Parkinsonism

Etiology

Parkinson's disease (PD) is the most common cause of parkinsonism. It is a gradually progressive disorder that manifests as asymmetric parkinsonism. There is dopaminergic neuronal loss in the midbrain due to neuronal degeneration, and this results in a decrease in dopamine levels, especially in the post-commissural putamen and other regions of the basal ganglia. PD typically responds to levodopa therapy.[2]

Secondary causes of parkinsonism typically do not respond to levodopa therapy. These include[1]: 

Normal-pressure Hydrocephalus (NPH)

It manifests 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 tumors of the posterior fossa.[4]

Vascular Parkinsonism (VP)

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

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

Drug-induced Parkinsonism (DIP)

Medications that block the dopamine receptors and interrupt the transmission of dopamine are known to cause secondary parkinsonism. The risk factors for the development of DIP include the route, potency, and dose of the drug administered. Individuals who are on medications administered via the intramuscular route or in the form of suppositories are more likely to develop DIP, especially at lower doses as compared to administration via the intravenous route.[7][8] At the same time, a drug with higher potency is more likely to cause DIP 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 (TIP)

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 PD. 

Chronic Traumatic Encephalopathy

A repeated head injury can often present with parkinsonian features. 

Brain Tumors

Several brain masses are responsible for the development of parkinsonian features. These include meningioma, astrocytoma, craniopharyngioma, and sometimes even metastatic brain tumors. 

Juvenile Parkinsonism (JP)

It is a rare entity seen in individuals who are less than 21 years of age. The clinical manifestations show similarity to PD but an earlier age of onset.[10]

• Hypoxia
• Postencephalitis
• Metabolic

Other genetically determined causes of parkinsonisms, like Huntington's disease in the juvenile form, or certain spinocerebellar ataxias, can start clinically as a rigid-akinetic syndrome (parkinsonism). Due to its rarity and specificity, this article will not cover these entities.

Parkinson-plus Syndromes

• Multiple system atrophy
• Cortical-basal ganglionic degeneration
• Progressive supranuclear palsy
• Shy-Drager syndrome
• Progressive Pallidal atrophy

Epidemiology

Parkinson Disease[11][12]

PD usually affects around 1 to 2 people in a population of 1000 at any given point in time. PD rarely occurs in individuals below 50 years of age. The prevalence rate of PD increases with an increase in age, with 1% of the population over 60 years being affected with PD. It is more commonly seen in men as compared to women, with a male-to-female ratio of 1.5 to 1.

Vascular Parkinsonism[13][14]

Out of the total cases of parkinsonism, VP is responsible for 2.5 to 5% of these cases. The Rotterdam study reported that 5% of the total 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 VP diagnosed based on imaging studies and response to levodopa.

Drug-induced Parkinsonism[15]

According to a community-based survey, DIP has a prevalence rate of 2.7%, whereas a population-based study suggested a prevalence rate of 1.7%.  The incidence rate of DIP also increases with age with the majority occurring between 60 and 80 years of age. 

Toxin-induced Parkinsonism[16]

A geographic study done in the US has revealed that there is a correlation between the areas in the US that have increased manganese emission 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 suffered exposure to manganese dioxide working in a manganese ore-crushing factory.  

Juvenile Parkinsonism[10]

The average age at which JP occurs is 17 years, and younger men are at increased risk with the male-to-female ratio being 4 to 1.

Pathophysiology

The extrapyramidal system, which is also known as the basal ganglia, comprises the following [17]: 

1) Substantia nigra

2) Striatum (caudate and putamen)

3) Globus pallidus

4) Subthalamic nucleus 

5) Thalamus 

Parkinson Disease[2]

A decrease in the levels of dopamine that occurs relative to a degeneration of the substantia nigra results in decreased levels reaching the caudate and putamen; this leads to denervation hypersensitivity of dopamine receptors in those targets, especially of D1 and D2 receptors, within the nigrostriatal pathway. This yields increased inhibition in the thalamus, which subsequently causes a decrease in excitatory input to the motor cortex, which eventually manifests as bradykinesia and rigidity, seen in parkinsonism presenting in PD.

Normal-pressure Hydrocephalus[18][19]

The proposed mechanisms for the development of parkinsonism in NPH include increased resistance to the outflow of cerebrospinal fluid (CSF) resulting in enlargement of the ventricles, abnormal cerebral blood flow, the pressure exerted by the brain parenchyma, and a rise in water content in the periventricular region. There is also a report of parkinsonism has also been reported in a patient with obstructive hydrocephalus caused as a result of shunt dysfunction. The study revealed fluorodopa PET showing decreased uptake in the caudate and putamen.

A study conducted by Sypert et al. reported that manifestations of parkinsonism seen in NPH occur due to mechanical disruption of the basal ganglia, which results in inadequate blood flow to the nigrostriatal pathway.

Vascular Parkinsonism[20]

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 occurred 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.[21]

Studies have also found that silent infarcts which are majorly present in the basal ganglia to be the causative factor for VP. 

Thus, there are various coexisting clinical and physiological factors in patients with basal ganglionic infarcts that play a significant role in the manifestation of parkinsonism. 

Drug-induced Parkinsonism

In DIP, the dopamine D2 receptor which is present in the striatum is structurally or functionally blocked by the dopamine D2 receptor antagonists, causing a decrease in the dopamine levels, which results in similar dysfunction as seen in PD [2]

Drugs Commonly Involved

1. First-generation antipsychotics:  The phenomenon of drug-induced parkinsonism has been predominantly observed with first-generation antipsychotics such as high-potency drugs like fluphenazine, haloperidol, trifluoperazine. The low-potency drugs chlorpromazine and thioridazine, are lesser-known causes of drug-induced parkinsonism. Out of the total number of individuals taking typical antipsychotics, 80% of them have extrapyramidal symptoms (EPS).[22]
2. Second-generation antipsychotics: These are also known as atypical antipsychotics. Overall, these medications have a lower risk as compared to first-generation antipsychotics since they have a lesser affinity for D2 receptors. Risperidone, ziprasidone, and olanzapine are more prone to cause drug-induced parkinsonism as compared to quetiapine and clozapine.
3. Antiemetic agents and prokinetic medications: Various drugs like metoclopramide, domperidone, levosulpiride, and prochlorperazine mediate their prokinetic action by blocking the enteric D2 receptors. At the same time, these drugs block the D2 receptors in the area postrema present in the medulla oblongata, thus bringing about the antiemetic action. The side effects of hyperprolactinemia and EPS occur when the central D2 receptors are blocked as well. Metoclopramide is most frequently associated with medication-induced movement disorders.[23] Among these drugs, domperidone has a lesser risk of causing DIP, since it cannot cross the blood-brain barrier, but reports have suggested the occurrence of reversible parkinsonism.[24][25]
4. Dopamine-depleting drugs: Vesicular monoamine transporters type 2 (VMAT2) receptor inhibitors like tetrabenazine, a reversible inhibitor, and reserpine, an irreversible inhibitor, resulted in decreased uptake of dopamine into the presynaptic vesicles. This activity leads to a reduction in dopamine levels. Reserpine has 10-20 times more potency as compared to tetrabenazine.[26]
5. Other drugs: Reports exist of valproic acid-induced parkinsonism. The proposed hypothesis is that there is gamma-aminobutyric acid (GABA)-induced suppression of the dopamine transported to the basal ganglia.[27] Very rarely, drugs like lithium, antidepressants like selective serotonin reuptake inhibitors, and calcium channel blockers can lead to DIP.[25] 

Toxin-induced Parkinsonism

1. Manganese: Manganism occurs when there is prolonged exposure to manganese, as seen in miners. When low amounts of manganese are exposed, reversible behavioral changes may present like aggressiveness, irritability, and hallucinations. When manganese exposure is for an extended time, neurological damage occurs. Extrapyramidal symptoms present, which are responsive to levodopa. The presence of more diffuse damage to the brain that is not responsive to levodopa results in dyskinesia. The predominant sites involved include the globus pallidus and the substantia nigra pars reticulata. 
2. Iron: There is literature to prove the actual mechanism of increased iron in the substantia nigra; the proposed hypothesis includes changes involved with the homeostasis of iron rather than exposure to iron.[28]

Chronic Traumatic Encephalopathy

It results due to neuronal loss, the presence of senile plaques, brain tissue scarring, and diffuse axonal injury, all of which are due to repeated head injury. It usually presents in individuals who are involved in contact sports such as wrestling, rugby, and most commonly boxing. A significant risk factor is a high concussion and sub-concussive blow exposure.  

Brain Tumors

Basal ganglionic and supratentorial tumors have been described to cause parkinsonism. Meningioma present at the sphenoid ridge is most commonly known to cause these symptoms. The mechanism by which brain tumors lead to the development of parkinsonian features includes compression of the basal ganglia and substania nigra leading to the destruction of the pathway, edema of the brain by the tumor causing decreased perfusion and infiltration by the tumor.[29]

Juvenile Parkinsonism 

Familial history plays a significant role in the development of JP. Patients with a family history of Huntington's disease and spinocerebellar ataxia are more likely to develop JP. A genetic mutation in any of the three genes; parkin, PTEN-induced putative kinase 1, and PARK7 can result in autosomal recessive parkinsonism.[10]

Histopathology

Parkinson Disease

On histopathology (HP), 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 that are present inside the cytoplasm. These bodies may occur in patients with PD, but it does not have high specificity for PD.[31]

Normal-pressure Hydrocephalus

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

Vascular Parkinsonism

VP denotes the presence of microangiopathy, lacunar infarcts, and very rarely large vessel infarcts. Lacunar infarcts are more commonly present in the basal ganglia and thalamus and may be visible both macro- and microscopically. Microangiopathy reveals perivascular pallor, arteriolar wall thickening, and gliosis.[5]

Drug-induced Parkinsonism

It includes loss of neurons present in the substantia nigra but no Lewy bodies.[33]

History and Physical

Parkinson Disease

Patients with PD usually complain of sleep abnormalities, reduced facial expressions, increased clumsiness on one side of the body, and a feeling of being persistently tired.

PD usually demonstrates the presence of asymmetric rigidity and bradykinesia and resting tremors. 

1) Rigidity: It is manifested as an increase in resistance when performing a passive movement. It is usually asymmetric. PD can have cogwheel rigidity, in which there is a ratchet-like movement at the beginning and end when a limb moves in a full range of motion.[34][35] Patients complain of the stiffness of the limbs. "Cogwheeling" rigidity is the classic description of this rigidity. 

2) Bradykinesia: Described as slowness of movement. Individuals may often complain of difficulty when carrying out simple, everyday tasks.[36] Mask-like facies where the face loses expression. Speech becomes soft and some patients have difficulty in speaking (dysarthria).

3) Tremor: The tremor seen in PD is characteristically the "pill-rolling tremor." It usually occurs when the individual is not involved in any activity, manifested at rest. The frequency of the resting tremor usually ranges between 4 to 5.3 Hz.[37] Tremor can also cause the involvement of lower limbs, lips, tongue but rarely manifests in the head.[38] Stress worsens the tremor. 

4) Postural Instability: An unstable posture results in an increased risk of falls due to the inability to balance. Walking is slow with a tendency to shuffle and decreased stride length.

Normal-pressure Hydrocephalus 

The Unified Parkinson Disease Rating Scale (UPDRS) is commonly used as a scale to rate PD.[39] The motor examination part (UPDRS-m) of this scale applies to parkinsonism seen in individuals with NPH. Previously conducted studies have reported bradykinesia in the upper half of the body in about 62% of patients with NPH whereas parkinsonism has reportedly occurred in about 71% of patients with NPH.[40][41]

Vascular Parkinsonism

Patients with VP characteristically have early instability of gait and posture. A 'parkinsonian-ataxic' type of gait presents in VP in which there is a presence of wide-based stance. Sometimes there may be a presence of shuffling gait and truncal ataxia. Pseudobulbar palsy also presents in VP which manifests as dysarthria and dysphagia. Upper motor neuronal signs include brisk tendon reflexes and extensor plantar reflexes. Hypertonia is a feature in VP.[5]

Drug-induced Parkinsonism

This condition includes symptoms similar to that seen in PD such as tremor, rigidity, and bradykinesia. The clues for the potential effect of medication apart from the temporal relation, to the onset of the offending drug, is the symmetry and generalization of motoric symptoms.

Toxin-induced Parkinsonism

The various manifestations include an increased tone causing cogwheel rigidity, bradykinesia, and risk of falling when trying to walk backward.[42] 

Brain Tumor

In a study conducted by Krauss, he reported that out of the total number of patients with supratentorial tumors, 0.3% had features of parkinsonism with a resting tremor. Most of these patients initially had symptoms of parkinsonism as compared to other symptoms of an intracranial mass, which lead to late diagnosis.[43]

Juvenile Parkinsonism

Typical features of parkinsonism such as bradykinesia and rigidity present. The age of onset under 40 to 45 years generally makes for the suspicion of this unusual cause of parkinsonism, once other etiologies have been ruled out.

Evaluation

 The diagnosis of parkinsonism is clinical. No single test can confirm the syndrome but sometimes can help in balance the suspicion towards a different cause.

Parkinson Disease

Motor parkinsonism that includes bradykinesia along with either rigidity or tremor is required to diagnose PD clinically.[44]

No blood test or otherwise is confirmatory to diagnose PD. 

Imaging

Transcranial color-coded sonography reveals an increased echogenicity of the substantia nigra in patients with PD. 

Magnetic resonance imaging can help to rule out causes of parkinsonism other than PD such as tumors, NPH, or cerebrovascular accidents. 

Dopamine transporters (DATs) are presynaptic proteins that cause dopamine uptake from the synaptic cleft. Single-photon-emission computed tomography (SPECT), and positron emission tomography (PET) scans use DAT ligands for the diagnosis of patients with parkinsonism. On DATscan, there is reduced uptake of DAT in PD patients. 

Normal-pressure Hydrocephalus

Neuroimaging is suggestive of enlarged ventricles with mild or absent atrophy of the parenchyma.[32] A decrease in cerebral blood flow in the thalamus, caudate, and putamen is also visible on positron emission tomography scan. DAT scan may reveal the presence of decreased striatal dopamine. 

Vascular Parkinsonism

CT/MRI may help to reveal the site of the infarct, but they are not conclusive of the diagnosis. MRI may show white matter and periventricular hyperintensities. DAT scan shows a decreased putaminal tracer uptake in patients with VP. 

Drug-induced Parkinsonism

Drugs that cause parkinsonism have the least affinity for DAT.[45] Thus, DAT scans reveal symmetric uptake in the striatum in pure DIP patients. 

Juvenile Parkinsonism

Genetic testing may help patients with a significant family history, to find out the underlying cause of secondary parkinsonism.[10]

Treatment / Management

Medications: Anti-parkinsonian drugs are the mainstay symptomatic treatment for parkinsonisms, with different response intensity and duration for the different causes. The most responsive etiology is Parkinson's disease.[46]

Levodopa-Carbidopa

Dopamine itself cannot cross the blood-brain barrier. Levodopa, an amino acid gets metabolized to form dopamine, which compensates for the dopamine deficiency seen in PD. Furthermore, a peripheral dopa decarboxylase inhibitor, carbidopa is given along with levodopa for therapeutic advantage. Small doses of combined carbidopa-levodopa are given in a dose of 25/100 mg half tablet twice or thrice a day along with meals. The common adverse effects include nausea, dizziness, and somnolence. Prolonged therapy with levodopa can lead to 'wearing off' phenomenon in which patients notice an improvement in mobility after an hour or two of levodopa dosing, however, the effect starts to wear off after dosing interval, and rigidity and bradykinesias manifest again. Abrupt cessation of levodopa may lead to the development of the neuroleptic malignant syndrome. 

A recent study intending to demonstrate a disease-modifying effect of the degeneration has proved the lack of such an effect, thus supporting the idea that this treatment is only symptomatic.[47](A1)

Dopamine Agonists

These drugs stimulate dopamine receptors directly. The ergot derivative includes bromocriptine, and the non-ergot derivatives are ropinirole and pramipexole. Both these drugs are immediate-release formulations that can be given three times daily. Pramipexole dosing is 0.125 mg three times a day whereas ropinirole is given as 0.25 mg thrice a day. Commonly seen adverse effects include nausea, vomiting, and orthostatic hypotension. 

Catechol-O-methyltransferase (COMT) Inhibitors

Entacapone results in the blockade of peripheral COMT, an enzyme responsible for the degradation of dopamine. It helps to decrease the breakdown of levodopa, thus increasing its availability to the brain. Entacapone dosing is 200mg with every dose of levodopa, and up to eight doses can be given each day, whereas the dose of tolcapone is 100 mg three times a day. The commonly seen adverse effects include hallucinations and dyskinesias. 

Monoamine Oxidase (MAO) Inhibitors

Drugs like selegiline and rasagiline decrease the metabolism of dopamine by blocking the enzyme, monoamine oxidase. The daily dosing of selegiline is 5 mg, usually given in the morning to avoid insomnia. A dose greater than 10 mg should not be used in PD patients as it can lead to nonselective MAO inhibition causing a hypertensive crisis as a result of interaction with tyramine-containing foodstuff. Rasagiline can be initiated with a dose of 0.5 mg once a day and gradually increased to 1 mg once a day. The commonly seen adverse effects of MAO B inhibitors include nausea and headache. 

Amantadine

It acts by blocking N-methyl-D-aspartate and acetylcholine receptors. It is available as immediate-release tablets or capsules 100 mg each given twice or thrice daily. It is excreted via the kidney and thus should be used cautiously in patients with kidney injury. The commonly seen adverse effects are livedo reticularis and pedal edema. 

Anticholinergic Drugs

Benztropine and trihexyphenidyl result in the blockade of acetylcholine receptors. They can be useful for the treatment of tremors and rigidity seen in parkinsonism as well as to treat DIP. Trihexyphenidyl is usually given in a dose of 0.5 to 1 mg twice a day that is gradually increased to 2 mg thrice a day. The benztropine dose is 0.5 to 2 mg twice in a day. Anticholinergic drugs adversely result in confusion and hallucinations. Also, antimuscarinic side effects like tachycardia, dry mouth, constipation, and urinary retention present. 

Treatment of Specific Causes of Parkinsonism

Normal-pressure Hydrocephalus

Literature reveals that shunt surgery or removal of CSF results in the reversibility of parkinsonism.[41] Shunt surgery helps to decrease the resistance and relieve the pressure on the brain parenchyma, allowing for an uninterrupted flow of the CSF, which helps in the resolution of parkinsonian features.  

Vascular Parkinsonism

Levodopa administration forms the primary treatment for VP, given in a dose of up to 1000 mg per day. Antiplatelet agents such as aspirin and clopidogrel are also an option when MRI is suggestive of massive white matter infarct [5]

Drug-induced Parkinsonism

Removal of the offending drug is the primary measure for DIP resulting in the resolution of symptoms. Patients with underlying psychiatric conditions can be alternatively started on atypical antipsychotics, as these drugs have a lesser risk of DIP. Anticholinergic drugs like benztropine and trihexyphenidyl are frequent choices for the treatment of DIP. If anticholinergics are not effective, amantadine with a dose of 100 mg twice or thrice daily can be used. Electroconvulsive therapy is also an option when all other treatment modalities fail to resolve symptoms. 

Brain Tumors

Literature reveals that most of the patients achieve complete remission after surgical removal of the neoplasm resolving the parkinsonian features.[43](B3)

Juvenile Parkinsonism

Management of the underlying condition leading to parkinsonism should be of paramount importance in patients with JP.

Differential Diagnosis

Atypical parkinsonian disorders are also known as Parkinson-plus syndromes.

All these syndromes may have parkinsonian features that have an inadequate response to levodopa.[1]

These include: 

1) Multiple system atrophy: It manifests as autonomic symptoms like orthostatic hypotension, erectile dysfunction in males, and urinary incontinence along with motor symptoms of parkinsonism. Individuals also have cerebellar ataxia and orofacial or craniofacial dystonia. 

2) Dementia with Lewy bodies (DLB): DLB has features of both cognitive dysfunction and parkinsonism. It characteristically presents by alternating cognition such as varying alertness and concentration, presence of visual hallucinations, and rapid eye movement sleep disorder along with motor symptoms of parkinsonism.  

3) Progressive supranuclear palsy (PSP): PSP occurs due to oxidative stress and mitochondrial dysfunction. Its presentation is with a vertical gaze palsy along with a decrease in blink rate due to eyelid dystonia. It also presents with an unstable posture resulting in an increased risk of fall. 

4) Corticobasal syndrome: It is manifested as an asymmetric movement in the form of limb dystonia along with myoclonus sometimes referred to as 'useless arm.' Patients also present with gait disturbances and cortical sensory loss. Patients have early-onset dementia, as well. 

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 PD may have a faster progression rate and earlier cognitive dysfunction. On average, PD has a duration of ten 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 in advanced PD such as[49]:  

• Late-onset dementia
• Autonomic dysfunction like constipation, urinary incontinence, sexual dysfunction, diaphoresis
• Mood disorders including depression
• Hallucinations and psychosis
• Sleep disorders including insomnia and restless leg syndrome 
• Treatment with high doses of levodopa can lead to the development of dyskinesias such as twitching and head shaking, which are involuntary in nature