Parkinson Plus Syndromes

The Parkinson plus syndromes are atypical, neurodegenerative parkinsonian syndromes that share some features with idiopathic Parkinson disease. They progress more rapidly and characteristically respond poorly or incompletely to standard dopaminergic treatment.

The group comprises progressive supranuclear palsy, multiple system atrophy and corticobasal degeneration. Dementia with Lewy bodies is formally classified in this group because of shared alpha-synuclein pathology and overlap with Parkinson disease dementia.

Dementia with Lewy bodies is frequently addressed as a related but somewhat distinct entity, because of its early and prominent cognitive and neuropsychiatric presentation.

Recognising the features that distinguish these conditions from idiopathic Parkinson disease matters for prognostic counselling and realistic treatment expectations. Symptomatic treatment options are more limited and functional decline is more rapid and severe.

Classification and pathophysiology

• Progressive supranuclear palsy is associated with tau protein pathology. It features early, prominent postural instability with falls, often backward, in contrast to the more typical forward falls of idiopathic Parkinson disease.
• Progressive supranuclear palsy also features vertical supranuclear gaze palsy. It initially affects downgaze before progressing to more complete ophthalmoplegia. Rigidity is symmetrical and axial predominant.
• Multiple system atrophy is associated with alpha-synuclein pathology within glial cells. This contrasts with the neuronal alpha-synuclein pathology of Parkinson disease and dementia with Lewy bodies.
• Multiple system atrophy has two clinical subtypes, defined by the predominant feature at presentation. The parkinsonian subtype has bradykinesia and rigidity, characteristically more symmetrical than idiopathic Parkinson disease, with poor or absent levodopa response. The cerebellar subtype has ataxia as the predominant feature.
• Both subtypes share prominent, early and severe autonomic dysfunction, the defining unifying feature of the condition.
• Corticobasal degeneration is also associated with tau protein pathology. It presents with a markedly asymmetric combination of parkinsonian and cortical features, typically affecting one side of the body substantially more than the other.
• The distinctive feature of corticobasal degeneration is the "alien limb" phenomenon, in which the affected limb appears to move involuntarily, outside the patient's conscious control or awareness. Apraxia, cortical sensory loss and myoclonus also occur.
• Dementia with Lewy bodies shares the neuronal alpha-synuclein pathology of idiopathic Parkinson disease. It combines fluctuating cognition, recurrent visual hallucinations (typically well formed and detailed) and parkinsonian motor features.
• The relative timing of cognitive and motor onset separates dementia with Lewy bodies from Parkinson disease dementia. Cognitive decline before, or within one year of, motor onset supports dementia with Lewy bodies. Motor symptoms preceding cognitive decline by more than one year support Parkinson disease dementia.
• These two closely related labels represent points along a shared underlying disease spectrum.

• Progressive supranuclear palsy presents with early, prominent postural instability and falls, frequently within the first year of symptom onset. This is notably earlier than typical in idiopathic Parkinson disease.
• Other features of progressive supranuclear palsy are vertical gaze palsy, axial rigidity, dysarthria and dysphagia.
• The face often has a characteristic appearance from reduced blink rate and frontalis muscle overactivity, sometimes described as a look of surprise or a startled expression.
• Multiple system atrophy is defined by prominent, early autonomic dysfunction together with parkinsonian or cerebellar motor features, according to subtype.
• Autonomic features include severe orthostatic hypotension, urinary dysfunction (incontinence or retention) and erectile dysfunction in men. Autonomic dysfunction is frequently particularly disabling and difficult to treat.
• Corticobasal degeneration presents with a markedly asymmetric combination of limb rigidity, apraxia, alien limb phenomenon, cortical sensory loss and myoclonus. Apraxia is difficulty performing learned, purposeful movements despite intact motor strength and coordination.
• Many patients with corticobasal degeneration develop progressive cognitive and language impairment as the disease advances.
• Dementia with Lewy bodies presents with fluctuating cognition, recurrent well formed visual hallucinations and parkinsonian motor features.
• Attention and alertness vary markedly, sometimes dramatically, over relatively short timeframes. This is a particularly characteristic and clinically useful diagnostic feature.
• Dementia with Lewy bodies carries a marked, well recognised sensitivity to antipsychotic medication, with potentially severe, sometimes life threatening neuroleptic sensitivity reactions. This is a critical safety issue requiring particular caution with antipsychotics, addressed further under major neurocognitive disorder generally.

• Diagnosis is predominantly clinical. It rests on recognising the features that distinguish each syndrome from idiopathic Parkinson disease and from each other.
• Screen systematically for "red flag" features in any patient presenting with parkinsonism. These are early falls, early and prominent autonomic dysfunction, early and prominent cognitive decline, marked early symmetry, poor or absent levodopa response, and additional features such as vertical gaze palsy or alien limb phenomenon.
• Structural neuroimaging may show characteristic patterns in more advanced disease, though not with full sensitivity or specificity.
• In progressive supranuclear palsy, midbrain atrophy is sometimes described as the "hummingbird sign" on midsagittal magnetic resonance imaging.
• In multiple system atrophy, pontine and cerebellar atrophy occurs with characteristic signal change patterns.
• Formal autonomic function testing characterises the severity and pattern of autonomic dysfunction in suspected multiple system atrophy.
• Formal neuropsychological assessment characterises the pattern of cognitive impairment in corticobasal degeneration and dementia with Lewy bodies.
• Dopamine transporter imaging (detailed under Parkinson disease) shows reduced uptake across this whole group of degenerative parkinsonian conditions. It helps distinguish degenerative from non-degenerative causes of parkinsonism.
• It cannot distinguish idiopathic Parkinson disease from the Parkinson plus syndromes, which share the same pattern of reduced striatal dopaminergic tracer uptake.

• A levodopa trial is generally reasonable in the initial assessment of any patient with parkinsonism. It provides symptomatic benefit and has supportive diagnostic value.
• A poor or absent response supports a Parkinson plus syndrome rather than idiopathic Parkinson disease. Response in Parkinson plus syndromes is characteristically limited and frequently absent, compared with the robust, sustained response of idiopathic Parkinson disease.
• Management is predominantly supportive and symptomatic, as no disease modifying treatment exists and standard dopaminergic treatment gives limited benefit.
• Multidisciplinary allied health input is central, with physiotherapy, occupational therapy, and speech and language therapy addressing the functional impairments present.
• Multiple system atrophy needs proactive, structured management of autonomic dysfunction. This is important and often clinically challenging.
• Treat orthostatic hypotension with non-pharmacological measures and, where required, fludrocortisone or midodrine. Manage urinary dysfunction.
• Dementia with Lewy bodies needs particular caution with antipsychotics because of its well recognised neuroleptic sensitivity.
• Cholinesterase inhibitors, used on similar principles to Alzheimer disease, have useful evidence of benefit for cognitive symptoms and for the characteristic visual hallucinations.
• Disease progression is more rapid and the overall burden greater than in idiopathic Parkinson disease. Engage palliative care services early and hold advance care planning discussions.
• Provide structured, ongoing multidisciplinary support for patients, families and carers throughout the disease course.
• Give realistic, honest prognostic counselling from diagnosis, delivered sensitively. Treatment options are more limited and functional decline more rapid in this group.