Investigations
1st investigations to order
brain MRI
Test
Order as the initial diagnostic work-up for any patient with suspected PSP, to exclude differential diagnoses and look for characteristic imaging findings that can support a clinical diagnosis of PSP.[3]
The characteristic imaging features of PSP include significant atrophy of midbrain and superior cerebellar peduncles, which can result in the 'hummingbird', 'Mickey Mouse', and 'morning glory' signs.[3][14] While this typical imaging pattern is very frequent in PSP-Richardson's syndrome (PSP-RS), it is unclear how early in the disease course it appears. Moreover, it is not usually present in the other phenotypes; therefore, its absence does not exclude PSP.
The Magnetic Resonance Parkinsonism Index (MRPI) - calculated as the pons-midbrain width ratio multiplied by the middle cerebellar peduncles-superior cerebellar peduncles width ratio) - has a high sensitivity and specificity for distinguishing PSP from Parkinson’s disease (PD).[71][72][73] A newer version, MRPI 2.0, has high sensitivity and specificity (100% and 94.3%, respectively) in differentiating the parkinsonism subtype of PSP (PSP-P) from PD.[74]
[Figure caption and citation for the preceding image starts]: MRI of the brain in a patient with clinically diagnosed PSP. Image A: sagittal T1-MRI through the brainstem demonstrates atrophy in the midbrain with relative preservation of the pons, giving the appearance of a hummingbird. Image B: on axial T1-weighted imaging, the dorsal midbrain is reduced in volume, giving a “Mickey Mouse” appearanceSchott JM. Practical Neurology 2007; 7: 186-190; used with permission [Citation ends].
Result
pronounced atrophy in the midbrain and superior cerebellar peduncles with relatively intact pons is supportive (but not definitive) of a PSP diagnosis; this feature can result in various radiographic signs, including 'hummingbird', 'Mickey Mouse', and 'morning glory' signs in the midsagittal and axial planes
levodopa trial
Test
Strongly recommended for patients who are affected by parkinsonism.[3][10]
Progressively increase the dose to the recommended range and continue the highest tolerated dosage for at least 1 month before determining the response.[3][10]
Note that many patients with PSP are initially diagnosed with Parkinson’s disease, and a lack of response of parkinsonism symptoms to levodopa is one feature that points towards PSP as the correct diagnosis.
Result
minimal or no benefit (as defined by ≤30% improvement on the Movement Disorder Society Unified Parkinson’s Disease Rating Scale [MDS-UPDRS]) supports a diagnosis of PSP
Investigations to consider
polysomnography
Test
Consider ordering only if a patient with parkinsonism has a clear history of dream enactment obtained from a bed partner.
Not routinely used but may be helpful (if available) in distinguishing PSP from Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).[3]
Rapid eye movement (REM) sleep behaviour disorder is uncommon in PSP and more supportive of a diagnosis of PD, DLB, or MSA. However, be aware that its presence does not exclude PSP, with reported prevalence in this patient group ranging from 14% to 33%.[10]
Result
REM sleep behaviour disorder unlikely to be identified
tilt table test/active stand test
Test
Useful to distinguish PSP from multiple system atrophy (MSA) or dementia with Lewy bodies (DLB).[3]
Orthostatic hypotension points to a diagnosis of MSA or DLB rather than PSP.
Consider performing an active stand test first, with measurement of BP and heart rate in the supine and standing position. A significant drop in BP with no significant increase in heart rate from supine to standing is indicative of neurogenic orthostatic hypotension.[3] A tilt table test is indicated if the active stand test is inconclusive.
Result
no evidence of significant orthostatic hypotension
biopsy of bone marrow or skin
Test
Bone marrow biopsy or skin biopsy with fibroblast culture and filipin test can be used to exclude Niemann-Pick disease type C (NPC), which can also present with vertical supranuclear gaze palsy. It is indicated in patients under age 45 years, particularly if other clinical clues suggest NPC as a possible diagnosis.[3]
Positive filipin test on cultured fibroblasts indicates NPC as the correct diagnosis.
Result
no abnormality identified
PCR for Tropheryma whippelii
Test
Polymerase chain reaction (PCR) for Tropheryma whippelii on a cerebrospinal fluid (CSF) sample or intestinal biopsy can be used to exclude Whipple's disease, which can also present with vertical supranuclear gaze palsy.[76] It is indicated if other clinical clues (gastrointestinal symptoms, arthralgias, fever, younger age, and atypical neurological features) suggest Whipple's disease as a possible diagnosis.[3]
A positive result indicates Whipple's disease.
Result
negative
24-hour urinary copper
Test
Can help to distinguish PSP from Wilson’s disease, which can also present with vertical supranuclear gaze palsy.[77] It is indicated in patients under age 45 years if other clinical clues suggest Wilson’s disease as a possible diagnosis.[3]
Result >40 micrograms may suggest Wilson’s disease, requiring further investigation.[77]
Result
normal urinary copper excretion
paraneoplastic antibody panel
Test
Can help distinguish PSP from autoimmune/paraneoplastic encephalitis, which can also present with vertical supranuclear gaze palsy. It is indicated if other clinical clues (e.g., particularly rapid disease progression) suggest encephalitis as a possible diagnosis.[3]
The presence of paraneoplastic antibodies (e.g., anti-Ma1/Ma2) excludes a diagnosis of PSP.
Result
negative
CSF biomarkers for prion disease
Test
Can help exclude prion disease. It is indicated in patients with particularly rapid disease progression.[3]
In prion disease, 14-3-3 protein (i.e., western blot) may be positive; total tau (T-tau) protein elevated (>1200 picograms/mL); neuron-specific enolase elevated (>35 nanograms/mL).[78]
Result
negative
genetic testing
Test
Genetic testing may be indicated if there is any suspicion of a genetic movement disorder that may mimic PSP (e.g., if one or more close relatives has a neurodegenerative condition with young age of onset).[3][42]
Known rare genetic variants that may mimic PSP clinically include mutations in C9orf72, microtubule-associated protein tau (MAPT), progranulin (GRN), Park9, and CSF-1R.[3][42]
Note that identification of rare MAPT variants does not exclude a diagnosis of PSP but indicates a rare instance of inherited as opposed to sporadic PSP.[3]
Result
negative
PET imaging
Test
Beta-amyloid PET imaging is indicated in patients with a suspected diagnosis of the corticobasal syndrome subtype of PSP (PSP-CBS) to exclude the possibility of Alzheimer’s disease pathology.[3] Pathological beta-amyloid PET imaging indicates Alzheimer’s pathology and excludes a diagnosis of PSP.
The European Association of Nuclear Medicine/European Academy of Neurology and the American College of Radiology recommend fluorodeoxyglucose (FDG)-PET imaging as potentially helpful in distinguishing PSP (in particular, the PSP-Richardson's syndrome [PSP-RS] phenotype) from Parkinson's disease, particularly in the first 2 years of symptom onset.[69][75] In PSP-RS, hypometabolism is typically seen.
Result
no evidence of pathological beta-amyloid deposition on PET imaging; evidence of hypometabolism in the medial frontal gyrus, anterior cingulate cortex, pons, and ventral striatum on FDG-PET imaging
CSF biomarkers for Alzheimer’s disease
Test
Cerebrospinal fluid (CSF) analysis may be used in patients with a suspected diagnosis of the corticobasal syndrome subtype of PSP (PSP-CBS) to exclude the possibility of Alzheimer’s disease pathology.[3]
Elevated total tau/phosphorylated-tau protein and reduced beta-amyloid 42 points towards Alzheimer’s disease.[3]
Result
negative
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