Multiple System Atrophy: MSA-C vs MSA-P

What is MSA?

Multiple System Atrophy (MSA) is a sporadic, progressive neurodegenerative disorder (synucleinopathy) characterized by a triad of:

Autonomic dysfunction (orthostatic hypotension, urogenital failure)
Parkinsonism
Cerebellar ataxia

It was previously known by three names that are now considered subtypes of the same disease: Shy-Drager syndrome, striatonigral degeneration, and olivopontocerebellar atrophy (OPCA).

Epidemiology:

Mean age of onset: ~54 years
Prevalence: ~4-5 per 100,000
Annual incidence: ~3 per 100,000
Mean survival: 5.7-9 years from symptom onset
No gender predilection

MSA-P vs MSA-C: Side-by-Side Comparison

Feature	MSA-P (Parkinsonian)	MSA-C (Cerebellar)
Former name	Striatonigral degeneration	Olivopontocerebellar atrophy (OPCA)
Predominant feature	Parkinsonism	Cerebellar ataxia
More common in	European populations (~58%)	Japanese populations (~84%)
Parkinsonism type	Symmetric, often no resting tremor, poor/absent L-dopa response, rapid progression	Parkinsonism present but cerebellar signs dominate; partial/transient L-dopa response possible
Cerebellar signs	Less prominent	Wide-based ataxic gait, limb ataxia, dysarthria (cerebellar)
MRI findings	T2 hyperintense lateral putaminal rim; T2 hypointensity of posterior putamen	Atrophy of pons, cerebellum, middle cerebellar peduncles; "hot cross bun" sign on T2 (cruciform pontine hyperintensity); T2 hyperintensity in middle cerebellar peduncles
Ataxia progression	Slower	Faster than other degenerative ataxias
Falls/instability	Early	Present
Diplopia	Less common	Intermittent diplopia may occur

Shared Features (Both Subtypes)

Autonomic Dysfunction (cardinal feature in both)

Orthostatic hypotension (OH): Drop of ≥30 mmHg systolic or ≥15 mmHg diastolic on standing - required for probable MSA
Urinary dysfunction: Urgency, frequency, retention - large post-void residual is a clue favoring MSA over PD
Erectile dysfunction in males
Sweating dysfunction / anhidrosis (central pattern on thermoregulatory sweat testing)
Bowel dysfunction (constipation, fecal incontinence)
REM sleep behavior disorder (RBD) - strongly associated with MSA

Motor Features

Pyramidal signs
Stridor (laryngeal / nocturnal) - important red flag
Dysarthria (early hypokinetic)
Dysphagia
Oculomotor dysfunction
Orofacial dystonia
Distal myoclonus
Pseudobulbar affect / emotional lability

Cognitive/Psychiatric

Significant dementia is rare and is a red flag against MSA diagnosis
Executive deficits and slowed processing speed may occur on neuropsychological testing
Depression and anxiety are common

Pathological Hallmark

The defining histological feature is glial cytoplasmic inclusions (GCIs) containing α-synuclein and ubiquitin in oligodendrocytes.

GCIs differ from Lewy bodies (seen in PD) in three key ways:

Shape: GCIs are irregular; Lewy bodies are concentric/target-shaped
Cell type: GCIs are in glia (oligodendrocytes); Lewy bodies are in neurons
Location in neuraxis: GCIs dominate in basal ganglia and pons; Lewy bodies dominate in midbrain, cortex, and autonomic ganglia

At autopsy, neuronal loss and gliosis are seen in: striatum, substantia nigra, locus coeruleus, inferior olive, pontine nuclei, Purkinje cells, intermediolateral cell column, and Onuf's nucleus (sacral cord).

Glial cytoplasmic inclusions in MSA, immunostained with α-synuclein

Glial cytoplasmic inclusions in basal ganglia, α-synuclein immunostain - typical of MSA

Diagnosis

Probable MSA requires:

Autonomic failure (OH or urinary dysfunction)
Plus parkinsonism (poor L-dopa response) OR cerebellar ataxia

Red Flags for MSA-P (any 2 of 6 increase specificity):

Early instability/falls
Rapid progression
Abnormal postures (Pisa syndrome, anterocollis, hand/foot contractures)
Bulbar dysfunction (dysphonia, dysarthria, dysphagia)
Respiratory dysfunction (inspiratory stridor, inspiratory sighs)
Emotional incontinence (inappropriate crying/laughing)

Investigations:

Autonomic testing: Heart rate variability, head-up tilt, thermoregulatory sweat test
MRI brain: Patterns differ by subtype (see table above) - "hot cross bun" sign is characteristic of MSA-C
Rectal sphincter EMG: Denervation is characteristic
FDG-PET: Hypometabolism in basal ganglia and cerebellum
Growth hormone response to clonidine: Blunted in MSA
CSF/serum neurofilament light (NFL) protein: Elevated in MSA (not PD) but doesn't differentiate from other atypical parkinsonism

Differentiating MSA from Parkinson's Disease

Feature	MSA	PD
Rest tremor	Typically absent (MSA-P)	Classic feature
L-dopa response	Poor/absent or transient	Good, sustained
Dementia	Rare	Common later
Autonomic dysfunction	Early, severe	Present but later/milder
Post-void residual	Large early	Less prominent
Progression	Faster	Slower
Wheelchair dependency	~5 years from onset	Much later

Treatment (Symptomatic Only - No Disease-Modifying Therapy Exists)

Symptom	Management
Orthostatic hypotension	Liberal salt/water, compression stockings, head-up sleeping; pharmacotherapy: fludrocortisone, midodrine, droxidopa
Parkinsonism	L-dopa (partial/short-lived benefit early in MSA-P); dopamine agonists poorly tolerated due to OH
Cerebellar signs	No effective treatment
Urinary retention	Self-catheterization if severe
Depression	SSRIs
Supine hypertension	Carefully manage (often worsened by OH treatment)

Prognosis: Poor. 10-year survival is rare. Common causes of death: pulmonary embolism, apnea (Ondine curse from sleep apnea/respiratory drive failure), aspiration pneumonia, intercurrent infection.

Sources: Bradley and Daroff's Neurology in Clinical Practice, Chapters on Autonomic Disorders and Movement Disorders

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