Parkinson-Plus Syndromes

Parkinson-plus syndromes, also termed atypical parkinsonian disorders, are a group of progressive neurodegenerative diseases that share the cardinal features of parkinsonism (bradykinesia, rigidity, tremor, and postural instability) but are distinguished from idiopathic Parkinson's disease by additional neurological deficits, a more rapid clinical course, and a poor or unsustained response to levodopa therapy. The three principal entities are progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal syndrome (CBS).

Collectively, atypical parkinsonian disorders account for approximately 5–10% of all patients presenting with parkinsonism in Australian movement disorder clinics. The combined population prevalence is estimated at 10–20 per 100,000, with PSP at 5–7 per 100,000, MSA at 3–5 per 100,000, and CBS at 1–2 per 100,000. The mean age of onset is in the sixth to seventh decade, with a slight male predominance for MSA and PSP.

In Australia, diagnosis is frequently delayed by 2–4 years due to initial misdiagnosis as idiopathic Parkinson's disease. This diagnostic delay has significant implications for prognostication, advance care planning, and access to allied health and support services. The Movement Disorder Society (MDS) updated diagnostic criteria for PSP (2017), MSA (2022), and CBS-related pathology (2021) have improved diagnostic sensitivity and specificity.

There is limited Australian-specific epidemiological data on parkinson-plus syndromes. However, the Australian Institute of Health and Welfare (AIHW) recognises that neurodegenerative diseases collectively represent one of the leading causes of disability-adjusted life years (DALYs) in Australians aged 65 and over. Access to specialist movement disorder services is concentrated in major metropolitan centres, creating significant care gaps for rural and remote populations, including Aboriginal and Torres Strait Islander communities.

Parkinson-plus syndromes are classified by their underlying protein pathology:

The basal ganglia degeneration in these disorders is more widespread and severe than in idiopathic Parkinson's disease, accounting for the poor levodopa response. In MSA, additional degeneration of autonomic preganglionic neurons in the intermediolateral cell column and Onuf's nucleus in the sacral spinal cord explains the severe autonomic and urinary dysfunction. In PSP, involvement of the midbrain tectum and rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) accounts for the characteristic vertical supranuclear gaze palsy.

None of these conditions currently have a proven disease-modifying therapy, although several tau-directed and α-synuclein-directed immunotherapies are in Phase II and III clinical trials as of 2024.

Progressive supranuclear palsy (PSP), historically known as Steele-Richardson-Olszewski syndrome, is the most common atypical parkinsonian disorder. The classic phenotype is PSP-Richardson syndrome (PSP-RS), but several clinical variants are now recognised by the MDS PSP diagnostic criteria (2017).

Clinical Variants

Hallmark Clinical Features of PSP-RS

• Vertical supranuclear gaze palsy (VSGP): Downward gaze limitation more specific than upward; progresses to complete vertical and then horizontal gaze restriction. The vestibulo-ocular reflex (VOR) is initially preserved (supranuclear), confirming the brainstem localization.
• Early unexplained falls: Occur within the first year in most PSP-RS patients; backward falls are characteristic ("en bloc" falls without protective responses).
• Axial rigidity greater than limb rigidity: Prominent neck extension (retrocollis) and trunk stiffness; the patient tends to sit rigidly upright or extend backward.
• Pseudobulbar palsy: Dysarthria (spastic-hypokinetic), dysphagia, and emotional incontinence (pseudobulbar affect with involuntary laughing or crying).
• Cognitive features: Subcortical dementia pattern — executive dysfunction, apathy, reduced verbal fluency, impaired response inhibition (e.g., "applause sign" — inability to clap exactly three times).
• Frontal release signs: Palmar grasp reflex, Myerson's sign (persistent glabellar tap response), and applause sign are common.
• Sleep disturbance: REM sleep behaviour disorder occurs in up to 30% of PSP patients.

Diagnostic Criteria (MDS 2017)

The MDS PSP criteria use a two-tier system:

• Possible PSP: A progressive disorder with age at onset ≥40, either vertical supranuclear gaze palsy OR both slow vertical saccades and either postural instability within 3 years or unexplained falls within 3 years; no exclusion criteria met.
• Probable PSP: Requires vertical supranuclear gaze palsy or slow vertical saccades PLUS postural instability or unexplained falls within the first year; onset age ≥40; no exclusion criteria met.
• Definite PSP: Requires histopathological confirmation (tau-positive tufted astrocytes, neurofibrillary tangles, and threads in characteristic distribution).

Multiple system atrophy (MSA) is a progressive synucleinopathy characterised by any combination of parkinsonism, cerebellar ataxia, and autonomic dysfunction. It is classified into two motor subtypes according to the predominant motor feature:

Hallmark Clinical Features

Autonomic Dysfunction (present in all MSA patients — mandatory for diagnosis)

• Orthostatic hypotension: Systolic blood pressure drop ≥20 mmHg or diastolic drop ≥10 mmHg within 3 minutes of standing; may be symptomatic (dizziness, presyncope, syncope) or asymptomatic. Often presents before motor features.
• Urinary dysfunction: Urgency, frequency, urge incontinence, and incomplete bladder emptying are nearly universal. Post-void residual volume >100 mL is characteristic and distinguishes MSA from idiopathic Parkinson's disease, where post-void residuals are typically normal.
• Constipation: Severe and often predates motor symptoms by years.
• Erectile dysfunction: Occurs in >90% of male MSA patients and typically precedes motor symptoms by 2 or more years.

Parkinsonian Features (MSA-P)

• Symmetrical, akinesia-predominant parkinsonism; rest tremor is less common and less prominent than in idiopathic Parkinson's disease.
• Anterocollis (forward flexion of the neck) is a characteristic sign.
• Camptocormia (severe forward flexion of the thoracolumbar spine) may occur.
• Pseudo-athetosis or myoclonus of the fingers (from proprioceptive loss) — "polyminimyoclonus."
• Cold, discoloured hands and feet (cold hands and feet sign) from peripheral vasomotor dysfunction.

Cerebellar Features (MSA-C)

• Gait and limb ataxia, cerebellar dysarthria, and nystagmus.
• Cerebellar features in isolation should prompt consideration of hereditary ataxias — MSA-C typically has concurrent autonomic failure.

Respiratory Features — High Mortality Risk

• Stridor: Inspiratory stridor (particularly nocturnal) due to vocal cord abductor paralysis is a red-flag feature of MSA and carries significant mortality risk from sudden respiratory arrest.
• Sleep-disordered breathing — obstructive and central apnoea, nocturnal stridor.
• Respiratory insufficiency may be the cause of sudden death in MSA.

Diagnostic Criteria (MDS 2022)

The updated MDS criteria use a classification of neuropathological, clinically established, and clinically probable MSA:

• Clinically established MSA: Sporadic, progressive, adult-onset (≥30 years) disorder with autonomic failure (urinary incontinence with erectile dysfunction, or orthostatic hypotension within 3 min) AND either parkinsonism or cerebellar syndrome, plus at least one additional feature (e.g., stridor, anterocollis, camptocormia, polyminimyoclonus, disproportionate antecollis).
• Clinically probable MSA: Sporadic, progressive, adult-onset disorder with autonomic failure (not meeting full criteria above) AND parkinsonism or cerebellar syndrome.

Corticobasal syndrome (CBS) is a clinical syndrome characterised by asymmetric progressive parkinsonism and cortical dysfunction. CBS is a clinicopathological entity where the clinical syndrome can be caused by several different pathologies, most commonly corticobasal degeneration (CBD, a 4R-tauopathy) but also Alzheimer's disease pathology, PSP, frontotemporal lobar degeneration with TDP-43, and other proteinopathies. This pathological heterogeneity has important implications for diagnosis and future therapeutic trials.

Hallmark Clinical Features

• Asymmetric parkinsonism: Bradykinesia and rigidity markedly worse on one side; the initial clinical presentation is frequently mistaken for limb-specific complaints (e.g., "my left hand doesn't work properly").
• Alien limb phenomenon: Purposeful, involuntary movements of one limb that the patient does not feel ownership of; most commonly affects the upper limb. Classic "alien hand" signs include involuntary grasping, manipulation of objects, or intermanual conflict.
• Ideomotor apraxia: Inability to perform learned skilled movements on command despite intact comprehension and motor strength (e.g., demonstrating how to use scissors or salute).
• Cortical sensory loss: Astereognosis (inability to identify objects by touch), agraphaesthesia (inability to identify letters traced on the palm), and impaired two-point discrimination — in the context of otherwise normal primary sensory modalities.
• Myoclonus: Stimulus-sensitive myoclonus, particularly of the affected limb.
• Dystonia: Limb dystonia (often a fixed posturing of the hand or foot) is common.
• Cognitive impairment: May develop later; executive dysfunction and language difficulties (progressive aphasia variant) are seen in some cases.

Diagnostic Challenges

CBS is a clinical syndrome, not a pathological diagnosis. At autopsy, only approximately 40–50% of patients with a clinical CBS diagnosis have corticobasal degeneration (CBD) pathology. The remainder may have PSP tauopathy, Alzheimer's disease, frontotemporal lobar degeneration (FTLD) with TDP-43, or mixed pathologies. This has led to the development of new MDS diagnostic criteria for CBD pathology (2021) that distinguish between "probable CBD" and "possible CBD" based on clinical phenotype (corticobasal syndrome, frontal behavioural-spatial syndrome, progressive supranuclear palsy syndrome, or nonfluent/agrammatic variant primary progressive aphasia).

Differential Diagnosis of Asymmetric Parkinsonism with Cortical Features

• Corticobasal degeneration (CBD) pathology — most common underlying pathology
• Alzheimer's disease presenting as CBS (particularly if early language decline)
• PSP presenting as CBS variant
• Frontotemporal dementia with motor neurone disease (FTD-MND)
• Posterior cortical atrophy (visuospatial predominant variant of Alzheimer's disease)
• Large-vessel ischaemic stroke (unilateral features, acute onset)

Diagnosis of parkinson-plus syndromes remains primarily clinical, supported by neuroimaging and, where available, functional nuclear medicine studies. There is no single biomarker that confirms the diagnosis during life.

Key MRI Findings

No disease-modifying therapy is currently available for PSP, MSA, or CBS. All pharmacological treatment is symptomatic. A trial of levodopa is essential in all patients with suspected atypical parkinsonism, as a small proportion may show transient benefit (particularly PSP-P and MSA-P).

Parkinsonism

Orthostatic Hypotension (primarily MSA)

Other Symptomatic Treatments

Medications to Avoid

Parkinson-plus syndromes are progressive, incurable conditions requiring ongoing monitoring with a focus on functional maintenance, symptom management, safety, and quality of life. The rate of progression varies by syndrome and individual but is faster than idiopathic Parkinson's disease in most cases.

Monitoring Schedule

Key Monitoring Parameters

Palliative Care Integration

Palliative care should be introduced early in the disease trajectory — ideally at or shortly after diagnosis — as a concurrent model of care alongside active symptom management. Palliative care is not synonymous with end-of-life care; it focuses on quality of life, symptom burden, psychosocial support, and advance care planning throughout the disease course.

• Refer to specialist palliative care when symptoms become difficult to manage, functional decline accelerates, or goals of care discussions indicate a focus on comfort.
• Consider specialist palliative care referral for intractable pain, refractory dysphagia, severe respiratory distress, or significant carer burden.
• Residential aged care facility (RACF) placement should be considered when home-based care is no longer safe or feasible; ensure neurological follow-up continues.
• In Australia, palliative care services are available through state health networks and community palliative care programmes. The Palliative Care Australia directory can assist with locating services: palliativecare.org.au.

Red-Flag Features Suggesting Atypical Parkinsonism

The following clinical features should raise suspicion for a parkinson-plus syndrome rather than idiopathic Parkinson's disease:

Prognosis

Supportive Management & Allied Health

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