Multiple system atrophy (MSA) is a sporadic adult-onset α-synucleinopathy distinct from Parkinson disease and dementia with Lewy bodies. Where PD and DLB feature α-synuclein accumulation in neurons (Lewy bodies), MSA is characterized by α-synuclein deposition in oligodendrocytes as glial cytoplasmic inclusions (GCIs, Papp-Lantos bodies). The disease produces a clinically distinctive constellation: prominent autonomic failure plus either striatonigral degeneration (MSA-P, parkinsonian variant) or olivopontocerebellar atrophy (MSA-C, cerebellar variant) or mixed. This page covers MSA pathology and clinical-pathologic features.

Pathology

Glial Cytoplasmic Inclusions (GCIs / Papp-Lantos Bodies)

  • α-synuclein-positive intracytoplasmic inclusions in oligodendrocytes.
  • Sickle-shaped, flame-shaped, or oval; argyrophilic.
  • Distinguished from Lewy bodies by their oligodendrocytic (rather than neuronal) location.
  • Distribution: widespread but heaviest in olivopontocerebellar and striatonigral systems.

Neuronal Pathology

  • Neuronal cytoplasmic inclusions (less common than GCIs).
  • Neuronal nuclear inclusions.
  • Neuropil threads.

Selective Vulnerability — MSA-P (Striatonigral)

  • Substantia nigra pars compacta loss.
  • Posterior putamen atrophy (dorsolateral).
  • External globus pallidus.
  • Subthalamic nucleus.

Selective Vulnerability — MSA-C (Olivopontocerebellar)

  • Pontine nuclei atrophy.
  • Cerebellar cortex (Purkinje cells).
  • Inferior olivary nucleus.
  • White matter loss in cerebellar peduncles and pons.

Autonomic / Other Involvement

  • Intermediolateral cell column of spinal cord (preganglionic sympathetic).
  • Edinger-Westphal nucleus (pupillary).
  • Onuf nucleus (sacral motor for bladder/bowel) — though traditionally said to be spared, recent work shows variable involvement.
  • Locus coeruleus.
  • Dorsal motor nucleus of vagus.

Clinical Features (MDS Criteria 2022)

Core Features

  • Autonomic failure (severe, early): orthostatic hypotension (drop of 30 mmHg systolic or 15 mmHg diastolic within 3 minutes of standing), urinary dysfunction (urgency, retention, incontinence), erectile dysfunction.
  • Parkinsonism (MSA-P) or cerebellar (MSA-C) or mixed.

Distinguishing from PD/DLB

  • Early, severe autonomic failure (vs late in PD).
  • Poor L-dopa response (or only modest, transient).
  • Rapid progression.
  • Symmetric onset.
  • Absence of tremor (especially rest tremor).
  • Early speech and swallowing involvement.
  • Cognitive impairment relatively late.

Imaging Findings

MSA-P

  • Putaminal atrophy (especially posterior/dorsolateral).
  • Putaminal hypointensity on T2 (iron accumulation) with hyperintense rim (“slit-like rim sign”).
  • Reduced T1 signal in posterior putamen.

MSA-C

  • “Hot cross bun” sign: cross-shaped T2 hyperintensity in pons — pathognomonic for MSA-C (reflects degeneration of pontocerebellar tracts).
  • Cerebellar atrophy: prominent.
  • Middle cerebellar peduncle atrophy/T2 hyperintensity.
  • Pontine atrophy.

Cardiac Imaging (MIBG)

Preserved cardiac MIBG uptake distinguishes MSA from PD/DLB (where MIBG is reduced due to postganglionic sympathetic denervation — a feature absent in MSA where the denervation is preganglionic).

Diagnosis

  • Wenning 2022 MDS criteria require:
    • Sporadic adult-onset disease (>30 years).
    • Autonomic failure.
    • Parkinsonism or cerebellar syndrome.
    • Supportive imaging features.
    • Exclusion of mimics.
  • Skin biopsy α-synuclein seed amplification assay (syn-SAA): emerging tool; positive in MSA as well as PD/DLB, distinguishing from non-synucleinopathies.
  • Definitive diagnosis still requires autopsy.

Course and Prognosis

  • Faster progression than PD.
  • Median survival ~9-10 years from onset (vs 15+ for PD).
  • Death often from aspiration, respiratory complications, autonomic failure.
  • Disability accumulates quickly.

Treatment

  • No disease-modifying therapy.
  • L-dopa: trial; some MSA-P patients have modest, often transient response. Most do not.
  • Orthostatic hypotension: non-pharmacologic measures, midodrine, droxidopa, fludrocortisone, pyridostigmine.
  • Urinary dysfunction: catheterization often needed.
  • Sialorrhea: anticholinergics, botulinum toxin to salivary glands.
  • Speech and swallowing therapy.
  • Falls prevention.
  • Trials of anti-α-synuclein, gene-targeted therapies underway.

Differential Diagnosis

  • PD/DLB: later autonomic failure; L-dopa responsive; rest tremor; longer course.
  • PSP: vertical gaze palsy + axial rigidity; tauopathy.
  • CBD: asymmetric, cortical features.
  • Pure autonomic failure: autonomic without parkinsonism/cerebellar (some progress to MSA or DLB over time).
  • Hereditary cerebellar ataxias (SCAs): family history; cerebellar predominant; younger onset typically.
  • Fragile X-associated tremor/ataxia syndrome (FXTAS): FMR1 premutation; tremor + ataxia in older men; MRI middle cerebellar peduncle sign.

🔍 Did You Know?

The recognition that multiple system atrophy is an oligodendrocytic synucleinopathy rather than a neuronal one was one of the most important advances in 20th-century neuropathology. For decades, MSA was thought to be a variant of Parkinson disease — the autonomic failure and cerebellar features were attributed to widespread degeneration of similar substrate. The discovery in 1989 by Papp and Lantos that α-synuclein-positive glial cytoplasmic inclusions accumulate in oligodendrocytes rather than neurons defined MSA as a distinct disease with a fundamentally different pathologic substrate. The implications were profound: it explained why MSA progresses differently from PD (oligodendrocyte loss affects myelin and supportive functions across tracts, not just specific neurons), why L-dopa is generally ineffective (the lesion isn’t primarily in nigrostriatal dopaminergic neurons), why autonomic failure is so prominent (oligodendrocyte involvement throughout the autonomic preganglionic pathways), and why the prognosis is worse. The discovery also provided a mechanistic question that remains unresolved: where does the α-synuclein come from? Oligodendrocytes do not normally express α-synuclein in significant amounts — current hypotheses include transfer from neurons (prion-like propagation), increased expression in disease, or impaired clearance. The pathologic shift from “PD variant” to “distinct oligodendrocytic synucleinopathy” reshaped both research approaches and clinical management of MSA. The lesson: pathologic categorization matters because it determines what we look for in trials and how we counsel patients about prognosis.

Pitfalls and Pearls

  • MSA = oligodendrocytic α-synucleinopathy with GCIs/Papp-Lantos bodies (distinct from neuronal Lewy bodies of PD/DLB).
  • MSA-P: parkinsonism + autonomic failure; poor L-dopa response.
  • MSA-C: cerebellar + autonomic failure.
  • Early severe autonomic failure: hallmark.
  • Hot cross bun sign on pons MRI: MSA-C.
  • Putaminal atrophy with hyperintense rim (slit sign): MSA-P.
  • Cardiac MIBG preserved in MSA; reduced in PD/DLB. Distinguishes them.
  • Faster progression than PD: median survival ~9-10 years.
  • Poor or no L-dopa response: characteristic of MSA.
  • Orthostatic hypotension: treat with droxidopa, midodrine, fludrocortisone.
  • Skin biopsy syn-SAA: positive in MSA as well as PD/DLB.
  • 2022 MDS-MSA criteria: updated diagnostic standard.
  • Pure autonomic failure: may progress to MSA or DLB.
  • Symmetric onset + lack of tremor: differs from typical PD.

References

  1. Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy. J Neurol Sci. 1989;94(1-3):79-100.
  2. 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.
  3. Fanciulli A, Wenning GK. Multiple-system atrophy. N Engl J Med. 2015;372(3):249-263.
  4. Halliday GM, Holton JL, Revesz T, Dickson DW. Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol. 2011;122(2):187-204.
  5. Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71(9):670-676.