Multiple system atrophy

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

Terminology

The umbrella term multiple system atrophy unifies several historically recognized conditions. Two clinical phenotypes are recognized based on the predominant motor syndrome ¹:

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

A third, historically recognized entity known as Shy-Drager syndrome, was sometimes referred to as MSA-A (autonomic type), but the 2022 diagnostic criteria of the Movement Disorder Society considers autonomic symptoms to be a core part of both clinically established MSA-C and MSA-P ¹. Thus, MSA-A is no longer used.

Epidemiology

Multiple system 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 ^1,10:

• neuropathologically established MSA

  • postmortem examination showing 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*

  • ≥1 clinical motor feature:

    • cerebellar syndrome (at least two of gait ataxia, limb ataxia, cerebellar dysarthria, or oculomotor features)

    • parkinsonism poorly responsive to levodopa

  • ≥2 supportive clinical features:

    • motor features: rapid disease progression, postural instability, severe speech impairment, or severe dysphagia, each within 3 years of motor onset; levodopa induced craniocervical dystonia; Babinski sign; myoclonic jerks or kinetic tremor; or postural deformities

    • non-motor features: stridor, inspiratory sighs, cold discolored hands and feet, erectile dysfunction, pathologic laughter or crying

  • ≥1 brain MRI marker

    • MSA-C

      • putamen atrophy and susceptibility effect, or increased diffusivity

      • pons and middle cerebellar peduncle atrophy

      • hot cross bun sign

    • MSA-P

      • putamen atrophy and susceptibility effect, or increased diffusivity

      • middle cerebellar peduncle atrophy or increased diffusivity

      • pons atrophy

      • cerebellum atrophy

      • hot cross bun sign

    • note: these diagnostic criteria should not be considered equivalent to the most commonly seen features in clinical practice. For example, counterintuitively, although atrophy of the cerebellum and increased diffusivity of the middle cerebellar peduncles are common in MSA-C, they are not included as diagnostic criteria to help distinguish MSA-C from other cerebellar diseases that have similar clinicoradiologic features (e.g. genetic ataxias) ¹

  • absence of exclusion criteria:

    • parkinsonism responsive to levodopa

    • unexplained anosmia

    • fluctuating cognition/attention/alertness with early visuoperceptual decline

    • recurrent visual hallucinations within 3 years of onset

    • dementia within 3 years of onset

    • downgaze supranuclear palsy or slow vertical saccades

    • brain MRI findings of an alternative diagnosis (eg, progressive supranuclear palsy, small vessel disease causing vascular parkinsonism, multiple sclerosis, or normal pressure hydrocephalus)

    • 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 under clinically established criteria)

  • brain MRI markers are not required

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

• possible prodromal MSA (research criteria)

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

  • ≥1 of:

    • rapid eye movement sleep behavior disorder (proven by polysomnography)

    • autonomic dysfunction* (with erectile dysfunction also required to be associated with urinary issues in males under 60)

  • ≥1 clinical motor feature:

    • subtle parkinsonian signs

    • subtle cerebellar signs

  • absence of exclusion criteria (see under clinically established criteria, as well as abnormal cardiac sympathetic imaging)

*Autonomic dysfunction is defined at least one of the following:

• unexplained voiding difficulties with post-void residual at least 100 mL (for clinically established MSA) or of any volume (for clinically probable or possible prodromal MSA)

• unexplained urinary urge incontinence

• neurogenic orthostatic hypotension (at least 20/10 mm Hg blood pressure drop) after standing or head-up tilt test within 3 minutes (for clinically established MSA) or 10 minutes (for clinically probable or possible prodromal MSA)

Clinical presentation

Clinical presentation is variable.

MSA-P presents predominantly with parkinsonism with mild cerebellar and pyramidal symptoms and signs. Autonomic dysfunction is also common. Ataxia and bulbar symptoms are less evident.

MSA-C presents predominantly with cerebellar and brainstem symptoms and signs. Typically ataxia and bulbar dysfunction are pronounced. Autonomic dysfunction is also common. Parkinsonism is less evident.

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 neurons but also in oligodendroglia ². 

Radiographic features

MRI is the modality of choice for imaging patients with suspected MSA. It is emphasized that MSA-C and MSA-P are clinical forms and cannot be reliably differentiated on MRI due to significant overlap of imaging findings ^1,10. 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 ¹.

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) ^1,7 (see case 3)

• disproportionate atrophy

  • putamen

  • pons

    • the rate of atrophy may also be helpful, with one study suggesting the rate of atrophy to be characteristic of MSA-C at the following thresholds ¹²:

      • rate of atrophy in measuring the anterior–posterior pons: -0.87 mm/year (highly specific but not very sensitive)

      • rate of atrophy of -0.4 mm/year had a sensitivity of 92% and a specificity of 87%

  • middle cerebellar peduncle

    • the rate of atrophy may also be helpful, with one study suggesting the rate of atrophy to be characteristic of MSA-C at the following thresholds ¹²:

      • a rate of -0.84 mm/year (highly specific but not very sensitive)

      • a rate of -0.5 mm/year had a sensitivity of 85% and specificity 79%

  • cerebellum

• 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 dopamine transporter brain imaging with I-123 ioflupane SPECT/CT, 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.

On cardiac sympathetic imaging with I-123 MIBG scintigraphy, abnormal heart/mediastinum ratio 4 hours after tracer injection is an exclusion criterion for possible prodromal MSA ¹.

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. 

Differential diagnosis

Clinical and radiological mimics of MSA include the following ¹¹:

• fragile X-associated tremor ataxia syndrome

• spinocerebellar ataxia

• Parkinson disease

• progressive supranuclear palsy

• dementia with Lewy bodies

• corticobasal degeneration

• paraneoplastic cerebellar degeneration