# Atypical Parkinsonism: MSA, PSP, and CBD

## Overview

Atypical parkinsonian syndromes (APS) account for approximately 10-15% of all parkinsonism. They are distinguished from Parkinson disease by a poor or absent levodopa response, symmetric onset, rapid progression, and prominent non-dopaminergic features. Average survival is significantly shorter than PD (6-10 years from symptom onset versus near-normal life expectancy in PD). Neuropathologically, these conditions are defined by distinct protein aggregates: alpha-synuclein in MSA, or tau in PSP and CBD. Early accurate diagnosis is important for prognosis counseling and avoiding futile surgical interventions such as DBS.

## Red Flags for Atypical Parkinsonism

| Feature | PD | MSA | PSP-RS | CBS |
|---|---|---|---|---|
| Onset symmetry | Asymmetric | Symmetric | Symmetric/axial | Profoundly asymmetric |
| Levodopa response | Excellent | Poor/transient | Poor | Poor |
| Falls | Late | Early | Very early (backward) | Late |
| Tremor | Rest, 4–6 Hz | Absent or jerky | Absent | Absent or myoclonic |
| Eye movements | Normal | Normal | Vertical supranuclear gaze palsy | Normal |
| Autonomic failure | Mild, late | Severe, early | Mild | Absent |
| Cognitive pattern | Late dementia | Mild | Frontal/executive | Asymmetric apraxia |
| Key imaging sign | Normal MRI | Hot cross bun (MSA-C), putaminal slit | Hummingbird sign (midbrain atrophy) | Asymmetric frontoparietal atrophy |
| Pathology | Alpha-synuclein (Lewy bodies) | Alpha-synuclein (GCIs) | 4R tau (tufted astrocytes) | 4R tau (astrocytic plaques) |
| Median survival | Near-normal | 6–9 years | 5–7 years | 6–8 years |

Clinical features that should raise suspicion for an atypical syndrome include early postural instability and falls (within the first 3 years), symmetric parkinsonism from onset, rapid progression (wheelchair-bound within 5 years), poor or unsustained levodopa response, early severe autonomic failure, supranuclear gaze palsy (especially vertical), early severe dysarthria or dysphagia, cerebellar signs, apraxia, alien limb phenomenon, cortical sensory loss, inspiratory stridor, and early cognitive or behavioral changes with a frontal pattern.

<image>Comparison table of clinical features distinguishing PD from MSA, PSP, and CBD including onset symmetry, levodopa response, key examination findings, and typical survival</image>

## Multiple System Atrophy (MSA)

### Pathology

MSA is an alpha-synucleinopathy characterized by glial cytoplasmic inclusions (GCIs) in oligodendrocytes. There is neuronal loss and gliosis in striatonigral, olivopontocerebellar, and autonomic pathways.

### Clinical Subtypes

MSA-P (parkinsonian predominant, previously striatonigral degeneration) presents with symmetric, poorly levodopa-responsive parkinsonism, postural instability, and falls. It may show a transient levodopa response early, but patients often develop severe dyskinesia at low doses, characteristically affecting the face and neck in a pattern different from PD dyskinesia. MSA-C (cerebellar predominant, previously sporadic olivopontocerebellar atrophy) presents with cerebellar ataxia, gait ataxia, limb dysmetria, and scanning dysarthria. This subtype is more common in Asian populations.

### Autonomic Failure (Both Subtypes)

Orthostatic hypotension is defined more stringently in MSA as a systolic BP drop of 30 mmHg or greater or diastolic drop of 15 mmHg or greater within 3 minutes of standing. Urogenital dysfunction manifesting as urinary retention, incontinence, or erectile dysfunction is often the earliest symptom. Supine hypertension complicates the management of orthostatic hypotension.

### Other Features

Inspiratory stridor from laryngeal dystonia of the vocal cord abductors may require CPAP and carries a risk of sudden death. REM sleep behavior disorder is present in most MSA patients. Disproportionate anterocollis, Raynaud phenomenon with cold hands and feet, and emotional incontinence (pseudobulbar affect) are additional features.

### Imaging

MRI may show the "hot cross bun sign" (cruciform hyperintensity in the pons on T2/FLAIR) in MSA-C, putaminal atrophy with lateral slit hyperintensity and hypointensity on T2, and cerebellar and pontine atrophy in MSA-C. FDG-PET demonstrates hypometabolism in the striatum and cerebellum.

### Diagnostic Criteria (2022 MDS Criteria)

Clinically established MSA requires autonomic dysfunction (orthostatic hypotension or urinary dysfunction) plus poorly levodopa-responsive parkinsonism or cerebellar ataxia, plus additional supportive features.

### Prognosis

Median survival is 6-9 years from symptom onset. Death usually results from aspiration pneumonia, respiratory failure, or sudden death related to stridor.

## Progressive Supranuclear Palsy (PSP)

### Pathology

PSP is a four-repeat (4R) tauopathy with neurofibrillary tangles and tufted astrocytes. Neuronal loss occurs in the subthalamic nucleus, substantia nigra, striatum, brainstem, and frontal cortex.

### Clinical Subtypes (2017 MDS Criteria)

#### PSP-Richardson Syndrome (PSP-RS) -- Classic Form

PSP-RS presents with vertical supranuclear gaze palsy (downgaze is affected first, then upgaze), early postural instability with backward falls within the first year, axial rigidity greater than limb rigidity, and a frontal cognitive/behavioral syndrome featuring apathy, executive dysfunction, and impulsivity. Pseudobulbar affect and a characteristic "surprised" or "worried" facial expression (procerus sign) are common. Slow vertical saccades precede frank gaze palsy and can be detected using optokinetic nystagmus testing.

#### PSP-Parkinsonism (PSP-P)

PSP-P presents with asymmetric parkinsonism and some levodopa response, initially resembling PD. Vertical gaze palsy develops later in the course. Progression is slower than in PSP-RS.

#### Other Variants

PSP-PGF (progressive gait freezing) presents with early onset freezing of gait without other features. PSP-CBS presents with a corticobasal syndrome phenotype. PSP-F (frontal) presents with prominent frontal behavioral changes mimicking behavioral variant FTD. PSP-SL (speech/language) presents with progressive nonfluent aphasia.

### Imaging

MRI shows midbrain atrophy producing the "hummingbird sign" or "penguin sign" on sagittal view, reflecting a decreased midbrain-to-pons ratio. The "morning glory sign" on axial view reveals concavity of the lateral midbrain tegmentum. A midbrain area below 70 mm squared on sagittal MRI is suggestive. FDG-PET shows frontal and midbrain hypometabolism.

### Prognosis

PSP-RS has a median survival of 5-7 years. PSP-P has somewhat longer survival at 7-9 years.

<image>Sagittal MRI comparison showing normal midbrain versus the "hummingbird sign" of midbrain atrophy in progressive supranuclear palsy</image>

## Corticobasal Degeneration (CBD) / Corticobasal Syndrome (CBS)

### Important Distinction

CBS refers to the clinical syndrome (phenotype), which can be caused by CBD, Alzheimer disease, PSP, or other pathologies. CBD refers to the specific pathological diagnosis: a 4R tauopathy with astrocytic plaques and ballooned neurons. Only about 50% of patients with clinical CBS have CBD pathology at autopsy. Conversely, CBD pathology can present as CBS, a PSP-like syndrome, behavioral variant FTD, or nonfluent primary progressive aphasia.

### Clinical Features of CBS

CBS presents with profoundly asymmetric parkinsonism (rigidity and akinesia that is poorly levodopa-responsive), limb apraxia (inability to perform learned motor tasks despite intact motor and sensory function), cortical sensory loss (astereognosis, agraphesthesia with intact primary sensation), alien limb phenomenon (involuntary, purposeless movements of a limb perceived as "not belonging" to the patient), stimulus-sensitive cortical myoclonus, fixed dystonic posturing of the affected limb that may develop contractures, and mirror movements with involuntary levitation of the affected limb.

### Imaging

MRI shows asymmetric cortical atrophy in the parietal and frontal regions, contralateral to the clinically affected side. FDG-PET demonstrates asymmetric cortical hypometabolism. DaTscan shows asymmetric reduction but cannot distinguish CBS from PD.

### Diagnostic Criteria (2013 Armstrong Criteria)

Probable CBS requires an asymmetric presentation with at least 2 of limb rigidity/akinesia, limb dystonia, and limb myoclonus, plus at least 2 of orobuccal/limb apraxia, cortical sensory deficit, and alien limb phenomenon.

### Prognosis

Median survival is 6-8 years from symptom onset. Progressive immobility, contractures, and dysphagia dominate the late stages.

## Supportive Management (All APS)

### Pharmacotherapy

A levodopa trial is warranted in all cases, up to 1000 mg per day before declaring failure. Some MSA-P and PSP-P patients may have modest early benefit. Amantadine may help freezing of gait. Clonazepam is used for myoclonus in CBS. Botulinum toxin can address dystonia, sialorrhea, and blepharospasm.

### Autonomic Management (Especially MSA)

Orthostatic hypotension is managed with compression stockings, abdominal binders, midodrine, droxidopa, and fludrocortisone. Supine hypertension is addressed by elevating the head of the bed and using short-acting antihypertensives at bedtime. Urinary retention may require intermittent catheterization; anticholinergics should be avoided as they worsen constipation and cognition.

### Multidisciplinary Care

Physical therapy focuses on balance and fall prevention. Speech therapy addresses dysarthria and dysphagia with early discussion of PEG placement. Occupational therapy provides ADL strategies. Palliative care integration should occur early in the disease course, with advance care planning discussions initiated at diagnosis.

<image>Axial brain MRI showing asymmetric frontoparietal cortical atrophy in corticobasal syndrome compared with the symmetric putaminal and pontine changes of multiple system atrophy</image>

## Clinical Pearls

If a patient with "PD" falls backward within the first year, PSP-RS should be the primary consideration. Inspiratory stridor in a parkinsonian patient is virtually pathognomonic for MSA; it should be assessed with a sleep study and CPAP considered. The applause sign (inability to stop clapping after being asked to clap 3 times) is suggestive of PSP but not specific. Alien limb phenomenon is dramatic but uncommon; limb apraxia and cortical sensory loss are more reliable diagnostic features of CBS. Levodopa-induced orofacial or cervical dyskinesia at low doses is characteristic of MSA and differs in pattern from PD dyskinesia. Vertical supranuclear gaze palsy can be "unlocked" by the vestibulo-ocular reflex (doll's head maneuver), confirming that the deficit is supranuclear rather than nuclear. DaTscan cannot distinguish PD from atypical parkinsonism; it only confirms presynaptic dopaminergic deficit. Tau PET (such as flortaucipir) is emerging but has limited binding affinity for 4R tauopathies compared to AD tau.

## References
- Hoglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear palsy: the Movement Disorder Society criteria. Mov Disord. 2017;32(6):853-864.
- Wenning GK, Stankovic I, Vignatelli L, et al. The Movement Disorder Society criteria for the diagnosis of multiple system atrophy. Mov Disord. 2022;37(6):1131-1148.
- Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80(5):496-503.
- Boxer AL, Yu JT, Golbe LI, et al. Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. Lancet Neurol. 2017;16(7):552-563.
- Fanciulli A, Wenning GK. Multiple-system atrophy. N Engl J Med. 2015;372(3):249-263.