Pinning down Parkinson's disease

Parkinson's disease (PD) is a diagnosis that requires constant questioning, according to Stephen G. Reich, MD.

“It's not uncommon at day one to think that someone has PD, and by year two or three or four, it's clear that the diagnosis is not evolving true to form,” he said.

Dr. Reich provided a comprehensive rundown on classic presentations of PD and its mimics at a session at the 2022 International Congress on Parkinson's Disease and Movement Disorders, held this past September in Madrid, Spain.

Many studies have demonstrated that the initial diagnosis of PD is often incorrect, said Dr. Reich, who is the Frederick Henry Prince Distinguished Professor of Neurology at the University of Maryland School of Medicine in Baltimore.

One meta-analysis published in the Feb. 9, 2016, Neurology indicated that about 20% of patients who had been diagnosed with PD actually had a different condition, usually a parkinsonian syndrome such as multiple system atrophy or progressive supranuclear palsy. Another study done at Dr. Reich's clinic looked at PD diagnoses at a first medical encounter, most commonly in primary care, and found that while about 29% of patients were correctly diagnosed, about the same percentage were misdiagnosed, and most did not receive a specific diagnosis. The most common misdiagnoses were essential tremor, musculoskeletal disorders, and stroke.

“Not only was there a misdiagnosis and the implications of that, but these misdiagnoses often led to extensive and unnecessary testing,” Dr. Reich said. “The diagnosis of Parkinson's disease, even in the hands of specialists, initially can still be a challenge.”

Criteria for diagnosis

Clinicians should base diagnosis of PD on the Movement Disorder Society (MDS) criteria, published in the October 2015 Movement Disorders, Dr. Reich said. “If you're seeing patients with Parkinson's, you really need to be familiar with this.”

The criteria have four main categories, he explained. First, patients should have bradykinesia with either a resting tremor or rigidity. Second, there should be no absolute exclusionary criteria, including cerebellar signs, vertical supranuclear ophthalmoplegia, cortical sensory loss (e.g., apraxia or aphasia), treatment consistent with drug-induced parkinsonism, and normal functional imaging of the presynaptic dopamine antagonist transporter.

Dr. Reich stressed that imaging of the dopamine transporter is not required for the diagnosis and is indicated only to resolve uncertain cases. “I encourage you to carefully scrutinize the need for additional imaging when someone has otherwise what seems to be straightforward, going through the criteria, Parkinson's disease,” he said.

The third category is supportive criteria, most importantly a clear and dramatic response to dopaminergic therapy, but this has a few caveats, Dr. Reich said. Some patients with parkinsonian syndromes but not true PD might initially respond to levodopa, although not dramatically, whereas some patients with true PD, including those with large-amplitude tremor, may not respond. “The other instance is, if someone is given levodopa at a time where they're having very little functional impairment, there's no room to notice improvement,” said Dr. Reich, adding that clinicians should not consider a patient to be unresponsive to levodopa until trying a dose of 1,000 mg.

The fourth and final MDS category involves vigilance for red flags, Dr. Reich said. These include rapid progression, early bulbar dysfunction, early falls, early autonomic failure, and absence of expected nonmotor features of PD, such as hyposmia and sleep disorder, within five years. “The lack of nonmotor symptoms, either preceding the motor onset or along with it, is also an important red flag. … They're not only important for the diagnosis, but just general care of the patient with Parkinson's disease, as they're very common,” he said. He noted that many patients with PD have multiple nonmotor symptoms, including impaired olfaction and particularly REM sleep behavior disorder.

Sorting through symptoms

Tremors are a classic symptom of PD and often emerge with mental distraction, Dr. Reich explained. “Although about a third of people with Parkinson's don't have tremor, you like to see the classic resting tremor.”

When looking for bradykinesia, have patients do a series of rapid repetitive movements, such as finger, toe, or heel tapping, he said. “They may start off good, but then they start to decrement, so maybe 15 or 20 in a series of these movements is important,” Dr. Reich said.

Clinicians can usually find mild bradykinesia or other subtle symptoms on the patient's asymptomatic side, he noted. Other symptoms to look for are a decreased arm swing and micrographia when the dominant side is affected, Dr. Reich said.

Although the classic Parkinson's presentation involves a pill-rolling resting tremor, it's not uncommon to also see tremor of the jaw, tongue, lips, chin, or lower extremity, he said. “In Parkinson's disease, when these other parts of the body are involved, you usually have very clear other signs of Parkinson's,” he said.

A type of PD tremor called re-emergent tremor can sometimes cause diagnostic confusion, Dr. Reich said. “Basically, this is a postural continuation of their resting tremor. Typically, there's a short latency after patients maintain posture, and then you'll see the same tremor come back. This is in contrast to the fact that many people with PD, in addition to their resting tremor, if you look carefully, will have a very slight, bilateral, often a little bit faster postural tremor, but there's often no latency there.”

False-negatives, false-positives

It's important to recognize that about 25% or 30% of people with PD do not have tremor, and in these situations, clinicians might not consider the diagnosis, Dr. Reich said. “It's because patients don't come in with a chief complaint of bradykinesia. They usually complain of weakness, and this often leads someone to think that maybe they've had a stroke or that they have cervical stenosis. They may not think about PD.”

Other presentations of PD can lead to a false-negative diagnosis, Dr. Reich explained, such as pain or frozen shoulder. A study published in the January 1989 Journal of Neurology, Neurosurgery, and Psychiatry found that 40% of patients with PD had shoulder symptoms and that about 12% had a true frozen shoulder; frozen shoulder was the initial PD symptom about 8% of the time. “Don't necessarily discount the diagnosis of Parkinson's in someone presenting with musculoskeletal complaints,” he said, noting that clinicians can also misdiagnose young-onset disease, particularly in patients under age 45 years.

False-positive PD diagnoses may occur when patients are taking a medication that can induce tremor, Dr. Reich said. He used the example of a patient referred to him for untreated PD who had been taking metoclopramide and subsequently developed tardive dyskinesia. “In terms of drug-induced parkinsonism, it's usually symmetrical and usually atremulous but not always, and it can look just like PD,” he said.

Dr. Reich stressed the importance of taking a very careful drug history, since drug-induced parkinsonism takes time to resolve and the patient may no longer be on the offending medication. “It's not just a matter of what drugs they're on the day that you see them, but what drugs they've been on over the past year,” he said.

Essential tremor is another common PD misdiagnosis, Dr. Reich said. In contrast to Parkinson's, which typically features a unilateral or asymmetrical tremor at onset, essential tremor is a bilateral action tremor that has been present for at least three years.

“In fact, patients with essential tremor, at least by the time they see a movement disorder specialist, have many times had the tremor for a very long time, years or sometimes even decades, whereas patients with PD who have tremor typically present within six or 12 months,” he said. “So just from the history, if they say they've had the tremor for 10, 15, 20 years, that alone is an important historical differential diagnostic point.”

Other indications of essential tremor include a positive family history (usually autosomal dominant), improvement with alcohol, coexistent tremor of the head or voice (both of which are uncommon with PD), and tremulous handwriting, he said. In addition, while PD tremor often persists when people walk, essential tremor usually does not.

Dr. Reich also discussed lower-body symptoms in patients who may have some parkinsonian features but do not have PD. Patients with normal-pressure hydrocephalus, for example, typically present with impaired gait or balance and little or no involvement of the upper limbs, ventriculomegaly, and no response to levodopa. Patients also usually maintain their arm swing when they walk, whereas patients with PD do not.

Other examples of PD mimics include highest-level gait disorders in which patients, especially the elderly, have some but not all parkinsonian features and don't respond to levodopa, and so-called vascular parkinsonism. The latter condition is probably overdiagnosed, usually in patients with a gait disorder and some white matter changes on the MRI, Dr. Reich said. “Again, this notion of lower-half parkinsonism should cast some doubt on the diagnosis of actual PD.”

The most common mimickers of Parkinson's disease are parkinsonian syndromes, such as progressive supranuclear palsy, corticobasal degeneration, multiple-system atrophy, and dementia with Lewy bodies, all of which tend to progress faster than Parkinson's disease does, Dr. Reich said. He recommended becoming familiar with the red flags and diagnostic criteria for these conditions.

“Lastly,” he said, “it's really important, once you diagnose someone with PD, that every time you see them from then on, you clinically reevaluate the diagnosis.”