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Review
, 113 (5), 61-9

The Differential Diagnosis and Treatment of Atypical Parkinsonism

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Review

The Differential Diagnosis and Treatment of Atypical Parkinsonism

Johannes Levin et al. Dtsch Arztebl Int.

Abstract

Background: Aside from idiopathic Parkinson syndrome (Parkinson's disease), there are a number of other, so-called atypical parkinsonian syndromes: dementia with Lewy bodies (DLB), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). DLB is a common disease, with a prevalence of 0.4% (400 cases per 100 000 persons) in the elderly; MSA and PSP both have a prevalence of 5 to 10 per 100 000 persons, while the prevalence of CBD is about 1 per 100 000.

Methods: This review is based on pertinent publications retrieved by a selective literature search.

Results: The atypical parkinsonian syndromes are synucleinopathies and tauopathies, i.e., disorders characterized by the abnormal deposition of the proteins α-synuclein and tau. The site of deposition is correlated with the clinical features. In DLB, synuclein is mainly deposited in neocortical neurons, with some brain stem involvement as well. The main clinical features are dementia and, later on, parkinsonism. In MSA, synuclein is deposited in oligodendrocytes, mainly in the cerebellum but also in the brain stem; the main clinical feature is autonomic dysfunction combined with parkinsonism or cerebellar ataxia. Synucleinopathies often impair REM (rapid eye movement) sleep. PSP and CBD, on the other hand, are primary tauopathies. PSP usually causes predominantly supranuclear vertical gaze palsy and early postural instability with falls, less commonly parkinsonism (PSP-P) or frontotemporal dementia (PSP-FTD) as its most prominent feature. CBD typically manifests itself as markedly asymmetrical parkinsonism with apraxia or cortical sensory disturbance. At present, there is no accepted causal treatment for any of these disorders; the available symptomatic treatments are of limited efficacy and are supported only by low-level evidence.

Conclusion: Causal treatments for neurodegenerative diseases are now being developed and tested, and thus a molecular diagnosis is desirable. This will require the cooperation of primary care physicians with specialized centers.

Figures

Figure 1
Figure 1
Disease definitions. Neurodegenerative parkinsonian syndromes are synucleinopathies or tauopathies which are defined by the intracellular aggregates of the alpha-synuclein or tau protein. The disease entities multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) are characterized neuropathologically by glial cytoplasmic inclusions, Lewy bodies, tuft-shaped astrocytes, or astrocytic plaques, respectively. The resulting clinical syndromes: MSA with predominantly cerebellar symptoms (MSA-C), MSA with predominantly parkinsonian symptoms (MSA-P), pure autonomic failure (PAF), idiopathic rapid eye movement sleep behavior disorder (iRBD), Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), dementia with Lewy bodies (DLB), pure akinesia with gait freezing (PAGF), PSP with predominantly parkinsonian symptoms (PSP-P), Richardson’s syndrome (RS), corticobasal syndrome (CBS), progressive non-fluent aphasia (PNFA), or the behavioral variant of frontotemporal dementia (bvFTD). PD and PDD are the most common parkinsonian syndromes. From a clinical perspective the syndromes in bold print—MSA-C, MSA-P, DLB, PAGF, PSP-P, RS, and CBS—are classed among the atypical parkinsonian syndromes. The other syndromes are characterized primarily by non-motor symptoms. The estimated positive predictive value (PPV) of the clinical syndromes for an underlying neuropathological disease entity is indicated by arrows (bold: high PPV; regular: medium to low PPV)
Figure 2
Figure 2
Imaging results. On magnetic resonance imaging, the midsagittal plane of the brainstem does not show a specific atrophy pattern in Parkinson’s disease (PD) (A), whereas in progressive supranuclear palsy (PSP) (B) midbrain atrophy (*) is visible, and in multiple system atrophy (MSA) (C), atrophy of the pons (*) and in the upper portion of the cerebellar vermis (#) can be seen. Further characteristic imaging findings of atypical parkinsonian syndromes are shown in the eFigure
eFigure
eFigure
Magnetic resonance imaging shows in the midsagittal plane no specific atrophy pattern for Parkinson’s disease (PD) (A), whereas in progressive supranuclear palsy (PSP) (B), midbrain atrophy (*) is visible, and for multiple system atrophy (MSA) (C) the image shows pontine atrophy (*) and atrophy in the upper portion of the cerebellar vermis (#). Furthermore, signal anomalies in T2 weighted MRI with 1.5 Tesla are suggestive of, but not highly sensitive for, MSA—especially a cross-shaped hypointensity in the pons (hot cross bun sign, *, D) and a hypointense putamen (*) with hyperintense putaminal rim (putaminal rim sign, arrow, E). In corticobasal syndrome (CBS) (F), what is typically seen is asymmetric parietal atrophy with atrophy of the gyri and accentuation of the sulci (arrows). In the coronal plane, atrophy of the hippocampus (*) and the temporal lobe (#) with dilatation of the temporal horns of the lateral ventricles (+) are typically seen in Alzheimer’s dementia (AD). However, findings are normal in dementia with Lewy bodies (DLB) (H). Molecular diagnosis of these disorders is the objective of current research, such as has been shown in the example of a patient with PSP by confirming tau deposition in the basal ganglia and the brainstem on positron emission tomography (PET) using the radiopharmaceutical 18-F-T807, which binds to tau (I, Prof Drzezga, Clinic and Outpatient Clinic of Nuclear Medicine, University Hospital Cologne)

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