The diagnosis of MSA can be challenging because its initial symptoms resemble those of other diseases.

MSA can only be conclusively diagnosed through examination of the brain and nervous system. A finding of glial cytoplasmic inclusions with an abnormal build up of alpha-synuclein in combination with degeneration of the specific areas of the brain indicates a definitive diagnosis of MSA.

Otherwise, clusters of MSA symptoms can be ranked as possible or probable. Possible MSA is diagnosed in an adult with Parkinsonism or cerebellar syndrome, at least one symptom of autonomic or urogenital dysfunction, and one additional symptom. The diagnosis becomes probable if the same patient is resistant to a medication used to treat Parkinson's disease.

Some patient characteristics do not support a diagnosis of MSA. Symptom onset before the age of 30 or after 75 is not consistent with MSA. As well, a family history of ataxia or Parkinson's disease makes MSA unlikely. Hallucinations and dementia are inconsistent with MSA, as is a classic, Parkinsonian “pill rolling” tremor or clinically significant neuropathy. Some physical exam and laboratory findings are also contradictory to MSA.

Differential Diagnosis for MSA-P

MSA-P, or MSA with features of Parkinsonism, strongly resembles Parkinson's disease. Both diseases cause slow movement, muscle rigidity, tremors, and a shuffling gait. There are some distinguishing features of MSA, however, that can be used for diagnostic purposes. Some MSA patients only have symptoms on one side of the body, whereas Parkinson's disease affects the body symmetrically.

In MSA, postural instability is an earlier and faster-progressing symptom than in Parkinson's disease. As well, the characteristic pill-rolling tremor of Parkinson's is not present in MSA.

Progressive supranuclear palsy (PSP), Lewy body dementia, and corticobasilar degeneration are other potential alternative diagnoses. Lewy body dementia is a form of Parkinsonism that features cognitive impairment and hallucinations in addition to the autonomic nervous system symptoms. As mentioned above, hallucinations and dementia are inconsistent with MSA and would point toward another condition.

When cognitive impairment is present, multiple sclerosis is a possibility. Since cognitive impairment can also affect patients with MSA, brain imaging studies may be needed to differentiate the specific patterns of tissue damage in the brain to rule out multiple sclerosis.

Differential Diagnosis for MSA-C

Cerebellar ataxia, or uncoordinated movement, is the primary symptom of MSA-C. Ataxia affects gait and can produce uncoordinated movements of arms and hands, impaired speech, and problems with eye movement. These symptoms can overlap with a number of other cerebellar disorders, including spinocerebellar ataxia (SCA). However, SCA is a genetically inherited disorder.

Autonomic symptoms of MSA like erectile dysfunction and neurogenic orthostatic hypotension are vague and may be confused with normal changes of aging. This group of symptoms could be caused by pure autonomic failure (PAF). PAF is a less severe disorder, and patients will not develop Parkinsonian or cerebellar symptoms.

Because MSA is difficult to diagnose in its early stages, there is sometimes a delay in getting the correct diagnosis.