Parkinson-plus syndromes

Parkinson-plus syndromes, also known as atypical parkinsonian syndromes, are a group of rare, adult-onset neurodegenerative disorders manifesting with parkinsonism and additional differentiating clinical features. Unlike in Parkinson disease, varying combinations of basal ganglia, cerebral cortical, cerebellar, midbrain, and/or brainstem structures are affected. Differentiating features from Parkinson disease (e.g., poor levodopa response, rapid progression, prominent early cognitive decline, and/or significant autonomic dysfunction) prompt consideration of a Parkinson-plus syndrome. Management is primarily symptomatic and supportive. The prognosis is less favorable than in Parkinson disease, with a more accelerated progression.

Differentiating features from Parkinson disease

Features that distinguish Parkinson-plus syndromes from Parkinson disease include: ^[1]

• Motor features
  • Early onset of postural instability with frequent falls
  • Bulbar and speech disturbances (e.g., severe dysarthria, dysphagia)
  • Levodopa responsiveness: poor or transient
  • Pathological reflexes (e.g., Babinski sign)
• Autonomic dysfunction: early involvement of the autonomic nervous system
  • Orthostatic hypotension
  • Erectile dysfunction
  • Urinary incontinence
• Cognitive impairment: early onset, progressive neurocognitive decline
• Disorder-specific symptoms, e.g.:
  • DLB: visual hallucinations
  • PSP: vertical gaze palsy
  • Corticobasal degeneration: alien limb phenomenon

Definition ^[2]

Dementia with Lewy bodies (DLB) is an α-synucleinopathy characterized by the abnormal deposition of Lewy bodies (made of α-synuclein) in neurons primarily in cortical and subcortical brain regions.

Epidemiology ^[3][4]

• Second most common form of neurodegenerative dementia
• Incidence: 3–7% of all dementia diagnoses; increases with age ^[3][4]
• Mean age of onset: 75 years ^[5]
• ♂ > ♀ (up to 4:1) ^[3]

Clinical features ^[6][7]

• Cognitive impairment: : early or concurrent dementia relative to motor symptoms ^[6]
• Motor features
  • Parkinsonism (e.g., bradykinesia, rest tremor, rigidity) with poor response to levodopa
  • Postural instability and frequent falls
• Neuropsychiatric features
  • Visual hallucinations and paranoid episodes
  • Fluctuations: episodic impairment of cognition and/or vigilance
  • REM sleep behavior disorder (RBD) and hypersomnia
  • Mood disorders (e.g., depression) and anxiety
  • Increased sensitivity to neuroleptic medication
• Autonomic dysfunction
  • Orthostatic hypotension
  • Syncope
  • Urinary incontinence

Individuals with dementia with Lewy bodies have visual hallewynations.

Dementia typically occurs within 1 year of motor symptom onset in DLB and is essential for diagnosis, whereas dementia typically develops later in Parkinson disease dementia. ^[8]

Diagnosis ^[6][9]

General principles

• DLB is a clinical diagnosis supported by neuroimaging.
• Perform a comprehensive clinical evaluation, including cognitive testing.
• Neuroimaging excludes alternative diagnoses; findings may suggest DLB.
• Refer to neurology for polysomnography, EEG, and specialized investigations (e.g., myocardial scintigraphy).
• Definitive diagnosis requires postmortem neuropathological confirmation.

Neuroimaging

• MRI brain: ↑ Atrophy of the substantia innominata and mesopontine gray matter and relative preservation of the medial temporal lobes compared to individuals with Alzheimer disease ^[10]
• SPECT or PET-CT: reduced dopamine transporter uptake in basal ganglia

Pathology ^[11]

• Macroscopic
  • Cerebral atrophy, particularly of the frontal lobe
  • Relative sparing of the hippocampi
• Microscopic
  • Lewy bodies; : α-synuclein positive, hyaline cytoplasmic inclusions (especially in cortical and subcortical neurons); cause neuronal degeneration
  • Lewy neurites
  • Amyloid plaques
  • Neurofibrillary tangles

Treatment ^[2]

General principles

• Symptom management is the primary goal.
• Management is led by neurology and supported by a multidisciplinary team (e.g., psychiatry, physical therapy).
• Supportive care for dementia and other nonpharmacological interventions (e.g., behavioral therapy) are indicated in all patients.
• Reserve pharmacological treatment for bothersome symptoms and limit polypharmacy.

Pharmacological treatment

• Cognitive impairment
  • Anti-dementia medications (e.g., AChEIs, memantine)
  • See “Management of major neurocognitive disorders.”
• Motor symptoms: antiparkinson medication (e.g., levodopa) ^[2]
• Neuropsychiatric symptoms
  • AChEIs
  • Second-generation antipsychotics (e.g., quetiapine, clozapine): Consider low dose for severe and/or refractory psychotic features.
• Autonomic dysfunction:
  • Orthostatic hypotension: medications for noncardiac syncope
  • Bladder symptoms: Consider beta-3 agonists (e.g., mirabegron) in consultation with urology. ^[12]

Antipsychotic treatment, especially with typical antipsychotics, is associated with severe sensitivity reactions, may worsen parkinsonism, and may precipitate a life-threatening akinetic crisis. ^[2]

Prognosis ^[13]

• Variable prognosis; generally progresses more rapidly than Alzheimer disease
• Mean survival: 4–6 years from diagnosis ^[13]
• Common causes of death include failure to thrive, pneumonia, and complications from falls. ^[14]

Definition ^[15]

Multiple system atrophy (MSA) is an α-synucleinopathy characterized by the abnormal deposition of α-synuclein aggregates, primarily in glial cells, leading to neurodegeneration, including in the substantia nigra, cerebellum, brainstem, and autonomic nervous system structures.

Epidemiology ^[15]

• Incidence: 1–3/100,000 individuals/year
• Mean age of onset: ∼ 56 years

Clinical features ^[15][16]

• Motor features
  • Parkinsonism (e.g., bradykinesia, rest tremor, rigidity) with poor response to levodopa
  • Postural instability
  • Dystonia
  • Speech impairment (e.g., dysarthria, croaky voice due to laryngeal dystonia)
  • Dysphagia
  • Stridor
  • Pyramidal signs (e.g., unexplained extensor plantar reflex)
• Autonomic dysfunction
  • Urinary symptoms (e.g., unexplained voiding difficulties)
  • Orthostatic hypotension
  • Erectile dysfunction
• Cerebellar features
  • Gait ataxia
  • Limb ataxia
  • Ataxic dysarthria
  • Oculomotor features (e.g., nystagmus)
• Neuropsychiatric features: sleep disorders (e.g., RBD)

MSA is classified into two subtypes based on the predominant features at initial presentation: MSA-C (cerebellar features) or MSA-P (parkinsonian features).

Diagnosis ^[15]

General principles

• MSA is a clinical diagnosis supported by neuroimaging findings.
• Perform a comprehensive clinical evaluation, including cognitive testing.
• Neuroimaging excludes alternative diagnoses; findings may suggest MSA.
• Definitive diagnosis requires postmortem neuropathological confirmation.

Neuroimaging

• MRI brain
  • Hot cross bun sign: a cross-shaped T2 hyperintensity on axial images of the pons ^[17]
  • Atrophy of putamen, middle cerebellar peduncle, pons, and/or cerebellum
• PET-CT scan: hypometabolism in putamen, brainstem, or cerebellum ^[15]

Pathology ^[18]

• Macroscopic: olivopontocerebellar and striatonigral atrophy
• Microscopic: glial cytoplasmic inclusions
  • Characterized by gliosis and axonal degeneration
  • Glial and neuronal loss in the substantia nigra, putamen, locus ceruleus, pontine nuclei, cerebellum, and inferior olivary nuclei

Treatment ^[15]

General principles

• Symptom management is the primary goal.
• Management is led by neurology and supported by a multidisciplinary team (e.g., urology, occupational therapy, speech therapy).
• Provide nonpharmacological management of orthostatic hypotension (e.g., compression stockings, ↑ salt intake).
• Reserve pharmacological treatment for bothersome symptoms.

Pharmacological treatment

• Motor symptoms
  • Parkinsonism: Antiparkinson medication (e.g., levodopa) usually provides a poor or transient response.
  • Dystonia: Consider botulinum toxin injections.
• Autonomic dysfunction
  • Orthostatic hypotension: medications for noncardiac syncope (e.g., fludrocortisone, midodrine, droxidopa)
  • Bladder symptoms: Consider beta-3 receptor agonists (e.g., mirabegron) or antimuscarinic agents in consultation with urology.
  • Erectile dysfunction: See “Treatment of erectile dysfunction.”
• Neuropsychiatric symptoms
  • Depression: antidepressants
  • Sleep disorders: Consider melatonin or clonazepam.

Prognosis

Mean survival: 7–9 years ^[19]

Definition ^[20]

Progressive supranuclear palsy (PSP) is a tauopathy characterized by the abnormal deposition of tau protein in the form of neurofibrillary tangles, causing brain atrophy and degeneration (e.g., in the brainstem, basal ganglia, and frontal lobe).

Epidemiology ^[21]

• Incidence: ∼ 1/100,000 individuals/year
• Mean age of onset: 60–70 years

Clinical features ^[7][22]

• Motor features
  • Postural instability
    • Frequent unprovoked falls (often first symptom)
    • Retropulsion
  • Parkinsonism (e.g., gait freezing, bradykinesia, and axial rigidity)
  • Bulbar dysfunction (e.g., dysarthria, dysphagia, dysphonia)
  • Dystonia
• Ocular features: : ranges from vertical gaze palsy (especially downward gaze) to complete external ophthalmoparesis
• Cognitive impairment: characterized by predominant frontal lobe abnormalities
  • Apathy
  • Disinhibited behavior
  • Impaired reasoning
  • Emotional lability (e.g., pseudobulbar affect)

Diagnosis ^[23]

General principles

• PSP is a clinical diagnosis supported by neuroimaging findings.
• Perform a comprehensive clinical evaluation, including cognitive testing.
• Neuroimaging excludes alternative diagnoses; findings may suggest PSP.
• Definitive diagnosis requires postmortem neuropathological confirmation.

Neuroimaging

MRI brain findings include the hummingbird sign, which represents atrophy of midbrain structures with a relatively intact pons region. ^[24]

Pathology ^[20]

• Macroscopic: brain atrophy
  • Frontal lobe
  • Pontomesencephalic area
  • Lower brainstem
  • Nigrostriatal pallidal area
• Microscopic: neurofibrillary tangles

Treatment

General principles

• Symptom management is the primary goal.
• Management is led by neurology and supported by a multidisciplinary team (e.g., ophthalmology, physical therapy, occupational therapy).
• Supportive care and other nonpharmacological interventions (e.g., ophthalmological interventions for gaze palsy) are indicated in all patients.
• Reserve pharmacological treatment for bothersome symptoms and limit polypharmacy.

Pharmacological treatment ^[23]

• Motor symptoms
  • Parkinsonism
    • Levodopa: may provide a transient benefit ^[23]
    • Amantadine: may reduce axial rigidity and improve mobility
  • Dystonia: Consider botulinum toxin injections.
• Neuropsychiatric symptoms
  • Depression: SSRIs (e.g., citalopram or sertraline)
  • Pseudobulbar affect: SSRIs may improve symptoms.
  • Sleep disorders: Consider zolpidem, melatonin, or short-term benzodiazepines.

Prognosis

Median survival: ∼ 5 years ^[25]

Definition ^[26]

Corticobasal degeneration is a tauopathy characterized by the abnormal deposition of tau protein, leading to degeneration primarily in the cerebral cortex and basal ganglia.

Epidemiology ^[26]

• Incidence: ∼ 1/100,000 individuals/year
• Mean age of onset: ∼ 64 years

Clinical features ^[26][27]

• Motor features: asymmetric, progressive motor abnormalities (e.g., parkinsonism, dystonia, and/or myoclonus) initially affecting only one limb
• Cortical features, e.g.:
  • Ideomotor apraxia
  • Agnosia
  • Cortical sensory deficits
  • Alien limb phenomenon; : involuntary yet purposeful movement of a limb, accompanied by the perception that it does not belong to the affected individual
• Cognitive impairment
  • Memory deficit
  • Language disturbances
• Neuropsychiatric features (e.g., depression)

Diagnosis ^[26]

General principles

• Corticobasal degeneration is a clinical diagnosis supported by neuroimaging findings.
• Perform a comprehensive clinical evaluation, including cognitive testing.
• Neuroimaging excludes alternative diagnoses; findings may suggest corticobasal degeneration.
• Consider referral to neurology for specialized investigations (e.g., SPECT or PET-CT scan, CSF biomarkers).
• Definitive diagnosis requires postmortem neuropathological confirmation.

Neuroimaging

MRI brain findings include asymmetric focal cortical atrophy and atrophy of the basal ganglia.

Pathology ^[26]

• Macroscopic: asymmetric frontal and striatal atrophy
• Microscopic: intracellular inclusions of hyperphosphorylated microtubule-associated tau protein in neuronal and glial cells

Treatment ^[26]

General principles

• Symptom management is the primary goal.
• Management is led by neurology and supported by a multidisciplinary team (e.g., occupational therapy, speech therapy).
• Nonpharmacological management is indicated in all patients (e.g., physical therapy may improve rigidity and prevent contractures).
• Reserve pharmacological treatment for bothersome symptoms and limit polypharmacy.

Pharmacological treatment

• Motor symptoms
  • Parkinsonism: Antiparkinson medication (mainly levodopa) usually provides a poor or transient response.
  • Dystonia: Consider botulinum toxin injections.
  • Myoclonus: clonazepam
• Cognitive impairment: AChEIs (off-label) may be considered.
• Neuropsychiatric symptoms: Consider antidepressants for depression.

Prognosis

Mean survival: ∼ 6.5 years ^[26]