Which disorder is characterized by autonomic dysfunction (Shy-Drager), cerebellar ataxia, and poor response to levodopa, with glial inclusions?

• A. HIV-Associated Neurocognitive Disorder
• B. Normal Pressure Hydrocephalus
• C. Semantic Dementia
• D. Multiple System Atrophy

Answer: (D)

The key idea is recognizing a neurodegenerative disorder that uniquely combines autonomic failure, cerebellar ataxia, and poor response to levodopa, with glial inclusions on pathology. This triad points to Multiple System Atrophy (MSA), historically described as Shy-Drager syndrome when autonomic dysfunction is prominent. In MSA, autonomic symptoms such as orthostatic hypotension and urinary incontinence are common early features, and cerebellar involvement leads to ataxia, which helps distinguish it from other parkinsonian disorders. The parkinsonism in MSA typically does not respond well to levodopa, unlike idiopathic Parkinson disease where levodopa often provides meaningful benefit. Pathologically, MSA shows glial cytoplasmic inclusions rich in alpha-synuclein within oligodendrocytes, a hallmark that sets it apart from other conditions.

This helps differentiate from HIV-associated neurocognitive disorder, which centers on cognitive impairment related to HIV and lacks the specific autonomic-ataxia profile with glial inclusions. Normal Pressure Hydrocephalus presents with gait disturbance, cognitive changes, and urinary symptoms but lacks cerebellar ataxia and the characteristic glial inclusions. Semantic dementia is a language-dominant neurodegenerative syndrome without prominent autonomic failure or ataxia, and it has different neuropathology. Thus, the combination of autonomic failure, cerebellar ataxia, poor levodopa response, and glial inclusions most appropriately points to Multiple System Atrophy.