early bulbar dysfunction: severe dysphonia or dysarthria (speech unintelligible most of the time) or severe dysphagia (requiring soft food, NG tube, or gastrostomy feeding) within first 5 years

4. Inspiratory respiratory dysfunction: either diurnal or nocturnal inspiratory stridor or frequent inspiratory sighs

5. Severe autonomic failure in the first 5 y of disease.

6. Recurrent (> 1 per year) falls because of impaired balance within 3 years of onset

7. Disproportionate anterocollis (dystonic) or contractures of hand or feet within the first 10 years

8. Absence of any of the common nonmotor features of disease despite 5 years of disease duration. These include sleep dysfunction (sleep-maintenance insomnia, excessive daytime somnolence, symptoms of REM sleep behavior disorder), autonomic dysfunction (constipation, daytime urinary urgency, symptomatic orthostasis), hyposmia, or psychiatric dysfunction (depression, anxiety, or hallucinations)

9. Otherwise-unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic hyperreflexia (excluding mild reflex asymmetry and
isolated extensor plantar response)

10. Bilateral symmetric parkinsonism. The patient or caregiver reports bilateral symptom onset with no side predominance, and no side predominance is observed on objective examination

Signs and Symptoms

Prodrome

Often, patients may have prodromal symptoms that occur decades before the classic symptoms present. The most common being REM sleep behaviour disorder (RBD), autonomic dysfunction, obstructive sleep apnea, and late onset depression.
Loss of smell (hyposmia) can be an early sign of PD as well.^[5]
Early signs of Parkinson's may include:^[6]
- Visual illusions (misinterpretations of a real external stimulus )
- A “sense of presence” (a vivid sensation that somebody is present nearby, when no one is there and no one is seen)
- Passage hallucinations (brief visions of a person or an animal passing sideways)

Motor

The classic motor features of PD include rigidity, asymmetric resting tremors, bradykinesia, shuffling gait (festination, falls, block turn, freezing), and postural instability. In addition, patients may develop hypophonia (soft/hoarse voice), dysphagia, and drooling, micrographia, and seborrhea. As the disease progresses, patients may developing orthostatic hypotension due to progressive destruction of dopaminergic neurons.
Patients may also report a general “slowing down” of their day-to-day movements, and have difficulty getting or rolling out of bed in the mornings. Frozen shoulder, either on one or both sides, can also be an early sign of Parkinson's.^[7]

Anxiety

Anxiety is a common non-motor comorbidity in Parkinson’s disease that contributes to reductions in quality of life, higher levels of care dependency and increased caregiver distress. A combination of medical, neurochemical and psychosocial phenomena contribute to anxiety in Parkinson's.
The degeneration of subcortical nuclei and ascending dopamine, norepinephrine and serotonin pathways within the basal ganglia–frontal circuits may be responsible for symptoms of anxiety.^[8]
There are a few studies on treatment of anxiety in Parkinson's. SSRIs and SNRIS in particular have been used, with citalopram having the most evidence.

Psychosis

See also: Fernandez, H. H. et al. (2005). Rebound psychosis: effect of discontinuation of antipsychotics in Parkinson's disease. Movement disorders: official journal of the Movement Disorder Society, 20(1), 104-105.

Psychotic symptoms in Parkinson's disease (PD) are relatively common.
- PD psychosis has unique clinical features, in that patients are usually aware and have insight.
- Parkinson's psychosis is a poor prognostic factor, and there is a higher risk for weight loss, caregiver burden, placement, and death.^[9]
The use of Parkinson's medications (particularly dopamine receptor agonists) has been the most widely identified risk factor for psychosis. The psychosis most commonly involves visual hallucinations, which progresses over time. Other symptoms may include auditory hallucinations, delusions, and illusions.
Clozapine is the most effective treatment for Parkinson's-related psychosis,^[10] and should be used if patients can tolerate the required blood monitoring.
There is actually limited positive evidence for the use of quetiapine in Parkinson's-related psychosis.^[11] However, it is often clinically used due to the lack of need for regular bloodwork.
Anticholinesterase inhibitors are the first line of treatment of psychosis, with rivastigmine having the most evidence, followed by donepezil.^[12]
More recently, pimavanserin was approved for the treatment of PD psychosis in the USA.

Dementia

See main article: Parkinsons's Disease Dementia (PDD)

Though not present in early stages, the majority of patients with Parkinson's Disease will have cognitive impairment and subsequently develop dementia.

Scales

Parkinson's Rating Scales

Name	Rater	Description	Download
Unified Parkinson's Disease Rating Scale (UPDRS)	Clinician	The UPDRS is a comprehensive 50 question assessment of both motor and non-motor symptoms associated with Parkinson's	Download

Pathophysiology

The exact pathogenesis of Parkinson’s disease is not known. At the most basic level, Parkinsonism is due to loss the of dopaminergic neurons and excess cholinergic activity.
The disease may have multiple causes, including both genetic and sporadic causes. The motor impairments of the disease are due to selective loss of pigmented midbrain neurons in the substantia nigra pars compacta. These neurons project to the putamen and caudate (the striatum), where dopamine is released. When more than half the dopaminergic nerve terminals in the striatum are lost, Parkinsonian symptoms begin to emerge.

Differential Diagnosis

Many neurodegenerative disorders are on the differential diagnosis. These disorders may first present with neuropsychiatric symptoms, and patients may see a psychiatrist before any other specialist. A differential diagnosis for Parkinson's includes:

Vascular Parkinsonism (VP)
- This is a parkinsonian disorder temporally-related or associated with ischemic cerebrovascular disease, individuals will have the same symptoms as idiopathic PD, such as muscle stiffness, bradykinesia, and balance problems
- Generally, vascular parkinsonism has a poor response to L-dopa treatment compared to idiopathic PD^[13]
Dementia with Lewy Bodies (DLB)
Wilson's Disease
Progressive Supranuclear Palsy (PSP)
- First signs include early falls and swallowing difficulties
- Later, look for saccadic breakdown, downgaze palsy > upgaze vertical palsy, axial rigidity (in PD, this only happens in severe stages)
- “Surprised look” on face
Corticobasal Degeneration (CBD)
- Apraxia, aphasia, neglect, dystonia, and other cortical features, and striking asymmetry
Huntington's disease
Normal pressure hydrocephalus
- NPH may exhibit a classic triad of clinical findings (known as the Adams/Hakim's triad) of urinary incontinence, gait disturbance, and dementia (commonly referred to as “wet, wacky and wobbly” or “weird walking water”)
Tremor syndrome unrelated to Parkinson's
Substance use disorders (e.g. - alcohol withdrawal)
Brain lesions or mass effects
Medication-induced parkinsonism (i.e. - extrapyramidal symptoms)
- In these cases of potential confounding effects from medications such as antipsychotics, the clinician should try to elicit a clear history if the Parkinsonian symptoms developed before or after the initiation of antipsychotics.

Atypical Parkinson's

Don't forget that there are atypical features in some Parkinson's patients, including:

Symmetry at on set
Lack of resting tremor
Dysautonomia such as urinary symptoms, retention, and erectile dysfunction
Poor response to levodopa (some patients may need to hit 900mg/day of carbidopa/levodopa before their symptoms resolve)

How do we determine whether parkinsonism is due to the use of antipsychotics or Parkinson disease?

It could be both! Especially in the case in geriatric populations. If older patients have been receiving antipsychotics and develop parkinsonism, these patients may have been developing idiopathic Parkinson disease and the psychiatric symptoms may have been related. It is not always easy to tell the difference between the disease and its adverse effects. The first thing to do, if possible, is to stop the antipsychotic agent and wait 1 to 3 months to see if the symptoms resolve. In most cases, patients with parkinsonism will have a tremor of one or both hands. If it is unilateral, a resting tremor suggests idiopathic Parkinson disease, but if it is symmetric, it is difficult to determine whether it is idiopathic or medication-induced.

Physical Exam

Observe for reduced facial and limb expressions and gestures (e.g. - decreased smiling and decreased affect)
- PD patients will have fewer eye blinks and a tendency to stare

Neurological Exam

See main article: The Neurological Exam

See also: Stanford 25: Approach to the Exam for Parkinson's Disease

On examination, there may be mask facies, decreased eye blink rate, or flattened nasolabial folds.^[14]
Anosmia (loss of sense of smell) is a common non-motor feature of Parkinson's
Check for primitive reflexes
Motor Exam
- Check for axial rigidity
- Check for decreased amplitude or fatiguability (meaning the patient can start with fast movements, but then the movements slow down considerably)
- Check for toe tapping (the most sensitive exam for picking up bradykinesia) and finger tapping, look at both the speed and amplitude of these movements
- Check for slowness (bradykinesia) in upper and lower limbs
- Check for slowness in upper and lower gaze on the extra-ocular exam

Medications and the Physical Exam

When assessing for Parkinsonian features, it is important to know if an individual has been on antipsychotics, and if there is any recent dopaminergic medication use.

Gait Assessment and Special Tests

See also: The Neurological Exam: Gait Exam

Observe for normal arm swing - a lack of normal swinging on one or both sides is consistent with parkinsonism
Festination - a gait disturbance characterized by short rapid steps
“Chair Test”
- Get the patient to stand up from a chair without using their arms
“Pull Test” (Retropulsion)
- With the patient standing, the examiner stands behind the patient (with a wall behind the examiner!), put hands on the patient’s shoulders, and say “At the count of three, I’m going to pull you back a little.”
- On a normal exam: the patient will take a step or two back or bend the shoulders backwards to keep maintain balance when pulled back.
- In a Parkinson's patient: the patient will either take many steps backwards (“retropulsion”), or fall over like a statue (“falling en bloc”).

Tremor

See main article: Approach to Tremors

Remember that cogwheel rigidity is a tremor that is superimposed on the rigidity from Parkinson's
Check for cogwheeling (rotate the wrists) bilaterally
- In patients with a unilateral tremor, that same wrist will have rigidity, while the other one will not.
- Use activation techniques (tell your patient to “open and close your (contralateral) hand” and then examine the ipsilateral side for rigidity and cogwheeling)
Check for hidden tremors using distraction techniques (ask patient to count the months backwards, or subtracting numbers - this can often bring out resting tremors)
Is there any reemergence of tremor when someone goes from resting their hands on their palms to moving it forward with hands facing forward in a pronator drift position?

Writing and Drawing

See also: Alty, J. et al. (2017). How to use pen and paper tasks to aid tremor diagnosis in the clinic. Practical Neurology, 17(6), 456-463.

Pen and paper tasks including handwriting, Archimedes spirals, and line drawings are easy to perform tasks that can provide objective evidence of abnormal neurological signs and can help in the differential diagnosis of a tremor.

Treatment

Levodopa

See main article: Carbidopa-Levodopa (Sinemet)

The main treatment for PD is levodopa, a dopamine precursor (since dopamine itself cannot cross the blood–brain barrier). When taken orally, levodopa is rapidly converted to dopamine outside the CNS. Thus carbidopa, a DOPA decarboxylase inhibitor (DDCI), is added to inhibit the conversion of levodopa to dopamine outside the CNS.
Dietary considerations are important when taking levodopa – levodopa is a protein building block, so it also competes for absorption with other proteins.
- Taking levodopa with high-protein meals (e.g. - meat and fish) may reduce how much levodopa gets into the system and how well it works.

Mnemonic

The mnemonic BALSA can be used to remember the common treatments used in Parkinson's

B - Bromocriptine
A - Amantadine
L - Levodopa (with carbidopa)
S - Selegiline (and COMT inhibitors)
A - Antimuscarinics (benztropine, trihexyphenidyl)

Parkinson's Treatment Strategy and Mechanism

Strategy	Medication	Notes
Dopamine agonists	Dopamine agonists (bromocriptine, pramipexole, ropinirole)	-
Increase dopamine availability	Amantadine	Increases dopamine release and decreases dopamine reuptake
Increased L-dopa availability	Levodopa, entacapone, tolcapone	These agents prevent peripheral (pre-BBB) L-Dopa degradation and increases central L-Dopa available for conversion to dopamine. Entacapone and tolcapone prevent peripheral L-Dopa degradation by inhibiting COMT. Used in conjunction with levodopa.
Prevent dopamine breakdown	Selegiline, rasagiline	Block conversions of dopamine into DOPAC by selectively inhibiting MAO-B.
Decrease excess cholinergic activity	Benztropine, trihexyphenidyl	Improves tremor and rigidity but has little effect on bradykinesia.

Dyskinesias

Dyskinesias can either occur from having too much dopamine (peak-dose dyskinesia effects), or from a drop in dopamine levels.
Sometimes patients can have a difficulty time balancing their medications to avoid the peak-dose effects from dopaminergic agents, and the “off” (dopamine wearing off) symptoms
Sticking to a strict medication schedule is often one way of addressing this.

Levodopa-induced Dyskinesia

Dyskinesia is not caused by Parkinson's Disease. Long‐term use of levodopa often results in significantly disabling fluctuations and dyskinesias known as levodopa-induced dyskinesia (LID).^[15] Different types of movement disorders are seen in LID, including chorea, ballism, dystonia, myoclonus, or combination of any of these movements. These dyskinesias are seen in the neck, facial muscles, jaw, tongue, hip, shoulder, trunk, and limb or may appear as involuntary flexion of toes. These dyskinesias can often be very debilitating, and even more so than the original Parkinson's symptoms.

On-Off Phenomenon

The on-off phenomenon is a consequence of sustained levodopa treatment in patients with Parkinson's disease. It is characterized by a switch between mobility and immobility, which occurs as an end-of-dose or “wearing off” worsening of motor function or, much less commonly, as sudden and unpredictable motor fluctuations.^[16]

Dopamine Agonists

Dopamine agonists include the ergot derivatives: bromocriptine, cabergoline, dihydroergocryptine, lisuride, and pergolide. There are also the non-ergot derivatives: apomorphine, piribedil, pramipexole, ropinirole, rotigotine.

Dopamine Agonist Withdrawal Syndrome (DAWS)

Dopamine agonist withdrawal syndrome (DAWS) is a complication that affects up to 19% of PD patients who undergo a dopamine agonist taper. It was initially described in 2010 as a severe stereotypical cluster of psychiatric and physical symptoms occurring with dopamine agonist withdrawal.^[17]^[18] The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings.

Impulse-Control Disorders (ICD)

Impulse-control disorders (ICDs) such as compulsive gambling, buying, sexual, and eating behaviours, are a serious and increasingly recognized complication in Parkinson's disease (PD), occurring in up to 20% of PD patients over the course of their illness.
- ICDs are an iatrogenic cause and most commonly due to the use of carbidopa-levodopa and dopamine agonists such as pramipexole, bromocriptine, and ropinirole.^[19]
- The life-time estimated risk for ICDs in PD is approximately 15%.
Related behaviours include punding (stereotyped, repetitive, purposeless behaviours), dopamine dysregulation syndrome (DDS), levodopa misuse (compulsive medication overuse), hobbyism (e.g. - compulsive internet use, artistic endeavours, and writing), and hypersexuality or paraphilias.
These disorders have a significant impact on quality of life and function, strain interpersonal relationships, and worsen caregiver burden, and are associated with significant psychiatric comorbidity.
Patients often do not report these behaviours due to shame or guilt, and so it is important to ask these questions directly!
Management includes decreasing the dose of the offending agent (usually a dopamine agonist) or completely stopping it.
- It may take upto 4 months for ICD symptoms to dissipate after the agonist is discontinued.
- Once patients gain insight into their behaviour they are at higher risk of suicide.

Constipation

See main article: Constipation: Laxatives

Constipation is a very common and often overlooked problem in Parkinson's. It is important to treat it proactively, not only to improve discomfort but also to ensure prompt absorption of levodopa medications as well. Levodopa is absorbed in the small intestine, and constipation leads to reduced transport of food/medications from the stomach to the small intestine.
- Treating constipation will thus help to ensure reliable absorption of medication.
The goal is to aim for easy daily bowel movements and drink sufficient fluids (at least 2 litres) daily, fresh fruit, vegetables, fibre, and exercise.
To address constipation in Parkinson's aggressively, bowel motility promoting agents such as osmotic and laxatives should be used on a regular basis.