Differentials
Idiopathic Parkinson’s disease (PD)
SIGNS / SYMPTOMS
Gait abnormalities with falls and freezing commonly develop in the late stages of PD, whereas these symptoms occur early in PSP-Richardson's syndrome (PSP-RS).[3][28]
A therapeutic trial of levodopa will produce an excellent symptomatic response in PD, whereas in PSP a response is absent or weak and rapidly waning (PSP-parkinsonism [PSP-P] may be an exception).[3][10]
In PD, bradykinesia and rigidity predominantly affect the limbs, whereas in PSP the axial skeleton (trunk and neck) is most affected.[3][10]
Hyposmia (decreased sense of smell) may precede the development of motor symptoms in PD, whereas olfaction is generally preserved in PSP.[79]
INVESTIGATIONS
MRI brain is normal in most patients with idiopathic PD (disregarding any normal age-related changes).
Abnormal cardiac iodine-123 meta-iodobenzylguanidine (123-I-MIBG) scan showing decreased sympathetic innervation is in favour of PD diagnosis.[80]
A cerebrospinal fluid alpha-synuclein seed amplification assay can confidently diagnose PD and differentiate it from PSP. However, it is not yet widely available.[81]
Although not routinely used to differentiate PD from PSP, REM sleep behaviour disorder (RBD) confirmed by polysomnography is in favour of a PD diagnosis (although it does not exclude PSP). In PD, RBD typically predates the onset of motor symptoms whereas in PSP, when it is present, it does not.
Corticobasal degeneration (CBD)
SIGNS / SYMPTOMS
In CBD, ocular motor apraxia usually affects both the horizontal and vertical gaze, and saccades have an increased latency but normal speed.[82]
Asymmetric limb dystonia, apraxia, alien limb, and/or myoclonus are more indicative of underlying CBD, although they can also indicate the corticobasal phenotype of PSP (PSP-CBS).[83]
INVESTIGATIONS
None.
Multiple system atrophy (MSA)
SIGNS / SYMPTOMS
Autonomic dysfunction (orthostatic hypotension, severe urinary dysfunction, and/or erectile dysfunction before age 60 years) is typically seen in MSA.[3][84]
There is a very rare PSP phenotype (PSP cerebellar ataxia or PSP-C) that mimics MSA.
INVESTIGATIONS
Tilt table test indicative of neurogenic orthostatic hypotension is in favour of MSA diagnosis.
Urodynamic studies showing high post-void residual volume >100 mL is indicative of MSA.
REM sleep behaviour disorder confirmed by polysomnography is supportive of MSA diagnosis (although does not exclude PSP).[85]
MRI in patients with MSA shows atrophy in the infratentorial structures including pons, cerebellum with enlarged fissures, and middle cerebellar peduncles. In patients with PSP, midbrain atrophy with relatively preserved pons is seen.[85]
Dementia with Lewy bodies (DLB)
SIGNS / SYMPTOMS
In DLB there is typically fluctuating attention, frequent visual hallucinations, REM sleep behaviour disorder, and orthostatic hypotension.[86]
INVESTIGATIONS
RBD confirmed by polysomnography is a core feature of DLB but less frequent in PSP.
Abnormal cardiac 123-I-MIBG scan showing decreased sympathetic innervation is in favour of a DLB diagnosis.
Posterior slow-wave activity on electroencephalogram with periodic fluctuations is supportive of DLB.[86]
Vascular parkinsonism
SIGNS / SYMPTOMS
Lower limb parkinsonism tends to show more stepwise progression, and pyramidal signs occur earlier in the disease course compared with PSP.
INVESTIGATIONS
Brain MRI showing infarcts/vascular changes affecting basal ganglia and/or mesencephalon.
Alzheimer’s disease (AD)
SIGNS / SYMPTOMS
Early and predominant impairment of episodic memory and encoding is more consistent with AD, whereas in PSP difficulties are typically confined to retrieving information.[3][10]
AD also tends to present with more prominent behavioural symptoms and lack of motor impairment.
Note that age-associated AD may occur in patients with PSP.[3][14]
INVESTIGATIONS
Hippocampal atrophy in brain imaging.
Abnormal amyloid PET imaging.
High plasma phospho-tau 217.[87]
Prion disease
SIGNS / SYMPTOMS
Very rapid progression of motor and cognitive impairment with prominent myoclonus is indicative of prion disease.[3]
INVESTIGATIONS
High 14-3-3 protein in cerebrospinal fluid.
Electroencephalogram showing periodic sharp wave complexes typical of prion disease.[88]
Positive prion real time quaking-induced conversion (RT-QuIC).
Wilson’s disease
Niemann-Pick disease type C (NPC)
SIGNS / SYMPTOMS
Younger age of onset (usually childhood or early adulthood), slower progression, dystonia, cerebellar ataxia, cataplexy, more severe dementia, psychiatric symptoms, and hepatosplenomegaly may help distinguish NPC from PSP.[90][91]
INVESTIGATIONS
Positive filipin test on cultured fibroblasts from skin biopsy.
Foam cells on bone marrow biopsy.
NPC 1 and 2 gene sequencing shows evidence of mutations.
Whipple's disease
SIGNS / SYMPTOMS
May show neurological features such as oculomasticatory myorhythmia, myoclonus, neuropathy, severe dementia, seizures, or decreasing level of consciousness.[76][92]
Severe gaze palsy without rigidity or gait impairment is suggestive of Whipple's disease.[76]
Gastrointestinal and constitutional symptoms such as fever, weight loss, arthralgia, and lymphadenopathy are indicative of Whipple's disease.[3]
INVESTIGATIONS
Polymerase chain reaction (PCR) for Tropheryma whippelii on a cerebrospinal fluid sample or intestinal biopsy.[76]
Paraneoplastic/autoimmune encephalitis
SIGNS / SYMPTOMS
Acute/subacute onset with rapid progression accompanied by an encephalopathic state.[3]
Prior diagnosis of malignancy.
INVESTIGATIONS
Serum and cerebrospinal fluid (CSF) paraneoplastic antibody panel and markers of inflammation.
Detection of antibodies (e.g., anti-Ma1, anti-Ma2, anti-Hu, anti-CRMP5, anti-LGI1, anti-IgLON5, anti-DPPX) on serum or CSF assay.
Genetic disorders that mimic PSP
SIGNS / SYMPTOMS
Varies depending on the precise disorder. In general, a young age of symptom onset and a relevant family history may be pointers to a genetic disorder.[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]
INVESTIGATIONS
Gene mutation identified on genetic testing
Normal pressure hydrocephalus (NPH)
SIGNS / SYMPTOMS
Classic triad of NPH is gait impairment, urinary incontinence, and cognitive impairment. Frontal gait with small steps and broad base in the absence of parkinsonian features. Improvement in gait after large-volume cerebrospinal fluid tap.[93][94]
INVESTIGATIONS
MRI might show idiopathic NPH features such as Evans' index >0.3 (ratio of the maximum width of frontal horns of lateral ventricles to maximum inner skull diameter), tight convexity, and disproportionately enlarged subarachnoid-space hydrocephalus (DESH).[95]
Motor neuron disease (MND)
SIGNS / SYMPTOMS
Presence of lower motor neuron features such as muscle fasciculation, atrophy, and decreased reflexes.
INVESTIGATIONS
Nerve conduction studies and electromyography showing evidence of diffuse, ongoing, and chronic denervation.[96]
Structural brain lesions (e.g., neoplastic, vascular)
SIGNS / SYMPTOMS
Variable, depending on the location and type of the lesion.
INVESTIGATIONS
Detection of lesion on brain MRI.
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