Penyakit Parkinson

01Pathophysiology

Parkinson's Disease (PD) is a chronic, progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). These neurons project to the corpus striatum via the nigrostriatal pathway, and their degeneration leads to a profound deficit of dopamine in the striatum. The hallmark histopathological finding is the presence of Lewy bodies, which are intracytoplasmic eosinophilic inclusions composed primarily of aggregated alpha-synuclein protein.

The basal ganglia circuit relies on a balance between dopaminergic (excitatory via the direct pathway, inhibitory via the indirect pathway) and cholinergic neurotransmission. When dopamine levels fall, the indirect pathway becomes overactive and the direct pathway becomes underactive. The net result is excessive inhibitory output from the globus pallidus internus (GPi) to the thalamus, which in turn reduces thalamocortical excitation. This is why patients develop bradykinesia and rigidity: the motor cortex receives less facilitatory input and voluntary movement becomes slow and difficult to initiate.

Resting tremor arises from oscillatory activity within the basal ganglia-thalamocortical loop. It is characteristically present at rest and diminishes with voluntary movement, which distinguishes it from the action/intention tremor of cerebellar disease. The tremor is typically asymmetric and described as "pill-rolling."

Postural instability tends to appear later in the disease course and reflects involvement of non-dopaminergic pathways (cholinergic, serotonergic, noradrenergic). It responds less well to levodopa than bradykinesia or rigidity.

The non-motor symptoms of PD, including constipation, hyposmia, REM sleep behavior disorder, depression, and autonomic dysfunction, are explained by the widespread nature of alpha-synuclein deposition beyond the substantia nigra. According to the Braak staging hypothesis, Lewy body pathology begins in the lower brainstem and olfactory bulb before ascending to the midbrain, which is why non-motor prodromal symptoms can precede motor manifestations by years.

The PERDOSNI guideline emphasizes that PD remains a clinical diagnosis. There is currently no biomarker with sufficient sensitivity and specificity, and imaging findings on routine CT or MRI are not pathognomonic. Up to 20% of patients diagnosed clinically with PD during life are found to have an alternative diagnosis at autopsy.

02Classification and Clinical Manifestation

Motor Symptoms

Non-Motor Symptoms

MDS Clinical Diagnostic Criteria (2015)

The International Parkinson and Movement Disorders Society (MDS) published two tiers of clinical certainty in 2015, adopted by the PERDOSNI guideline:

The guideline recommends that diagnosis be reviewed every 6 to 12 months, especially when new atypical features arise, given the known risk of early misdiagnosis.

Key Differentiating "Red Flags" Suggesting an Alternative Diagnosis

03Diagnostic Workup

The PERDOSNI guideline makes clear that PD should be suspected in any patient presenting with tremor, rigidity, slowness of movement, balance difficulty, or gait disturbance. The best initial step is a thorough neurological examination by a neurologist (or movement disorder specialist), looking for the combination of bradykinesia plus at least one of resting tremor or rigidity.

There is no single laboratory or imaging biomarker that can reliably diagnose PD at the first visit. Routine CT or MRI of the brain is not indicated for diagnosis of PD itself but should be performed when atypical features ("red flags") raise suspicion for structural pathology such as normal pressure hydrocephalus, multiple lacunar infarcts (vascular parkinsonism), or a space-occupying lesion.

A long-term levodopa trial is a critical step. The guideline explicitly states that an acute levodopa or apomorphine challenge test should not be used as the sole diagnostic method. Rather, patients with suspected PD should be started on a therapeutic course of levodopa, and their sustained clinical response over weeks to months supports the diagnosis. If a patient shows no meaningful response to adequately dosed levodopa, the diagnosis should be reconsidered.

Functional imaging with I-FP-CIT SPECT (DaTSCAN) should be reserved for cases where genuine diagnostic uncertainty exists between PD and a non-degenerative tremor disorder (such as essential tremor). It is not indicated for routine screening or for differentiating PD from other neurodegenerative parkinsonisms (MSA, PSP), as dopaminergic deficit is present in all of those conditions.

04Management and Treatment

The PERDOSNI guideline states that current treatment of PD is purely symptomatic; no pharmacological therapy has been shown to modify disease progression.

Principles of Early-Stage Management

No single drug is universally recommended as the first choice. The decision is individualized based on symptom severity, impact on the dominant hand, social and occupational needs, cost, and patient preference.

Levodopa is considered the treatment of choice and the most effective oral agent for motor symptom control. The guideline recommends starting at the lowest effective dose (Grade A), because higher levodopa doses correlate with a higher risk of motor complications (dyskinesia, wearing off). Clinical benefit has been demonstrated at 150 to 300 mg per day of levodopa, and dyskinesia risk is lower when the total daily dose stays below 400 mg. Taking levodopa with meals can reduce nausea in early disease but may impair absorption in advanced disease due to competition with dietary amino acids.

Dopamine agonists (pramipexole, rotigotine) may be used as initial dopaminergic therapy in patients below 60 years to delay levodopa initiation and postpone motor fluctuations. They carry a lower dyskinesia risk but are less effective than levodopa. They should be avoided in patients above 70 years and in those with a history of impulse control disorders (pathological gambling, hypersexuality, compulsive shopping/eating), excessive daytime sleepiness, hallucinations, or cognitive impairment.

MAO-B inhibitors (rasagiline, selegiline) can serve as first-line monotherapy for mild symptoms. Most patients on MAO-B inhibitor monotherapy will need additional therapy within 2 to 3 years.

Anticholinergics (trihexyphenidyl) must never be first-line. They are reserved for younger patients (below 70) with dominant resting tremor refractory to other agents, and only after weighing the risk of cognitive side effects.

Advanced-Stage PD: Motor Complications

Over time, response to levodopa becomes less predictable. The guideline identifies the following motor complications:

Wearing off: the therapeutic effect of each levodopa dose becomes shorter, and symptoms re-emerge before the next dose is due. Management begins with adjusting levodopa dosing (shortening the interval between doses without increasing the total daily dose, and separating intake from meals by at least 1 hour). If this is insufficient, adding an adjuvant agent is the next step:

Dyskinesia: involuntary movements related to levodopa use. Peak-dose dyskinesia is managed by reducing individual levodopa doses and increasing dosing frequency. Amantadine (200 to 400 mg/day) is the only oral agent with proven efficacy in reducing dyskinesia without worsening parkinsonism (Grade A). It should be given in the morning to avoid insomnia. Clozapine is an alternative (Grade U) for patients who cannot tolerate amantadine.

Device-Aided Therapy for Refractory Motor Complications

When oral medications fail to control motor fluctuations and dyskinesia, the guideline recommends considering:

Non-Motor Symptom Management Highlights

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students lose points on PD questions is by confusing the initial drug choice based on patient age and symptom severity. The guideline draws a clear line: for patients above 60 years, levodopa at a low dose is the preferred starting agent; for patients below 60 years with mild to moderate symptoms, dopamine agonists (pramipexole or rotigotine) or MAO-B inhibitors may be used first to delay levodopa-associated motor complications. Anticholinergics are never first-line.

A second frequent trap involves the management of dyskinesia. Students often select "reduce levodopa" as the answer and stop there. While dose adjustment is the initial approach, the guideline emphasizes that amantadine is the only proven pharmacological agent that reduces dyskinesia without worsening parkinsonism, and it should be the answer when a question asks about persistent dyskinesia despite dose optimization.

Third, remember that PD is a clinical diagnosis. There is no role for routine DaTSCAN, PET, or MRI in confirming PD. Imaging is indicated only to exclude structural causes when red flags are present or when there is genuine diagnostic uncertainty between PD and a non-degenerative tremor disorder.

Fourth, students sometimes forget that dopamine agonists carry a meaningful risk of impulse control disorders (gambling, hypersexuality, compulsive shopping and eating), excessive daytime sleepiness, and sudden-onset sleep. The guideline recommends screening with the QUIP questionnaire and Epworth Sleepiness Scale before and during dopamine agonist therapy.

Finally, be alert to the wearing off versus dyskinesia distinction. Wearing off is a loss of motor benefit before the next dose, and the strategy centers on smoothing out dopaminergic stimulation (shortening intervals, adding COMT or MAO-B inhibitors). Dyskinesia is an excess of involuntary movement during the peak effect of levodopa, and the strategy centers on reducing peak dopamine levels (smaller, more frequent doses) plus amantadine. Questions will test whether you can identify which complication is occurring and match it to the correct management approach.