Multiple system atrophy

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease and synucleinopathy characterised by varying degrees of cerebellar ataxia, autonomic dysfunction, parkinsonism, and corticospinal dysfunction. 

Epidemiology

Multiple systemic atrophy is a sporadic disease, with a prevalence of 4 per 100,000 ². Symptoms typically begin between 40 and 60 years of age ².

Diagnosis

The updated 2022 Movement Disorder Society criteria for MSA diagnosis has four diagnostic categories ^10,11:

• neuropathologically established MSA

  • can only be made by postmortem examination

  • widespread and abundant alpha-synuclein-positive glial cytoplasmic inclusions in the CNS associated with neurodegenerative changes in striatonigral or olivopontocerebellar structures

• clinically established MSA

  • sporadic, progressive, adult (>30 years) onset disease

  • autonomic dysfunction

  • either cerebellar ataxia syndrome or parkinsonism poorly responsive to levodopa

  • ≥2 supportive clinical features

    • includes: rapid disease progression, postural instability, levodopa induced craniocervical dystonia, severe speech impairment, severe dysphagia, Babinski sign, myoclonic or kinetic tremor, postural deformities, stridor, inspiratory sighs, erectile dysfunction, pathologic laughter or crying

  • ≥1 brain MRI marker

    • MSA-C:

      • atrophy of putamen (and signal decrease on susceptibility-weighted sequences), pons and middle cerebellar peduncle

      • hot cross bun sign

      • increased diffusivity of the putamen

    • MSA-P:

      • atrophy of putamen (and signal decrease on susceptibility-weighted sequences), pons, middle cerebellar peduncles and cerebellum

      • hot cross bun sign

      • increased diffusivity of the putamen and middle cerebellar peduncle

  • absence of exclusion criteria

    • includes: parkinsonism responsive to levodopa, unexplained anosmia, fluctuating cognition/attention/alertness with early visuo-perceptual decline, recurrent visual hallucinations, early dementia, downsize supra nuclear palsy or slow vertical saccades, brain MRI findings of an alternative diagnosis, or documented alternate cause for autonomic failure, ataxia or parkinsonism

• clinically probable MSA

  • sporadic, progressive, adult (>30 years) onset disease

  • ≥2 of:

    • autonomic dysfunction

    • parkinsonism

    • cerebellar ataxia syndrome

  • ≥1 supportive clinical features (see clinically established criteria above)

  • brain MRI markers are not required

  • absence of exclusion criteria (see clinically established criteria above)

• research criteria for possible prodromal MSA

  • sporadic, progressive, adult (>30 years) onset disease

  • ≥1 of:

    • rapid eye movement sleep behaviour disorder proven by polysomnography

    • neurogenic orthostatic hypotension

    • urogenital failure/dysfunction

  • ≥1 of:

    • subtle parkinsonian signs

    • subtle cerebellar signs

  • absence of exclusion criteria (see clinically established criteria above)

Clinical presentation

Clinical presentation is variable, but historically the disease presented in one of three patterns, initially described as separate entities ^1,2:

• Shy-Drager syndrome is used when autonomic symptoms predominate

• striatonigral degeneration shows predominant parkinsonian features

• olivopontocerebellar atrophy demonstrates primarily cerebellar dysfunction

In the 2007 consensus paper ⁶ and updated 2022 Movement Disorder Society criteria ^10,11, MSA is divided into two clinical forms according to the predominant motor syndrome:

1. multiple system atrophy cerebellar type (MSA-C), previously known as olivopontocerebellar atrophy

2. multiple system atrophy parkinsonian type (MSA-P), previously known as striatonigral degeneration

Some older texts refer to MSA-A (A for autonomic) to denote Shy-Drager syndrome. In the 2022 diagnostic criteria however, autonomic symptoms are considered part of both MSA-C and MSA-P, thus the term MSA-A is no longer used.

Pathology

Like other synucleinopathies, MSA results from abnormalities of alpha-synuclein metabolism, resulting in intracellular deposition. Unlike Parkinson disease and Lewy body dementia (two other synucleinopathies), these intracellular deposits are found not only in neurones but also in oligodendroglia ². 

Radiographic features

MRI is the modality of choice for imaging patients with suspected MSA. It is emphasised that MSA-C and MSA-P are clinical forms and cannot be reliably differentiated on MRI due to significant overlap of imaging findings ^10,11. Absence of MRI findings does not exclude a diagnosis of MSA (see diagnostic criteria above), due to low sensitivity (especially in early disease), however MRI has high specificity for differentiating MSA from Parkinson disease and progressive supranuclear palsy, which are important clinical mimics ¹⁰.

MRI

• T2 hyperintensities in the pontocerebellar tracts

  • pons (hot cross bun sign)

  • middle cerebellar peduncles

  • cerebellum

• abnormal putaminal signal

  • reduced signal on T2*, GRE or SWI sequences relative to the globus pallidus and red nucleus

  • abnormally high T2 linear rim surrounding the putamen (putaminal rim sign) seen at 1.5 T (this is normal at 3 T) ^7,10 (see case 3)

• disproportionate atrophy

  • MSA-C: putamen, pons and middle cerebellar peduncle ^10,11

  • MSA-P: putamen, pons, middle cerebellar peduncle and cerebellum ^10,11

• diffusion tensor imaging

  • ADC: higher in the pons, cerebellum, and putamen compared with Parkinson disease or controls

  • fractional anisotropy (FA): lower in the pons, cerebellum, and putamen compared with Parkinson disease or controls

Nuclear medicine

On SPECT/CT with I-123 ioflupane, there is loss of the normal comma- or crescent-shaped tracer uptake in the striatum. Instead, a period- or oval-shaped uptake is seen within the caudate nucleus head, without tracer uptake in the putamen. Quantitative assessment reveals reduced uptake in the putamen compared with norms.

Treatment and prognosis

Unfortunately, no effective disease-modifying treatment is available and management remains supportive (e.g. antiparkinsonian medications for parkinsonism, gait aids for gait ataxia, etc.). The disease progresses relentlessly, ultimately culminating in death, usually within 10 years of diagnosis ².