Red flags phenotyping: A systematic review on clinical features in atypical parkinsonian disorders

To establish a clinical diagnosis of a parkinsonian disorder, physicians rely on their ability to identify relevant red flags, in addition to cardinal features, to support or refute their working diagnosis in an individual patient. The term 'red flag', was originally coined in 1989 to define the presence of non-cardinal features that may raise a suspicion of multiple system atrophy (MSA), or at least suggest alternative diagnosis to Parkinson's disease (PD). Since then, the term 'red flag', has been consistently used in the literature to denote the clinical history or signs that may signal to physicians the possibility of an atypical parkinsonian disorder (APD). While most red flags were originally based on expert opinion, many have gained acceptance and are now included in validated clinical diagnostic criteria of PD and APDs. The clinical appreciation of red flags, in conjunction with standard criteria, may result in a more accurate and earlier diagnosis compared to standard criteria alone. However, red flags can be clinical signs that are non-neurological, making the systematic assessment for them a real challenge in clinical practice. Here, we have conducted a systematic review to identify red flags and their clinical evidence in the differential diagnosis of common degenerative parkinsonism, including PD, MSA, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy body (DLB). Increasing awareness and appropriate use of red flags in clinical practice may benefit physicians in the diagnosis and management of their patients with parkinsonism.