Differential Diagnosis of Parkinson’s Disease

Introduction

Parkinson’s disease (PD) is a neurological condition characterized by bradykinesia and rigidity, often accompanied by tremor, which affects approximately 1 million persons in the United States. A number of other disorders have a similar, “akineto-rigid” presentation, but often a different response to treatment, as well as additional symptoms that may present unique challenges to the patient and treating clinicians. For this reason, it is important to have some familiarity with the more common of these “non-PD” syndromes. It is not always easy to make the correct diagnosis; a study by Hughes and colleagues¹ correlating diagnoses with autopsy results found that in patients who ultimately were diagnosed with a form of parkinsonism besides PD, the original diagnosis was altered 60% of the time. For example, general neurologists correctly diagnosed multiple systems atrophy (MSA) initially only 50% of the time, while the rate for neurologists with special training in movement disorders was 88.2%.¹

These disorders can be categorized as primary or secondary forms of parkinsonism. Primary parkinsonian conditions comprise a group of disorders including idiopathic Parkinson’s disease (IPD), as well as other neurodegenerative disorders. These are atypical parkinsonian conditions, previously known as “Parkinson’s Plus” syndromes. This group includes MSA, progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), and a variety of less common disorders. Secondary forms of parkinsonism include those caused by infection, vascular disease, metabolic derangement, medications, and toxins.

PARKINSONIAN DISORDERS

Parkinson’s disease, with rigidity and bradykinesia, is the most common type of parkinsonism. Commonly, PD begins on one side of the body, and the patient will note a resting tremor in the affected limb or limbs.

However, the atypical forms of parkinsonism often have a similar presentation, with some bradykinesia, perhaps an early gait disorder, or postural reflex impairment. Often, tremor is lacking. These patients may not have obvious manifestations of a particular disease, such as impaired volitional gaze or prominent orthostasis, to enable a diagnosis of PSP or MSA, respectively. They may even have some response to dopaminergic therapy, although this is typically limited in magnitude and duration. Frequently, a patient with this presentation is given a diagnosis of PD. As the disease progresses, the clinical presentation will usually evolve to make the diagnosis more evident.

In some cases, it is not possible to make a definitive diagnosis, as a patient simply does not develop the hallmarks of a particular form of atypical parkinsonism. Differentiation of the type of parkinsonism is important for several reasons. Prognosis and survival may vary significantly depending on the diagnosis. Patients with PD tend to live out their normal life-spans and, in general, have symptoms that are more amenable to treatment. Symptoms that can threaten viability, such as dysphagia and falling, tend to occur earlier in atypical parkinsonism. This, along with lack of effective treatments and more rapid disease progression, tend to shorten survival length in these patients.

Choice of treatment is also affected by diagnosis. Deep brain stimulation (DBS), for example, has been shown to be less effective in atypical parkinsonism than in IPD, and patients with dementia could actually be made worse by surgery.²

Finally, the study of treatment options for all forms of parkinsonism can only be conducted effectively if patients are classified appropriately.

PRIMARY PARKINSONISM

Discoveries related to the pathophysiology of several neurodegenerative diseases have added to the understanding of PD, as well as atypical parkinsonisms. These disorders can often be classified as familial (rigid forms of Huntington’s disease, frontotemporal dementia with parkinsonism-17 [FTDP-17]) or sporadic (PSP, MSA). In addition, we have learned much about the structure and content of the inclusion bodies characteristic of many of these diseases. We can therefore classify many of these conditions as either synucleinopathies (PD, DLB, MSA) or tauopathies (FTDP-17, PSP, corticobasal degeneration [CBD]),³ depending on the predominant characteristic of the protein inclusion body.

Synucleinopathies refer to conditions in which the inclusion contains alpha-synuclein, a protein generally found in synaptic terminals. In PD, for example, abnormal alpha-synuclein is an important component of the Lewy body dementia. The inclusions in tauopathies contain depositions of tau, a protein associated with microtubules. Abnormal tau is found in neurofibrillary tangles in Alzheimer’s disease, and in the neurons and glia in PSP and CBD.⁴ The hope is that understanding the molecular and pathophysiologic mechanisms of these conditions will eventually yield new treatments.

Synucleinopathies
Parkinson’s Disease Parkinson’s disease is a progressive, neurodegenerative disorder characterized pathologically by loss of dopaminergic cells in the substantia nigra and by the presence of Lewy bodies.

Most commonly, the patient presents with a unilateral resting tremor, bradykinesia, and rigidity, and frequently nonmotor symptoms as well. These may include depression, anxiety, orthostatic hypotension, cognitive changes, and sleep disturbance. Response to dopaminergic medications is generally robust, and there are no atypical features such as early dementia or marked autonomic dysfunction. There are a variety of other presentations, particularly in patients with a younger age of onset.

The etiology of PD appears to involve both environmental exposures and some degree of genetic susceptibility. Several environmental factors have been identified, including exposure to certain pesticides, well water, and agriculture.⁵ In the last decade, at least five genes have been identified that have the potential to cause neuropathological changes that are similar to those seen in PD.⁶ Further study is needed to determine the significance of these mutations, but it does appear likely that some of these early-onset cases will come to be associated with genetic factors.³ Genes seem to play some role in late-onset PD as well: monogenic forms such as LRRK2, Parkin, PINK1, DJl, and others accounting for about 3% of cases,⁷ with LRRK2 in particular producing a relatively common and clinically typical form of late-onset PD.⁸ Other genes, such as alpha-synuclein (SNCA) may play a role in the pathogenesis of sporadic PD under certain conditions, such as oxidative stress.⁹ However, a study published by Fung and colleagues¹⁰ used single nucleotide polymorphism (SNP) genotyping to search for a single gene that might be related to PD in a group of 267 patients with PD. Despite the use of more than 408,000 SNPs, no single gene emerged as a clear causal agent for PD.¹⁰ Persons with early-onset PD were not included in the analysis. This seems to support the findings of previous studies, such as the evaluation of the prevalence of PD in twin pairs of soldiers from WWII, suggesting a lack of prominent hereditary factors in PD presenting over age 50.¹¹

Multiple Systems Atrophy Multiple systems atrophy is a progressive neurodegenerative synucleinopathy in which the parkinsonian signs of akinesia and rigidity are accompanied by other features such as autonomic dysfunction, neuropathy, or cerebellar signs. Because the clinical presentation is variable, the syndromes were named as separate entities when first described: Shy Drager Syndrome (SDS), for example, when dysautonomia was the prominent feature; olivopontocerebellar atrophy (OPCA) when the cerebellar dysfunction was marked. Most authors now include them under the name MSA, though the designations MSA-C may be used for a more cerebellar presentation and MSA-P for a more parkinsonian one.¹² In some cases, the nonmotor features outweigh the motor ones in terms of patient distress and limitation of function. For example, an individual with severe orthostatic hypotension may experience overwhelming fatigue, weakness, and other disabling symptoms from the hypotension that greatly outweigh the bradykinesia and rigidity. Persons with PD and DLB may also have some features of dysautonomia, but they generally are not as early or as prominent as in MSA, where problems with bladder, sexual function, and blood pressure control may develop well before motor symptoms.

Dementia with Lewy Bodies DLB is a condition in which dementia and parkinsonism present in close temporal proximity. Other features may also be present, such as hallucinations, dysautonomia, behavior disturbances, and fluctuations in cognitive function.¹³ This condition has been described in great detail by those who specialize in memory disorders as a separate entity from Parkinson’s disease with dementia (PDD). However, many aspects of the disorders are similar, including the clinical appearance, type of cognitive decline, and neuropathology. In the movement disorders clinic, DLB is suspected when a person with parkinsonian features develops hallucinations and cognitive decline, initially consisting more of behavioral abnormalities such as delusions or agitation than memory loss.

Tauopathies
Frontotemporal Dementia with Parkinsonism FTDP-17 is a rare, autosomal dominant neurodegenerative disease in which the behavioral manifestations and cognitive decline of frontotemporal dementia are accompanied by parkinsonian signs. A variety of mutations in the tau gene can occur in this condition. The most common occur within the microtubule-binding region.¹⁴ The clinical manifestations are variable but may include poor judgment, disinhibition, compulsive or inappropriate behaviors, substance abuse, or aggression. Memory loss may occur, but is often not prominent until later in the disease. The parkinsonism is generally an atypical presentation with balance difficulty, bradykinesia, and rigidity. Dystonia, neuropathies, and gaze palsies have also been described. Levodopa response is generally poor, and its use may even worsen the symptoms.

Progressive Supranuclear Palsy PSP was described in 1964 by Steele, Richardson and Olszewski as a condition in which extensor rigidity of the neck, volitional eye movement and facial spasticity, dysarthria, and dementia were the prominent features.¹⁵ It has since been recognized that a significant number of persons with atypical Parkinson’s disease will go on to develop those features as well. The typical presentation is of a person with akinesis and rigidity who has early balance impairment and falling, and who has little or no response to levodopa. Eventually, the patient is noted to have loss of downgaze, sometimes heralded by difficulty seeing steps or the food on his or her plate. Dysphagia may become severe, with recurrent aspiration pneumonias often prompting a decision about whether to insert a gastrostomy tube.

Corticobasal Degeneration CBD was described as a clinical syndrome in 1968 in a paper by Rebeiz, Kolodny and Richardson.¹⁶ This is another syndrome in which akinetic-rigid parkinsonism is combined with other neurologic signs to create a recognizable entity. In this condition, the symptoms are generally unilateral and may include an action tremor and signs of cortical involvement such as apraxia, frontal lobe reflexes, and the “alien limb sign,” in which the involved extremity seems not to belong to the patient or to function independently from his/her volitional control.¹⁶

SECONDARY PARKINSONIAN DISORDERS

Vascular parkinsonism is a term that refers to parkinsonian features due to strokes in the basal ganglia or associated white matter. Progression of symptoms may be insidious or step-wise, often reflecting the development of the vascular pathology. These patients are less likely to respond to levodopa than patients with IPD, and may have other abnormalities on neurological exam, such as pseudobulbar affect, incontinence, and corticospinal signs. They often have more prominent symptoms in the lower half of their bodies, with poor postural reflexes and early falls.¹⁷

Parkinsonism can also be caused by a variety of toxins. Some selectively attack dopamine cells, such as MPP+, the toxin that results from the conversion of 1-Methyl-4-phenyl-1,2,3,6-Tetrahydroperidine (MPTP) within the body. Others are less selective and cause more widespread damage but may result in parkinsonian signs as well as other CNS features; these include manganese poisoning, rotenone, and carbon monoxide exposure.

Drug-induced parkinsonism is usually related to agents that block dopamine receptors such as antipsychotics and metaclopramide.^18,19 Valproic acid has also been reported to cause parkinsonian symptoms.²⁰

CONCLUSION

In summary, this article reviews some of the common differential diagnoses to be considered when faced with a patient with features of parkinsonism. Recent advances in pathophysiology and genetics have begun to elucidate the heterogenous nature of this group of disorders.

The author reports no relevant financial relationships.