Parkinsonism

Etiology

Parkinson disease is the most common cause of parkinsonism, which gradually manifests as asymmetric parkinsonism. Due to neuronal degeneration, dopaminergic neuronal loss is evident in the midbrain, resulting in a decrease in dopamine levels, especially in the post-commissural putamen and other regions of the basal ganglia. 

Although Parkinson disease typically shows a positive response to levodopa therapy,[1][2] secondary causes of parkinsonism generally do not respond to this treatment, which include the below-mentioned conditions.

Specific Secondary Causes of Parkinsonism

Normal pressure hydrocephalus: Normal pressure hydrocephalus (NPH) presents with the classic triad of ataxia, urinary incontinence, and dementia. Parkinsonism may sometimes be the presenting symptom in NPH.[3] The earliest reporting of parkinsonian features and hydrocephalus included the involvement of posterior fossa tumors.[4]

Vascular parkinsonism: Critchley was the first to describe vascular parkinsonism as a distinct entity in 1929. Previously, clinicians referred to the disorder as arteriosclerotic parkinsonism, lower-body parkinsonism, and vascular pseudo-parkinsonism.[5]

Vascular Parkinsonism usually occurs due to an underlying vascular disorder, most commonly hypertension, that leads to subcortical infarcts, white matter ischemia, and large vessel infarcts. Diffuse white matter ischemic lesions that present bilaterally can destroy thalamocortical functioning, reducing the impulses sent to the higher centers via the basal ganglia and causing disruptions in motor movements. Imaging studies usually support the symptomatic diagnosis of vascular parkinsonism.[6]  

Drug-induced parkinsonism: Medications that block the dopamine receptors and interrupt the transmission of dopamine are known to cause secondary parkinsonism. The risk factors for developing this type include the route, potency, and dose of the drug administered. Individuals who are on medications administered via the intramuscular (IM) route or in the form of suppositories are more likely to develop drug-induced parkinsonism, especially at lower doses, as compared to administration via the intravenous (IV) route.[7][8] At the same time, a drug with higher potency is more likely to cause parkinsonism when compared to a drug with lower potency. Parkinsonism usually occurs at higher doses of medications since dopamine receptor blockade occurs at higher doses.[9]

Toxin-induced parkinsonism: Prolonged exposure to heavy metals and industrial toxins can result in parkinsonian features. Toxins result in vast neurological damage, resulting in parkinsonism as compared to that seen in Parkinson disease. 

Chronic traumatic encephalopathy: A repeated head injury can often present with parkinsonian features. 

Brain tumors: Various brain masses can lead to the development of parkinsonian features, which include meningioma, astrocytoma, craniopharyngioma, and occasionally metastatic brain tumors. 

Juvenile parkinsonism: This rare disease entity is observed in individuals aged 21 or younger. Clinical manifestations exhibit similarities to Parkinson disease but occur at an earlier age.[10]

Other causes of secondary parkinsonism include hypoxia, postencephalitis conditions, and metabolic disorders. Additional genetically determined causes of parkinsonism, such as juvenile-onset Huntington disease or certain spinocerebellar ataxias, may initially present clinically as a rigid-akinetic syndrome resembling parkinsonism. 

Parkinson-plus syndromes: Parkinson-plus syndromes include multiple system atrophy, corticobasal degeneration, and progressive supranuclear palsy.

Epidemiology

Parkinson Disease

Parkinson disease usually affects around 1 to 2 individuals per 1000 in the population at any given time. This disease is uncommon in individuals aged 50 or younger, but its prevalence increases with age, affecting about 1% of the population aged 60 and older. The disease shows a higher incidence in men than in women, with a 1.5:1 male-to-female ratio.[11][12]

Vascular Parkinsonism

Out of the total cases of parkinsonism, vascular parkinsonism is responsible for 2.5% to 5% of these cases. The Rotterdam study reported that 5% of participants had parkinsonian features due to cerebrovascular disease. Chang et al conducted a clinical cohort that revealed that out of the total patients with parkinsonism, 4.4% had been diagnosed based on imaging studies and response to levodopa.[13][14]

Drug-Induced Parkinsonism

According to a community-based survey, drug-induced parkinsonism has a prevalence rate of 2.7%, whereas a population-based study suggested a prevalence rate of 1.7%. The incidence of drug-induced parkinsonism also increases with age, with the majority occurring in individuals aged between 60 and 80.[15]

Toxin-Induced Parkinsonism

A geographic study in the United States has revealed a correlation between the areas with increased manganese emissions from industries and a high incidence of manganese-induced parkinsonian features. Couper was the first to report manganese-induced parkinsonism in 1837 in workers who were exposed to manganese dioxide while working in a manganese ore-crushing factory.[16]  

Juvenile Parkinsonism

Juvenile parkinsonism typically occurs in individuals around the age of 17, with a higher risk observed in younger men, resulting in a 4:1 male-to-female ratio.[10]

Pathophysiology

The extrapyramidal system, also referred to as the basal ganglia, includes the substantia nigra, striatum (caudate and putamen), globus pallidus, subthalamic nucleus, and thalamus.[17]

Parkinson Disease

Parkinson disease is characterized by decreased dopamine levels due to substantia nigra degeneration, leading to reduced dopamine reaching the caudate and putamen. This causes denervation hypersensitivity of dopamine receptors, particularly D1 and D2 receptors in the nigrostriatal pathway. The resulting increased inhibition in the thalamus reduces excitatory input to the motor cortex, manifesting as bradykinesia and rigidity.[2]

Normal Pressure Hydrocephalus

Normal Pressure Hydrocephalus (NPH) is associated with parkinsonism due to several proposed mechanisms, including increased resistance to cerebrospinal fluid (CSF) outflow, resulting in ventricular enlargement, abnormal cerebral blood flow, brain parenchymal pressure, and increased water content in the periventricular region. Additionally, parkinsonism has been observed in patients with obstructive hydrocephalus caused by shunt dysfunction, as evidenced by decreased fluorodopa positron emission tomography (PET) uptake in the caudate and putamen.

A study by Sypert et al suggests that the parkinsonian manifestations in NPH result from mechanical basal ganglia disruption, leading to inadequate blood flow to the nigrostriatal pathway.[18][19]

Vascular Parkinsonism

Vascular parkinsonism results from an underlying vascular condition resulting in the progression of symptoms. Various studies have reported that a history of ischemic cerebrovascular disease is responsible for the development of parkinsonism and occurs more often due to the presence of lacunar infarcts as compared to cortical infarcts. Strategic infarcts result in parkinsonism by destroying the putaminal-pallido and pallido-thalamic pathway.[5]

Peralta et al proposed that infarcts of the striatum are more likely to produce parkinsonism if they selectively result in damage of the putaminal-pallidal outflow, but more than often result in disruption of the pallidum leading to a contralateral "pallidotomy" effect.[20][21] Research has indicated that silent infarcts, commonly found in the basal ganglia, can be a causative factor for vascular parkinsonism. Therefore, the presence of infarcts in the basal ganglia, along with other clinical and physiological factors, contributes to the development of parkinsonism in affected patients. 

Drug-Induced Parkinsonism

In drug-induced parkinsonism, dopamine D2 receptors in the striatum are either structurally or functionally blocked by dopamine D2 receptor antagonists. This blockade leads to decreased dopamine levels, resulting in dysfunction similar to what is observed in Parkinson disease.[2]

Drug-induced parkinsonism commonly involves the drugs mentioned below.

First-generation antipsychotics: High-potency drugs such as fluphenazine, haloperidol, and trifluoperazine are frequently associated with drug-induced parkinsonism. Low-potency drugs such as chlorpromazine and thioridazine are also known causes but are less common. About 80% of individuals taking typical antipsychotics experience extrapyramidal symptoms.

Second-generation antipsychotics: These drugs are also known as atypical antipsychotics, and they generally pose a lower risk compared to first-generation antipsychotics due to their lower affinity for D2 receptors. However, risperidone, ziprasidone, and olanzapine are more likely to cause drug-induced parkinsonism compared to quetiapine and clozapine.

Antiemetic agents and prokinetic medications: Various drugs such as metoclopramide, domperidone, levosulpiride, and prochlorperazine exert their prokinetic effects by blocking enteric D2 receptors. Simultaneously, they block D2 receptors in the area postrema of the medulla oblongata, resulting in antiemetic action. However, blocking central D2 receptors can lead to adverse effects such as hyperprolactinemia and extrapyramidal symptoms. Metoclopramide is most commonly associated with medication-induced movement disorders. Domperidone carries a lower risk of causing drug-induced parkinsonism, as it does not cross the blood-brain barrier; however, reversible parkinsonism cases have been reported with its use.

Dopamine-depleting drugs: These drugs, such as vesicular monoamine transporter type 2 (VMAT2) receptor inhibitors like tetrabenazine (a reversible inhibitor) and reserpine (an irreversible inhibitor), decrease the uptake of dopamine into presynaptic vesicles ultimately leading to reduced dopamine levels. Reserpine is 10 to 20 times more potent than tetrabenazine.

Additional drugs: Other drugs have been reported to cause parkinsonism, including valproic acid. The proposed hypothesis suggests that gamma-aminobutyric acid (GABA) induced by valproic acid may suppress dopamine transport to the basal ganglia. In very rare cases, drugs such as lithium, selective serotonin reuptake inhibitors (antidepressants), and calcium channel blockers can also lead to drug-induced parkinsonism.[22][23][24][25][26][27]

Toxin-Induced Parkinsonism

Manganese: Manganism develops with prolonged exposure to manganese, commonly seen in miners. Low-level manganese exposure can cause reversible behavioral changes such as aggressiveness, irritability, and hallucinations. Extended manganese exposure can lead to neurological damage. Extrapyramidal symptoms can respond to levodopa. The presence of more diffuse damage to the brain that is unresponsive to levodopa results in dyskinesia. The primary affected areas include the globus pallidus and substantia nigra pars reticulata. 

Iron: Studies suggest that the increased iron levels in the substantia nigra are likely due to alterations in iron homeostasis rather than direct iron exposure, as supported by current literature.[28]

Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy is attributed to repetitive brain trauma leading to neuronal loss, senile plaques, brain tissue scarring, and diffuse axonal injury. This condition commonly occurs in individuals engaged in contact sports such as wrestling, rugby, and boxing, as well as those with a history of repeated concussions or sub-concussive head trauma. 

Brain Tumors

Brain tumors, particularly basal ganglionic and supratentorial tumors, have been associated with the development of parkinsonism. Meningiomas located at the sphenoid ridge are frequently implicated in causing these symptoms. The mechanism underlying the development of parkinsonian features involves compression of the basal ganglia and substantia nigra, resulting in pathway destruction and brain edema due to reduced perfusion and tumor infiltration.[29]

Juvenile Parkinsonism 

Juvenile parkinsonism is influenced significantly by familial history, especially in cases where there is a family history of Huntington's disease and spinocerebellar ataxia. Genetic mutations in any of the 3 genes—parkin, PTEN-induced putative kinase 1, and PARK7—can lead to autosomal recessive parkinsonism, contributing to the development of juvenile parkinsonism.[10]

Histopathology

Parkinson Disease

On histopathology, parkinsonism usually presents as depigmentation, gliosis, and a decrease in the population of neurons, predominantly in substantia nigra pars compacta and in the locus ceruleus in the pons.[30] Lewy bodies are eosinophilic, round neuronal inclusions inside the cytoplasm. These bodies may occur in patients with Parkinson disease, but the finding does not have high specificity.[31]

Normal Pressure Hydrocephalus

Histopathology in NPH shows the presence of tau-positive neurons and tufted astrocytes seen in the caudate nucleus or Lewy bodies in the substantia nigra.[32]

Vascular Parkinsonism

Vascular parkinsonism is characterized by microangiopathy, lacunar infarcts, and, rarely, large vessel infarcts. Lacunar infarcts are frequently found in the basal ganglia and thalamus and may be visible at both macroscopic and microscopic levels. Microangiopathy is associated with perivascular pallor, arteriolar wall thickening, and gliosis.[5]

Drug-Induced Parkinsonism

In drug-induced parkinsonism, histopathological examinations typically show neuron loss in the substantia nigra without the presence of Lewy bodies.[33]

History and Physical

Parkinson Disease

Patients with Parkinson disease commonly experience sleep disturbances, reduced facial expressions, increased clumsiness on one side of the body, and persistent fatigue. The defining features are listed below.

• Rigidity: Rigidity in Parkinson disease is characterized by increased resistance during passive movement, often observed asymmetrically. A classic presentation includes cogwheel rigidity, described as a ratchet-like movement at the beginning and end of a limb's full range of motion.[34][35] Patients commonly report limb stiffness, and "cogwheeling" rigidity is a hallmark feature of this condition. 

• Bradykinesia: Bradykinesia in Parkinson disease is characterized by slowness of movement, making it challenging to perform routine tasks.[36] Patients may also exhibit mask-like facies with reduced facial expression. Speech is often soft, and some individuals may experience difficulty speaking, known as dysarthria.

• Tremor: A tremor in Parkinson disease is typically the "pill-rolling tremor," occurring primarily at rest when the individual is not engaged in any activity. The frequency of the resting tremor usually ranges from 4 to 5.3 Hz.[37] Although tremors can involve the lower limbs, lips, and tongue, it rarely affects the head.[38] Stress exacerbates tremors in Parkinson disease. 

• Postural instability: Postural instability in Parkinson disease leads to an unstable posture, increasing the risk of falls due to difficulties in maintaining balance. Patients exhibit slow walking, often characterized by a shuffling gait and reduced stride length.

Normal Pressure Hydrocephalus

The Unified Parkinson's Disease Rating Scale (UPDRS) is a widely used tool for assessing Parkinson disease.[39] The motor examination part (UPDRS-m) of this scale also applies to parkinsonism observed in individuals with NPH. Previous studies have indicated that approximately 62% of patients with NPH exhibit bradykinesia in the upper half of the body, while parkinsonism is reported in about 71% of patients with NPH.[40][41]

Vascular Parkinsonism

Vascular parkinsonism is marked by early gait and posture instability in patients. They often exhibit a gait resembling a combination of parkinsonian and ataxic features, characterized by a wide-based stance and sometimes a shuffling gait along with truncal ataxia. Pseudobulbar palsy is another common feature, presenting as dysarthria and dysphagia. Patients may also show upper motor neuron signs, such as brisk tendon reflexes, extensor plantar reflexes, and hypertonia.[5]

Drug-Induced Parkinsonism

Drug-induced parkinsonism presents with symptoms similar to Parkinson disease, including tremors, rigidity, and bradykinesia. Key indicators of medication-induced parkinsonism, aside from the temporal relationship to starting the offending drug, include the symmetry and widespread nature of motor symptoms.

Toxin-Induced Parkinsonism

Toxin-induced parkinsonism is characterized by increased muscle tone leading to cogwheel rigidity, bradykinesia, and a higher risk of falling when attempting to walk backward.[42] 

Brain Tumor

A study by Krauss found that among patients with supratentorial tumors, 0.3% exhibited parkinsonian features characterized by a resting tremor. Many of these patients initially presented with parkinsonian symptoms rather than other signs of an intracranial mass, contributing to delayed diagnosis.[43]

Juvenile Parkinsonism

Juvenile parkinsonism typically presents with classical features of parkinsonism, including bradykinesia and rigidity. The onset of symptoms before the age of 40 to 45 years raises suspicion for this rare cause of parkinsonism, especially after ruling out other possible etiologies.

Evaluation

Diagnosing parkinsonism requires a thorough clinical assessment and the exclusion of alternative causes. Although a single test cannot confirm the syndrome, specific tests can aid in evaluating alternative etiologies or potential contributing factors. 

Parkinson Disease

Diagnosing Parkinson disease relies on identifying typical parkinsonian motor symptoms like bradykinesia and either rigidity or tremor.[44] No specific blood or imaging tests are necessary for diagnosis, although responsiveness to dopaminergic medication supports the diagnosis. Transcranial color-coded sonography may reveal increased echogenicity of the substantia nigra in Parkinson disease. Magnetic resonance imaging (MRI) can exclude other causes of parkinsonism, such as tumors, NPH, or cerebrovascular accidents. Dopamine transporters (DATs) play a role in dopamine uptake, and imaging techniques such as single-photon emission computed tomography (SPECT) and PET scans using DAT ligands can show reduced DAT uptake, aiding in diagnosis. 

Normal Pressure Hydrocephalus

In NPH, neuroimaging typically shows enlarged ventricles with mild or absent parenchymal atrophy.[32] PET scans may indicate reduced cerebral blood flow in areas such as the thalamus, caudate, and putamen. In addition, a DAT scan may show decreased striatal dopamine levels in NPH patients. 

Vascular Parkinsonism

Vascular parkinsonism diagnosis typically involves imaging studies such as computed tomography (CT) or MRI, which may show the location of the infarct but are often inconclusive. MRI may reveal white matter and periventricular hyperintensities. Additionally, a DAT scan can be helpful, as it shows decreased putaminal tracer uptake in individuals with vascular parkinsonism. 

Drug-Induced Parkinsonism

Drug-induced parkinsonism is characterized by drugs that have a low affinity for DAT.[45] Thus, DAT scans typically reveal symmetric uptake in the striatum in patients with drug-induced parkinsonism. 

Juvenile Parkinsonism

Genetic testing can be beneficial for individuals with juvenile parkinsonism and significant family history, as it may help identify the underlying cause of secondary parkinsonism.[10]

Treatment / Management

The usual treatment for Parkinson disease involves medications that help manage the symptoms. Anti-parkinsonian drugs are the mainstay symptomatic treatment for parkinsonism, exhibiting varied response intensities and durations depending on the underlying cause. Among the various etiologies, Parkinson disease is the most responsive to treatment.[46]

Medications for Parkinson Disease Management

Levodopa-carbidopa: Dopamine itself cannot pass through the blood-brain barrier. However, levodopa, an amino acid, can cross this barrier and is metabolized to form dopamine, compensating for dopamine deficiency in Parkinson disease. A peripheral dopa decarboxylase inhibitor, known as "carbidopa," is coadministered with levodopa to enhance its therapeutic effects. Small doses of combined carbidopa-levodopa, such as 25/100 mg half tablet, are typically administered 2 or 3 times daily with meals. Common adverse effects include nausea, dizziness, and somnolence.

Prolonged levodopa therapy can lead to a phenomenon known as "wearing off," where patients experience improved mobility for a short time after dosing but then experience a return of rigidity and bradykinesias before the next dose. Abruptly discontinuing levodopa treatment may result in neuroleptic malignant syndrome. Despite hopes for disease-modifying effects, recent studies have shown that levodopa does not modify the degeneration process in Parkinson disease, confirming its role as a symptomatic treatment rather than a cure.[47](A1)

Dopamine agonists: Dopamine agonists stimulate dopamine receptors directly and are used in the treatment of Parkinson disease. Examples include the ergot derivative bromocriptine and non-ergot derivatives ropinirole and pramipexole. These drugs are typically administered as immediate-release formulations and can be given 3 times daily. 

The usual pramipexole dosage is 0.125 mg 3 times daily, while ropinirole is given at 0.25 mg 3 times daily. Common adverse effects associated with dopamine agonists include nausea, vomiting, and orthostatic hypotension. 

Catechol-O-methyltransferase inhibitors: Catechol-O-methyltransferase (COMT) inhibitors, such as entacapone, block the peripheral enzyme responsible for dopamine degradation. These inhibitors help decrease the breakdown of levodopa, increasing its availability to the brain.

Entacapone is typically given 200 mg with each levodopa dose, and up to 8 doses can be administered daily. Tolcapone is another COMT inhibitor, given 100 mg 3 times daily. Common adverse effects of COMT inhibitors include hallucinations and dyskinesias. 

Monoamine oxidase inhibitors: Monoamine oxidase inhibitors (MAOIs), such as selegiline and rasagiline, reduce dopamine metabolism by inhibiting the enzyme MAO. Selegiline is typically prescribed at a daily dosage of 5 mg, taken in the morning, to minimize the risk of insomnia. Doses exceeding 10 mg should be avoided due to the potential for nonselective MAO inhibition, which can lead to a hypertensive crisis when interacting with tyramine-containing foods.

Rasagiline therapy usually starts at 0.5 mg daily and can be increased gradually to 1 mg daily. Common adverse effects associated with MAO-B inhibitors include nausea and headaches. 

Amantadine: Amantadine functions by blocking N-methyl-D-aspartate and acetylcholine receptors. This drug is typically available in immediate-release tablets or capsules containing 100 mg, administered 2 to 3 times daily. Due to renal excretion, caution is advised in patients with kidney impairment. Common adverse effects include livedo reticularis and pedal edema. 

Anticholinergic drugs: Benztropine and trihexyphenidyl result in the blockade of acetylcholine receptors. They can be helpful for the treatment of tremors and rigidity seen in parkinsonism, as well as for drug-induced parkinsonism. Trihexyphenidyl is typically administered at a dosage of 0.5 to 1 mg twice daily, which can be increased gradually to 2 mg 3 times daily. Benztropine is dosed at 0.5 to 2 mg twice daily. However, anticholinergic medications can lead to adverse effects such as confusion and hallucinations. Additionally, antimuscarinic adverse effects such as tachycardia, dry mouth, constipation, and urinary retention may also occur. 

Treatment of Specific Secondary Causes of Parkinsonism

Normal pressure hydrocephalus: Studies have revealed that shunt surgery or CSF removal can reverse parkinsonism symptoms.[41] Shunt surgery reduces resistance and relieves pressure on brain tissue, facilitating continuous CSF flow and resolving parkinsonian features.  

Vascular Parkinsonism: Treatment primarily involves administering levodopa, typically in doses of up to 1000 mg daily. Antiplatelet agents like aspirin and clopidogrel may also be considered when MRI indicates a significant white matter infarct.[5]

Drug-induced Parkinsonism: The first step in treatment involves discontinuing the causative drug, leading to symptom resolution. For patients with underlying psychiatric conditions, atypical antipsychotics are preferred due to their lower risk. Anticholinergic medications such as benztropine and trihexyphenidyl are commonly used. If anticholinergics are ineffective, amantadine at a dosage of 100 mg twice or thrice daily may be considered. In cases where standard treatments fail, electroconvulsive therapy can be an alternative option. 

Brain tumors: Literature reveals that surgical removal of the neoplasm often results in complete remission, resolving the parkinsonian features in most patients.[43](B3)

Juvenile Parkinsonism: Managing the underlying condition responsible for juvenile parkinsonism should be the primary focus of treatment.

Differential Diagnosis

Atypical parkinsonian disorders, also referred to as Parkinson-plus syndromes, are characterized by parkinsonian features that do not respond adequately to levodopa treatment.

• Multiple system atrophy: This syndrome presents with autonomic symptoms such as orthostatic hypotension, erectile dysfunction in males, and urinary incontinence, in addition to motor symptoms of parkinsonism. Patients also experience cerebellar ataxia and orofacial or craniofacial dystonia. 

• Dementia with Lewy bodies: This syndrome combines cognitive dysfunction and parkinsonism, showing alternating cognition such as varying alertness and concentration, presence of visual hallucinations, and rapid eye movement sleep disorder along with motor symptoms of parkinsonism.  

• Progressive supranuclear palsy: This syndrome results from oxidative stress and mitochondrial dysfunction, leading to features such as vertical gaze palsy, reduced blink rate due to eyelid dystonia, and an unstable posture that raises the risk of falls. 

• Corticobasal syndrome: This syndrome manifests as an asymmetric movement in the form of limb dystonia and myoclonus, sometimes referred to as "useless arm." This syndrome also presents with gait disturbances, cortical sensory loss, and early-onset dementia in patients.[1]

Prognosis

Parkinsonism prognosis is highly dependent on the cause and its potential for reversibility, and some other prognostic factors, like the age of onset of symptoms. Late-onset Parkinson disease may have a faster progression rate and earlier cognitive dysfunction. On average, the disease has a duration of 10 years. Individuals have a shortened life expectancy. Early initiation of therapy can help to increase life expectancy.[48] Other causes of parkinsonism also have a quicker onset and progression. 

Complications

Parkinsonism presents with various complications, including late-onset dementia, autonomic dysfunction such as constipation, urinary incontinence, sexual dysfunction, and diaphoresis, mood disorders such as depression, hallucinations, and psychosis, and sleep disorders such as insomnia and restless leg syndrome. In addition, treatment with high doses of levodopa can lead to the development of dyskinesia characterized by involuntary twitching and head shaking.[49]