Parkinson-plus syndromes

Parkinson-plus syndromes (or atypical parkinsonism) are a group of neurodegenerative diseases that present with parkinsonism and a variety of additional features. Depending on the particular syndrome, a combination of basal ganglia, cerebral cortical, cerebellar, midbrain, and/or brainstem structures are affected. The prognosis is less favorable than in Parkinson disease. Parkinson-plus syndromes should be considered if parkinsonism does not respond to levodopa treatment, if dementia progresses rapidly, or if gait instability occurs early in the course of the disease. In most cases, only symptomatic treatment is possible.

Parkinson-plus syndromes have a number of features that differentiate them from Parkinson disease (PD). ^[1]

• Poor response to levodopa
• Dementia
• Early involvement of the autonomic nervous system, including:
  • Orthostatic hypotension
  • Impotence
  • Incontinence
  • Anhidrosis
• Early onset of postural instability with frequent falls
• Visual hallucinations
• Signs of cerebellar involvement
• Presence of pathological reflexes, such as:
  • Babinski sign
  • Enhanced proprioceptive reflexes
• Eating and swallowing disorders
• Pronounced dysarthria
• Supranuclear vertical gaze palsy
• Apraxia

• Definition
  • Lewy body dementia if the onset of both cognitive and motor symptoms is within 1 year
  • Dementia secondary to Parkinson disease if cognitive symptoms occur > 1 year after the onset of motor symptoms
• Epidemiology
  • Second most common form of neurodegenerative dementia (10–20% of dementia cases)
  • ♂ > ♀ (up to 4:1)
• Clinical presentation: The sequence of symptoms is more variable than in most other types of dementia. ^[2]
  • Dementia
  • Extrapyramidal motor symptoms (parkinsonism), such as:
    • Bradykinesia
    • Rigor
  • Visual hallucinations and paranoid episodes
  • ↑ Sensitivity to neuroleptic medication and metabolic perturbation
  • Episodic impairment of cognition and/or vigilance
  • Rapid eye movement sleep behavior disorder (RBD)
  • Frequent falls
• Diagnostics: MRI shows atrophy of substantia innominata and mesopontine grey matter ^[3]
• Pathology
  • Macroscopic
    • Cerebral atrophy, particularly of the frontal lobe
    • Relative sparing of the hippocampi
  • Microscopic
    • Lewy bodies: alpha-synuclein-positive, hyaline cytoplasmic inclusions in neurons (mostly cortical) that cause neuronal degeneration
    • Lewy neurites
    • Amyloid plaques
    • Neurofibrillary tangles
• Therapy
  • No curative therapy available
  • Symptomatic treatment
    • Supportive therapy
    • Behavioral therapy
    • Physical therapy
    • Pharmacotherapy
      • Parkinsonian symptoms: generally analogous to treatment of Parkinson disease
      • Dementia symptoms: generally analogous to treatment of major neurocognitive disorder
      • Psychotic symptoms: In severe cases (e.g., functionally impairing psychosis), low-potency second-generation antipsychotic (e.g. quetiapine) can be administered.
• Prognosis: Median survival is ∼ 10 years.

Patients with Lewy body dementia have visual hallewynations.

Patients with Lewy-body dementia have an increased risk of life-threatening akinetic crises under antipsychotic treatment.

• Definition: rare, adult-onset, neurodegenerative disease characterized by neuronal degeneration in the substantia nigra
• Epidemiology ^[4]
  • Incidence: 0.6 cases per 100,000 individuals/year
  • Prevalence: 4–5 cases per 100,000 individuals
• Etiology
  • Unknown
  • Associated with single nucleotide polymorphisms at the SNCA locus coding for alpha-synuclein and changes in myelin basic protein
• Clinical features
  • Motor abnormalities
    • MSA-P: predominantly parkinsonian features (previously referred to as striatonigral degeneration)
    • MSA-C: predominantly cerebellar features (previously referred to as olivopontocerebellar atrophy)
  • Autonomic dysfunction
    • Orthostatic hypotension
    • Urinary incontinence
    • Erectile dysfunction
  • Cerebellar symptoms
    • Ataxia
    • Tremor
    • Dysarthria
  • Neuropsychiatric disorders
    • Depression
    • Sleep disorders
  • Ocular motility disorders
  • Myoclonus, dystonia
  • Pyramidal signs
• Diagnostics
  • Primarily clinical diagnosis (especially autonomic dysfunction, including urogenital symptoms)
  • MRI: hot cross bun sign ^[5]
    • Refers to a cross-shaped hyperintensity on T2-weighted axial images of the pons
    • Typical finding in MSA but also seen in various other neurodegenerative diseases
• Pathology ^[6]
  • Macroscopic: most commonly atrophy of olivopontocerebellar and striatonigral systems
  • Microscopic: glial cytoplasmic inclusions (GCIs)
    • Characterized by gliosis and axonal degeneration
    • Glial and neuronal loss in the substantia nigra, putamen, locus ceruleus, pontine nuclei, cerebellum, and inferior olives
• Differential diagnosis
  • Parkinson disease: differential diagnosis via IBZM-SPECT imaging ^[7]
    • MSA shows presynaptic and postsynaptic degeneration (↓ binding)
    • In contrast, Parkinson disease shows presynaptic degeneration and postsynaptic up-regulation due to ligand accumulation
  • Pure autonomic failure (PAF): disorder of the autonomous functions that is not associated with symptoms of the central nervous system ^[8]
    • Epidemiology: mainly affects male patients between the ages of 40 and 70
    • Clinical features: orthostatic dysregulation with life-threatening drops in blood pressure
    • Pathology: In contrast to MSA, postganglionic lesions predominate in PAF.
• Treatment: no causal therapy, only symptomatic treatment possible ^[9]
  • Orthostatic hypotension
    • Compression stockings
    • ↑ Salt intake
    • Fludrocortisone
    • Midodrine
    • Droxidopa
  • Bladder control: anticholinergics
    • Oxybutynin
    • Tolterodine
  • Dystonia
    • Physical therapy
    • Botulinum toxin injections
  • Sleep disorders
    • Clonazepam
    • Melatonin
    • Antidepressants

• Definition: a neurodegenerative disease characterized by atrophy of structures at the midbrain-diencephalic junction (e.g., superior colliculi, red nuclei, subthalamic nuclei, and globus pallidus) and cerebellum (dentate nuclei), and mild cortical atrophy
• Epidemiology ^[10]
  • Incidence
    • 1 case per 100,000 individuals/year
    • Peak incidence between 60 and 80 years
  • Prevalence: ∼ 5 cases per 100,000 individuals
• Clinical features
  • Vertical gaze palsy, especially downward gaze, to complete external ophthalmoparesis
  • Postural instability leading to frequent falls (often first symptom); retropulsion is characteristic
  • Frontal lobe abnormalities
    • Apathy
    • Disinhibition
    • Impaired reasoning
  • Bradykinesia
  • Dysarthria
  • Dysphagia
  • Rigor
  • Dementia
• Diagnostics: MRI shows hummingbird sign (atrophy of midbrain structures with a relatively intact pons region)
• Pathology
  • Macroscopic: involvement of a number of anatomical areas
    • Frontal lobe
    • Pontomesencephalic area
    • Lower brainstem
    • Nigrostriatopallidal area
  • Microscopic: neurofibrillary tangles
• Prognosis: usually fatal within 5–10 years

• Epidemiology ^[11]
  • Incidence: 1 case per 100,000 individuals/year
  • Mean age of onset: 64 years
• Clinical features
  • Asymmetric motor abnormalities, often initially affecting only one limb
  • Alien limb phenomenon: The patient perceives the affected limb as not belonging to him or her.
  • Dementia (at any stage)
• Diagnostics: MRI shows asymmetric focal cortical atrophy and bilateral atrophy of the basal ganglia ^[12]
• Pathology ^[11]
  • Macroscopic: frontal and striatal atrophy
  • Microscopic: intracellular inclusions (hyper-phosphorylated microtubule associated tau protein)
• Prognosis: estimated mean survival is ∼ 6.5 years ^[11]