Atypical Parkinsonian Syndromes

Atypical parkinsonian syndromes are a group of neurodegenerative disorders characterized by parkinsonian features although with different pathophysiology. These characteristics include progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD). Although each syndrome has its own distinctive features, common factors are a rarity. There is a general propensity to affect middle-aged and elderly populations and a lack of definitive management options.

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Progressive Supranuclear Palsy

Definition

Progressive supranuclear palsy (PSP; also known as a Parkinson-plus disorder) is a degenerative movement disorder that affects the brain stem, basal ganglia, diencephalon, and cortex, causing gaze dysfunction, extrapyramidal symptoms, and cognitive dysfunction.

Epidemiology and etiology

  • Prevalence: 7 per 100,000 in those > 55 years old
  • Affects 4%–6% of individuals with parkinsonism
  • Annual incidence: 0.3–0.4 per 100,000 
  • Male predominance
  • 6th to 7th decades of life
  • Unknown etiology
  • Incidence ↑ with age

Pathophysiology

  • Hyperphosphorylation of tau protein leads to ↓ affinity for microtubules.
  • Hyperphosphorylated tau protein is resistant to proteolysis and forms aggregates. 
  • As a result, tau protein is accumulated and neurofibrillary tangles are formed.
Tangle-like tau protein aggregate in a patient with progressive supranuclear palsy

Tangle-like tau protein aggregate in an individual with progressive supranuclear palsy

Image: “Tangle-like tau protein aggregate in a patient with progressive supranuclear palsy” by Ling et al. License: CC BY 2.0, cropped by Lecturio.

Clinical presentation

History:

  • Insidious onset
  • An akinetic-rigid form of parkinsonism
    • Falls and gait difficulty
    • Insomnia and difficulty maintaining sleep
    • Personality changes

Physical examination:

  • Parkinsonism
    • Pseudobulbar palsy: spastic dysarthria and dysphagia
    • Facial dystonia: expression of “perpetual surprise”
    • Bradykinesia
    • Micrographia
  • Eye movement abnormalities
    • Supranuclear ophthalmoplegia is the hallmark of PSP.
    • Blepharospasm and eyelid-opening apraxia
    • Eyes are immobile at the end of the disease.
  • “Drunken sailor” gait
    • Stiff and broad-based gait with extended knees and trunk
    • Turns by pivoting quickly on their toes, rather than turning “en bloc”
  • Pyramidal signs
    • Hyperreflexia
    • Babinski signs
  • Cognitive dysfunction
Parkinsonian syndrome - round the houses sign

Left: The photographs show the “round-the-houses” sign, illustrated for a downward saccade. Note the lateral curvature of downward path of eye movement (yellow arrows). The velocity may also be slow.
Right: This face gives many clues to the diagnosis. As shown by this man, there may be retrocollis, raised eyebrows, and frontalis overactivity. People with progressive supranuclear palsy may have a rather fixed smile, with lips drawn back rather than up.

Image: “‘Round-the-houses’ sign” by James B. Rowe, University of Cambridge Department of Clinical Neurosciences, Cambridge, Cambridgeshire, UK. License: CC BY 4.0

Diagnosis

Initial diagnosis requires fulfillment of diagnostic criteria for PSP. Definitive diagnosis can only be made via pathologic examination. 

  • Inclusion criteria:
    • Age at onset: > 40 years
    • Gradual progression
    • Vertical, supranuclear gaze abnormalities 
    • Postural instability with frequent falls 
  • Exclusion criteria (cannot have these):
    • Cortical dementia similar to Alzheimer’s 
    • Hallucinations or delusions not secondary to exogenous dopamine 
    • Neuroimaging suggestive of structural abnormality
    • Asymmetric parkinsonian signs

Testing

  • Neuroimaging with MRI:
    • Atrophy of the midbrain, quadrigeminal plate, pons, and cerebellum
    • Degeneration of the red nucleus
    • Enlargement of the aqueduct and 3rd ventricle
    • Atrophy of the frontal and temporal lobes indicate advanced disease
    • Hummingbird sign: Midsagittal cuts of midbrain look like a hummingbird because of atrophy.
  • Labs:
    • No diagnostic tests
    • Labs to rule out other conditions
MRI and DaTscan (nuclear imaging test that allows doctors to view the brain's dopamine levels) features in PSP

MRI and DaTscan (nuclear imaging test that allows doctors to view the brain’s dopamine levels) features in progressive supranuclear palsy (PSP)

Image: “‘Round-the-houses’ sign” by James B. Rowe, University of Cambridge Department of Clinical Neurosciences, Cambridge, Cambridgeshire, UK. License: CC BY 4.0

Management

  • No definitive treatment 
  • Medical therapy:
    • Levodopa/carbidopa for parkinsonian symptoms
    • Injections of botulinum toxin can be used for focal dystonia.

Prognosis

  • Rapid disease progression
  • Significant reduction in quality of life and dependency within 3–4 years
  • Death usually occurs within 6 years after diagnosis.
  • Dysphagia is associated with ↓ survival.

Multiple System Atrophy

Definition

Multiple system atrophy (MSA) is an adult-onset, sporadic, rapidly progressive, multisystem, fatal neurodegenerative disease characterized by parkinsonian features, cerebellar, autonomic, and urogenital dysfunction; and corticospinal disorders.

Epidemiology and etiology

  • Incidence: 3 per 100,000
  • Prevalence: 2–5 cases per 100,000
  • Mean age at onset: 54 years
  • Unknown etiology, but trauma has been suggested.

Pathophysiology

  • Spreading of aberrant α-synuclein from neurons to glial cells → chronic alterations in glial cells → impaired trophic function between oligodendrocytes and axons →  secondary neuronal damage + extensive myelin degeneration
  • Glial and myelin dysfunction occur.
  • An inflammatory cascade is induced, and secondary neurodegeneration follows.
Alpha-synuclein in the pathogenesis of MSA

Alpha-synuclein in the pathogenesis of multiple system atrophy (MSA):
Neuron-oligodendrocyte interaction mechanisms potentially involved in α-syn accumulation: oligodendroglial α-syn uptake from surrounding neurons and extracellular environment through endocytosis and passive transmembrane diffusion

Image by Lecturio.

Clinical presentation

History:

  • Depression
  • Anxiety

Physical examination:

  • In parkinsonism-predominant cases:
    • Akinesia/bradykinesia
    • Rigidity
    • Postural instability
    • Postural and action tremor
  • In cerebellar-predominant cases (cerebellar disorders):
    • Ataxia
    • Equilibrium and gait problems
    • Dysdiadochokinesia: difficulty making rapid alternating movements
    • Dysarthria
    • Ocular abnormalities
  • Cognitive function is usually preserved.

Diagnosis

Diagnosis is made clinically, and definitive diagnosis is done on postmortem pathologic examination. 

  • Clinical features:
    • Sporadic and progressive onset during adulthood (> 30 years old)
    • Autonomic failure involving either: 
      • Urinary incontinence or 
      • Orthostatic BP
    • Levodopa trial: does not reduce symptoms, unlike in Parkinson’s disease
  • Imaging:
    • Atrophy of the:
      • Putamen
      • Middle cerebellar peduncle
      • Pons
    • “Hot cross bun sign” on T2-weighted imaging: hyperintense shape of a cross within the atrophied pons
MRI of a brain showing multiple system atrophy (MSA)

MRI of a brain showing multiple system atrophy (MSA):
Note the brain stem and cerebellar atrophy (top, arrow), and the “hot cross bun” sign (bottom, arrow).

Image: “MRI of a patient with multiple system atrophy (MSA)” by J. Vijayan, S. Sinha, S. Ravishankar,1 and A. B. Taly. License: CC BY 4.0

Management

  • No definitive treatment 
  • Medical therapy:
    • Botulinum toxin injections can be used for focal dystonia.
    • Orthostatic hypotension: fludrocortisone acetate (1st-line therapy), midodrine (2nd-line therapy)
    • Urogenital symptoms: oxybutynin or tolterodine

Prognosis

  • Rapid progression
  • Death as soon as 6 years after diagnosis

Corticobasal Degeneration

Definition

Corticobasal degeneration (CBD) is a progressive, asymmetric dementia–movement disorder with sporadic neurodegenerative 4-repeat tauopathy.

Epidemiology and etiology

  • Prevalence: 5–7 per 100,000
  • Incidence: 0.6–0.9 per 100,000
  • 5% of cases of parkinsonism
  • 6th to 8th decades of life
  • May be related to abnormalities in the microtubule-associated protein tau (MAPT) gene

Pathophysiology

  • Hyperphosphorylation of tau protein leads to less affinity for microtubules → hyperphosphorylated tau protein resists proteolysis and forms aggregates → tau protein is accumulated and neurofibrillary tangles are formed
  • Classified as a 4-repeat tauopathy (a different interval than other tau-related syndromes)
  • Ballooned, achromatic, tau-positive neurons, astrocytic plaques, and other dystrophic glial tau findings, similar to those seen in PSP
  • Extensive neuronal loss

Clinical presentation

History:

  • Asymmetrical affectation
  • Frequent falls
  • Behavioral changes consistent with dementia

Physical examination:

  • May display PSP features
  • Bradykinesia/akinesia
  • Limb rigidity and dystonia
  • Speech disturbances
  • Action tremor, myoclonus, and hyperreflexia
  • “Alien-limb” phenomena: unintended motor actions such as grasping, groping, drifting, or undoing
  • Slow gait
  • Dementia 
  • Slow and saccadic eye movements

Diagnosis

Diagnosis is made clinically, and definitive diagnosis is by postmortem pathology examination. 

Magnetic resonance imaging of a patient with a pathology-proven diagnosis of corticobasal degeneration

MRI of a brain showing a pathologic diagnosis of corticobasal degeneration:
MRI shows the right greater than left parietofrontal atrophy typical of corticobasal syndrome.

Image: “Magnetic resonance imaging of a patient with a pathology-proven diagnosis of corticobasal degeneration” by Saeed et al. License: CC BY 4.0

Medical therapy

  • Levodopa trial: does not reduce symptoms, unlike in Parkinson’s disease
  • No definitive treatment
  • Propranolol or clonazepam can be used to treat tremor and myoclonus.
  • Cholinesterase inhibitors (e.g., donepezil, rivastigmine) can be used to treat cognitive dysfunction.

Prognosis

  • Poor
  • Death as soon as 5 years after diagnosis

Differential Diagnosis

  • Parkinson’s disease: degenerative disease of the basal ganglia. Parkinson’s disease is characterized by diminished facial expression, stooped posture, slowing of voluntary movement, festinating gait (progressively shortened and accelerated steps), cogwheel rigidity, and a “pill rolling” tremor at rest. 
  • Frontotemporal dementia: neurodegenerative disorder characterized by loss of cognitive functions (memory, abstract thinking, reasoning, and executive function), which severely impairs functioning and quality of life. Clinical presentation includes behavioral changes, such as apathy.
  • Wilson disease: autosomal recessive disorder associated with mutations in the ATP7B gene, which regulates copper transport within hepatocytes. This mutation causes copper to accumulate in the liver, brain, and cornea. Wilson disease often presents in young adulthood with signs of liver disease and neurologic and psychiatric symptoms (often resembling parkinsonism).
  • Niemann-Pick disease: rare inherited lysosomal storage disorder. Niemann-Pick disease is classified on the basis of the genetic mutation. Type A and type B result from mutations in the SMPD-1 gene, resulting in acid sphingomyelinase enzyme deficiency. Type C results from NPC1 or NPC2 gene mutations; these genes are needed for intracellular transport of lipids.
  • Myasthenia gravis: autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. Myasthenia gravis presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs leading to difficulty in movement.

References

  1. Agarwal S, Gilbert R. (2021). Progressive supranuclear palsy. StatPearls. Retrieved August 14, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK526098/ 
  2. Seeley WW, Miller BL. (2018). Frontotemporal dementia. Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J (Eds.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill. 
  3. Jankovic J. (2022). Parkinson Disease and Other Movement Disorders. In Jankovic, J., et al. (Eds.). Bradley and Daroff’s Neurology in Clinical Practice. pp. 1498–1534.e5. Elsevier.
  4. Höglinger GU, et al. (2017). Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Movement Disorders 32:853–864. https://doi.org/10.1002/mds.26987 
  5. Zibetti M. (2015). Parkinson disease: epidemiology, pathology, and clinical diagnosis. DeckerMed Medicine. Retrieved July 31, 2021, from https://doi.org/10.2310/7900.6353
  6. Factor, S. A., Doss Esper, C. (2021). Multiple system atrophy: Clinical features and diagnosis. UpToDate. Retrieved July 31, from https://www.uptodate.com/contents/multiple-system-atrophy-clinical-features-and-diagnosis
  7. Factor, S. A., Doss Esper, C. (2021). Multiple system atrophy: Prognosis and treatment. UpToDate. Retrieved July 31, from https://www.uptodate.com/contents/multiple-system-atrophy-prognosis-and-treatment
  8. Gibbons CH, Engstrom JW. (2018). Disorders of the autonomic nervous system. Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J (Eds.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill. 
  9. Factor, S.A., Tripathi, R. (2021). Corticobasal degeneration. UpToDate. Retrieved July 31, from https://www.uptodate.com/contents/corticobasal-degeneration
  10. Eggenberger, E. (2018). Progressive supranuclear palsy. Emedicine. Retrieved August 9, 2021, from https://emedicine.medscape.com/article/1151430-overview?ecd=ppc_google_rlsa-traf_mscp_emed_md-ldlm-cohort_us#a6 
  11. Diedrich A. (2018). Multiple system atrophy. Emedicine. Retrieved August 9, 2021, from https://emedicine.medscape.com/article/1154583-overview?ecd=ppc_google_rlsa-traf_mscp_emed_md-ldlm-cohort_us#a5
  12. Pantelyat A. (2019). Corticobasal syndrome and corticobasal degeneration. Emedicine. Retrieved August 9, 2021, from https://emedicine.medscape.com/article/1150039-overview#a5

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