When The Tremor Isn’t Essential –Parkinson’s Disease: One of the Most Commonly Misdiagnosed Neurological Conditions

By Jaivir S. Rathore, M.D, F.A.E.S & Idha Sood, M.B;B.S

A COMPREHENSIVE ARTICLE, ON THE OCCASION OF WORLD PARKINSON’S DAY • APRIL 11, 2023

WHAT IS PARKINSON’S DISEASE?

Parkinson’s disease (PD) is the second-most common neurodegenerative disease after Alzheimer’s dementia. More than 10 million people worldwide and nearly one million people in the U.S. are living with PD. This number is expected to rise to 1.2 million by 2030. Nearly 90,000 people in the U.S. are diagnosed with PD each year. The incidence of PD increases with age, but an estimated four percent of people with PD are diagnosed before age 50. Men are 1.5 times more likely to have PD than women. Within the US; Florida has the second highest population of people living with PD. It is a slowly progressive disorder which often first presents with a resting hand tremor. The patient can then develop other cardinal features of bradykinesia, rigidity and postural instability. Autonomic symptoms like constipation, poor sense of smell, excess salivation due to poor swallowing can be present years before the patient develops the classic PD symptoms. In some patients there can be signs of cognitive decline which could be part of “Parkinson’s Plus” or Parkinson’s dementia.

WHAT CAUSES PARKINSON’S DISEASE?

PD results from loss of dopaminergic neurons in the pars compacta of substantia nigra of basal ganglia which is responsible for subcortical control of motor activity. In most cases the exact cause is unknown (Idiopathic Parkinson’s Syndrome, IPS), up to 15% cases may have genetic components, most common being LRRK2, GBA and PRKN (associated with young onset PD). In some cases it has also been linked to exposure to certain pesticides, herbicides, and industrial chemicals. One such compound called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) accumulates in the mitochondria and generates free radicals, which can cause damage to basal ganglia and hence lead to PD. Latest research is also suggestive of alpha synuclein aggregation playing a role in the pathogenesis of PD. The earliest histopathological changes are hence seen in the myenteric plexus of the gastrointestinal tract, which then progresses to involve the dorsal motor nucleus of the vagus nerve and sleep centers in the ponto-medullary brainstem.

Many known figures in the world history have been affected by Parkinson’s disease including Pope John Paul II, Adolf Hitler, Mao Zedong, Michael J Fox and notably world heavyweight boxing champion Muhammad Ali, in his case repeated hits to his head is considered a risk factor to cause “dementia pugilistica” a neurode generative condition with Alzheimer’s like dementia. Neurode generation is a serious issue for boxing or for any traumatic brain injury for that matter.

WHAT ARE THE EARLY SIGNS OF PARKINSON’S DISEASE?

Patients typically have constipation, poor sense of smell and REM sleep disorder preceding the motor symptoms by around 10-15 years. Patients most commonly present with the earliest symptom of tremor. The tremor is usually present at rest and sometimes has classic pin rolling features involving the thumb and the index finger; it can disappear for some time while doing a task but returns when the patient is distracted. In cases where PD is not tremor dominant, patients usually present with the cardinal features of “overall slowness” or bradykinesia, mask facies, muffled speech (hypophonia), small handwriting (micrographia) etc. Patients can take a long time to do their usual daily activities and walk slowly. When prompted about mood or sleep issues, patients might elaborate on feeling depressed and can give a history of movements in their sleep, likely REM sleep disorder. Other autonomic features that a patient of PD might have include urinary retention, erectile dysfunction and orthostatic hypotension. Patients with advanced disease can also present with memory decline due to the neurodegenerative changes of the brain.

On examination, patients have the characteristic cog-wheel rigidity which can be elicited by slow rotatory movements of their wrists. Patients can appear to be stiff, they have shortened stride while walking and arm swing is typically reduced asymmetrically. They walk with a stooped posture and have to take multiple short steps to turn around. On pulling them back suddenly, called the posterior pull test, patients take a lot of steps to catch themselves or may even fall.

HOW DOES PARKINSON’S DISEASE PROGRESS?

In classic PD cases, the patient has tremor of one hand in stage 1. This can progress to the other hand in stage 2. Stage 3 is characterized by mild balance problems, which can worsen causing falls in stage 4 needing cane or a walker to walk and if it continues to worsen, in stage 5 patients can be wheelchair or bed bound. Not all patients progress to stage 5 and brain imaging such as (Dopamine Transporter, DaT) scan is not usually a good prognostication tool.

WHAT MIMICS PARKINSON’S DISEASE?

The PD tremor is most commonly mistaken for an essential tremor and it remains refractory of usual treatment of propranolol, primidone etc. In such situations, emphasis should be put on looking out for other clinical features of PD like bradykinesia and gait disturbances.

Progressive supranuclear palsy (PSP) can have similar features of bradykinesia, rigidity and gait disturbances but patients may also have vertical gaze paralysis and falling en-block while sitting which is not a feature of PD and MRI Brain of PSP patient may show midbrain atrophy which is described as “Hummingbird” sign.

Patients of Lewy Body Dementia (LBD) have many features of Parkinson’s but those symptoms usually tend to occur after dementia symptoms. In contrast dementia is progressively developed later in the course of disease in PD patients due to overall neurodegeneration. In addition, LBD patients have very vivid visual hallucinations along with wide mood fluctuation which are not a feature of PD, however PD dementia patients may get hallucination or psychosis which is treated with pimavanserin. Ischemic or hemorrhagic stroke, mass lesions, hydrocephalus and Wilson’s disease can be excluded using imaging techniques such as MRI brain.

HOW IS PARKINSON’S DISEASE DIAGNOSED?

The diagnosis of PD is primarily a clinical one. A comprehensive examination and proper staging of PD can be done using Unified Parkinson’s Disease Rating Scale (UPDRS) which is a gold standard tool to measure not only the severity and progression of PD but also helpful in monitoring the response to medications. While evaluating the patient it is also imperative to go over their list of medications to exclude the possibility of drug-induced PD. Traditional antipsychotic medications are most implicated in such a condition.

In clinically uncertain cases nuclear imaging DAT-SPECT scan may be helpful, however routine use of this test should be discouraged. A clear clinical improvement after levodopa treatment provides the best confirmation of PD.

HOW IS PARKINSON’S DISEASE TREATED?

There is no cure for PD at this time, however since the pathogenesis of PD involves loss of dopaminergic neurons, the primary mode of treatment is replenishing the dopamine levels with medications such as levodopa with carbidopa, which may also be used in combination with other classes of medications including Dopamine Agonists, COMT Inhibitors, MAO-B Inhibitors, and Anticholinergic agents. Treatment is individualized to the patient and adjusted over time based on symptoms, side effects and tolerability. Dopamine agonists like pramipexole, or ropinirole can be used in younger patients with the advantage of lesser side effects. If a patient primarily has tremor only, amantadine or anticholinergics may be used. In advanced stages of PD, patients may have psychosis with visual or auditory hallucinations and delusions. Pimavanserin, a serotonin 5-HT2 receptor antagonist is the only FDF approved treatment for psychosis associated with PD.

Most PD medications provide good improvement in symptoms for the first 3 to 6 years, but with the natural progression of the disease, results can decline with time. Levodopa-Carbidopa can have the “on-off” phenomenon where symptoms may worsen during the “off” periods. Apomorphine, a dopamine agonist, is the only FDA approved medication which can be used for symptom control during the off periods.

Typical Dopamine Transporter Ligands Single Photon Emission Tomography (DaT-SPECT) scan findings in patients with Idiopathic Parkinson’s Syndrome (IPS) showing reduced striatal DAT availability compared with a normal finding. The reduction is often left/right asymmetrical, usually more pronounced in the hemisphere contralateral to the clinically dominant side. The posterior “tail” of the putamen is almost always most strongly affected. The motor symptoms of IPS manifest only after a DAT loss of about 50% in the putamen. The atypical neurodegen erative parkinsonian syndromes, especially Progressive Supranuclear Palsy (PSP) and Multiple System Atrophy (MSA) of the parkinsonian type show similar patterns of findings on DAT-SPECT as IPS.

PD being a multi system disease requires a multi system ap proach. Patients can benefit a lot with physical therapy, like LS VT-BIG (Lee Silverman Voice Treatment), which encompasses physical therapy to improve their gait and balance coupled with speech therapy to address the hypophonia which can be pres ent. Patients should be encouraged to have an active lifestyle.

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