Progressive supranuclear palsy

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Progressive supranuclear palsy (PSP) is a clinical diagnosis based on the patient’s history and physical examination.[3][10]

PSP has multiple distinct phenotypic subtypes that vary in presentation. Oculomotor dysfunction, postural instability, akinesia, and cognitive dysfunction are the four characteristic clinical manifestations of typical PSP.

PSP is the most prevalent degenerative parkinsonian disorder after idiopathic Parkinson’s disease.[8][29]

At present there are no laboratory biomarkers, imaging findings, or other investigations that can confirm a diagnosis of PSP during the patient’s lifetime. Definitive diagnosis requires postmortem pathology.[3]
The most prevalent subtype is the classic form of PSP, also known as PSP-Richardson’s syndrome (PSP-RS).[4][13] Other subtypes vary according to the early predominant symptoms/signs.

Consider the possibility of PSP if a patient aged 40 years or older presents with these typical features of classical PSP (PSP-RS):[3][28]

Progressive falls (resulting from postural instability), especially within the first 3 years of the disease course and/or
Slow vertical eye movements (saccades)/vertical supranuclear gaze palsy. This typically causes the patient difficulty with tasks that require looking downwards (e.g., reading, eating).

Be aware that many patients with PSP are initially misdiagnosed with Parkinson's disease (PD) or other disorders that also present with parkinsonism, but a careful assessment for red flags points to the correct diagnosis in most patients.

As many as half of patients with PSP are initially diagnosed with PD.[29]
Examination of eye movements and postural stability, together with careful evaluation for other red flags, will point towards PSP as the correct diagnosis, particularly in the case of PSP-RS. A poor or absent response to levodopa is also an important clue to consider PSP. See History, below, for details.

In practice, the diagnosis of PSP is typically made 3-4 years after symptom onset, when the cardinal features of falls and supranuclear gaze palsy have become unequivocally apparent.[3]

Clinical diagnosis of the non-Richardson’s syndrome PSP subtypes is challenging due to their considerable clinicopathological overlap with other conditions.[3]

Other PSP phenotypes include PSP-parkinsonism (PSP-P, which mimics Parkinson’s disease), PSP with progressive gait freezing (PSP-PGF), PSP-corticobasal syndrome (PSP-CBS), PSP with speech/language disorders (PSP-SL), and PSP with frontal presentation (PSP-F).[3]

If you suspect a patient may have any form of PSP, refer them to a movement disorder specialist for further evaluation as confirmation of the diagnosis requires specialist expertise.

History

PSP can present with a wide variety of symptoms, according to the distinct disease phenotype.

At least 8 different clinical phenotypes are known that can represent an underlying PSP pathology. Classic PSP (PSP-RS) and PSP-P are the most prevalent and the other phenotypes are rare.
Although clinical history and examination varies initially for different phenotypes, as the disease progresses all patients are likely to develop the core clinical features of PSP-RS (postural instability with falls and vertical oculomotor dysfunction).[4]
The presenting clinical phenotype for an individual patient will depend on the site of the most severe brain pathology and the pattern of its spread across synapses in the brain.

The presenting features for the main PSP phenotypes are outlined below.

Note that non-classic PSP phenotypes are hard to diagnose based on clinical findings. More commonly, they are diagnosed retrospectively based on autopsy findings.[14]

PSP-Richardson’s syndrome (PSP-RS)

PSP-RS (also known as classic PSP) is the most common PSP presenting phenotype and is seen in about 40% to 50% of all people with a PSP pathology.[4][13] Symptoms usually start in the sixth or seventh decade of life and typically involve:[1][28]

Postural instability leading to early unprovoked falls.
Characteristic abnormal eye movements: slowness of vertical saccades, progressing to vertical supranuclear gaze palsy, typically causing the patient difficulty with looking downwards. Slow vertical saccades are defined by a slow enough speed of vertical eye movements for the examiner to see the movements in a bedside test. Vertical supranuclear gaze palsy presents as a clear limitation of the range of voluntary gaze in the vertical more than the horizontal plane, affecting both upwards and downwards gaze.[3]
Axial-predominant akinetic-rigid parkinsonism.
Speech and swallowing impairments.
Cognitive (mainly executive) dysfunction (e.g., difficulty planning/multitasking).

Be aware that many patients with PSP are initially incorrectly diagnosed with Parkinson’s disease or another parkinsonian disorder.[29] Red flags that point towards PSP-RS as the correct diagnosis include:[30][31][32]

Postural instability/unsteady gait with falls (often backwards falls) in the first 3 years of disease onset[33]
Slowness of vertical saccades or vertical supranuclear gaze palsy
Axial-predominant (trunk and neck) symmetric parkinsonism (bradykinesia, rigidity, and tremor) rather than asymmetric appendicular (limb) parkinsonism, with a lack of response to levodopa[3][34]
Early dysphagia and/or dysarthria
Significant early cognitive impairment mainly involving frontal executive function (e.g., difficulty planning/multitasking)
Freezing of gait not responding to levodopa
Rapid progression of symptoms.

Early postural instability occurring in the first 1-3 years of symptom onset is an important feature of PSP-RS. It presents with a sense of imbalance and repeated, usually backwards, falls.[3][28]

Neurodegeneration is rapidly progressive. Typically, within 3-4 years after symptom onset, patients become dependent on assistance for walking and the median survival has been reported as 6 to 7.4 years.[11][35]
Ask about autonomic symptoms and check orthostatic blood pressure changes to distinguish PSP from multiple system atrophy (MSA). MSA is another parkinsonian disorder that is sometimes misdiagnosed as PSP because it also presents with early balance impairment and falls and typically has a poor response to levodopa. A key difference is that MSA is typically preceded by autonomic disturbances.[3]

Slowing of vertical saccades, progressing to vertical supranuclear gaze palsy, is a defining feature of PSP-RS and usually presents within 2-3 years of symptom onset.[28]

Ask about difficulty with tasks that require a downwards gaze, such as reading, eating, or descending stairs. Such tasks are often affected by the initial visual symptoms but the symptoms are not always spontaneously reported or questioned.
Some patients may complain of diplopia or blurred vision due to difficulty with convergence.

Speech impairment is an early symptom observed in half of PSP-RS patients.[36]

The patient's voice may be hoarse, growling, or slurred.
At advanced stages, the patient may lose the ability to speak (anarthria).

Impaired swallowing, which presents with frequent coughing on swallowing liquids and drooling (sialorrhoea), usually occurs within 1-2 years after speech disturbances.[36]

At later stages, this can lead to weight loss and aspiration pneumonia.

Mild cognitive impairment involving mainly the executive domain is frequent early in the disease course, leading to dementia in at least half of patients in more advanced stages.[37][38] Behavioural and cognitive symptoms are the presenting feature in around 20% of patients with PSP.[10]

Patients usually complain of difficulties planning and multitasking. Memory disturbance is usually characterised by deficits in retrieval, with relatively preserved encoding (learning of new information).[10]
Significant memory impairment or hallucinations are rare in PSP and suggestive of other diagnoses.[39][40]

Behavioural changes in the frontotemporal spectrum are commonly seen in patients with PSP.[39][40]

Apathy and, less frequently, depression are the most common behavioural symptoms in PSP, presenting in about 60% of patients.[39][41]
Impulsiveness and disinhibition are seen in one third of patients and can lead to behaviours that increase the risk of falls.[33] These features usually present as motor recklessness: for example, carelessness when standing and walking to pick up something off the floor despite severe balance/gait problems, or overstuffing the mouth despite impaired swallowing.[3][39]
Pseudobulbar affect (PBA) may present in some patients and is characterised by labile emotions (e.g., inappropriate episodes of weeping or, less frequently, laughter). Anxiety is less frequent.[39][40]

Other non-specific symptoms that are often reported by patients with PSP are:

Sleep disturbances. Disordered sleep is an under-recognised feature of PSP and is often progressive, leading to impaired daytime functioning.[42] Patients (or carers) might report insomnia, excessive daytime sleepiness, and sleep fragmentation (e.g., obstructive sleep apnoea, periodic limb movement disorder, and restless leg syndrome), although all of these are also common in other neurodegenerative disorders.[10]
Constipation. This affects 71% to 80% of patients with PSP.[10] Putative causes include a sedentary lifestyle, hypodipsia, central dysautonomia, and medication adverse effects.
Urinary symptoms. These affect 53% to 93% of people with PSP and early onset indicates a worse prognosis.[10] Urgency, incontinence, and hesitancy are the most common urinary symptoms.[43] A urology referral is necessary to differentiate PSP-related symptoms from common age-related conditions such as benign prostatic hyperplasia in men and pelvic floor weakness in women.[10]

PSP-parkinsonism (PSP-P)

PSP-P is the second most common PSP phenotype, accounting for 30% to 40% of cases.[4][13][44]

Compared with classical PSP-RS, patients with a PSP-P phenotype have a more protracted disease course.
These patients present with asymmetric limb bradykinesia and rigidity that shows greater response to levodopa than other PSP subtypes. This is sometimes associated with rest tremor.
The defining PSP features of slow vertical saccades/supranuclear vertical gaze palsy and postural instability with falls typically appear later than in PSP-RS (usually ≥2 years after symptom onset).[44]

Rarer PSP subtypes: PSP-frontal presentation (PSP-F)

PSP-F presents with cognitive dysfunction or behavioural changes due to frontal lobe involvement. Common signs and symptoms are executive dysfunction, apathy, perseveration, disinhibition, and impulsivity.[10][45][46]

Rarer PSP subtypes: PSP-speech/language disorder (PSP-SL)

PSP-SL is characterised by progressive apraxia of speech and non-fluent aphasia.[47]

Apraxia of speech is a speech disorder that affects motor function, resulting in slow and effortful speech, with abnormal rhythm, intonation, and emphasis of speech (dysprosody).
Non-fluent aphasia is defined by hesitant and non-fluent spontaneous speech, omission or impaired use of grammatical elements (agrammatism), and phonemic errors, while comprehension of word meaning remains intact.[48][49]

Note that speech apraxia and non-fluent aphasia are also associated with other neurodegenerative conditions, such as frontotemporal lobar degeneration and corticobasal degeneration.

Rarer PSP subtypes: PSP-corticobasal syndrome (PSP-CBS)

PSP-CBS is a rare phenotype that manifests with a combination of cortical and basal ganglia dysfunction symptoms. These include cortical sensory loss, ideomotor apraxia, alien limb phenomenon, limb dystonia, and asymmetric rigidity and akinesia that is commonly levodopa-resistant.[3][50]

Rarer PSP subtypes: PSP-progressive gait freezing (PSP-PGF)

PSP-PGF, which is very rare, presents with progressive freezing of gait (sudden and transient motor blocks or start hesitation when walking) within the first year of the disease, accompanied by bradykinesia and/or rigidity.[3][51][52]

Symptoms typically do not respond to levodopa and, after several years, patients may develop the typical features of PSP-RS.[53][54]

Rarer PSP subtypes: Research-oriented intermediate phenotypes

PSP-oculomotor dysfunction (PSP-OM) is characterised by eye movement involvement (slowness of vertical saccades and vertical supranuclear gaze palsy) with mild or absent features of postural instability, akinesia, or cognitive impairment.[4][28]

PSP-postural instability (PSP-PI) is characterised by early postural instability and delayed involvement of abnormal eye movements.[4]

These are intermediate phenotypes of PSP-RS that have been developed for early recognition of patients for inclusion in therapeutic research studies.[3]

Risk factors

There is a paucity of research on risk factors that might predispose an individual to PSP.

The key risk factor is advancing age.[8][9] The typical age of onset is the mid 60s.[10] No autopsy-confirmed case has been demonstrated in an individual younger than age 40 years.[3] In most patients, older age will be the only identifiable risk factor.
Random genetic mutations can also play a part.[16][18][19]
Other reported risk factors are mainly environmental and include exposure to chromate/phosphate from textile dyeing and tanning or exposure to pesticides from well water.[20][21] A lower level of education, use of firearms, and stressful life events have also been associated with a higher risk of developing PSP, while use of oestrogen replacement therapy has been associated with a lower risk.[21][22][23][24]

Physical examination

Focus your physical examination on looking for the signs that are suggestive of the classical form of PSP (PSP-RS), PSP-P, or one of the rarer phenotypic subtypes of the condition.

Parkinsonism

Signs of parkinsonism include bradykinesia associated with rigidity, tremor, or postural instability.[10]

Bradykinesia is examined by gait assessment and finger or toe tapping tests, which show significant slowing, and/or dampening of amplitude, compared with healthy individuals.

While both Parkinson’s disease (PD) and PSP exhibit similar parkinsonian signs, there are distinct differences that can point towards PSP as the more likely diagnosis.[30][31][32]

In most PSP phenotypes, bradykinesia and rigidity involve the axial skeleton (trunk and neck) more severely than the limbs compared with PD.[3][10] The patient with PSP might report neck and back stiffness.
Tremor is less frequent in PSP than in Parkinson’s disease and, when present, is usually milder and bilateral.[42][44]
See Differentials.

Freezing of gait can be provoked by asking the patient to pass through a narrow space or to turn around while walking.

Postural instability

Patients with PSP-RS usually have an erect posture and tend to fall backwards due to imbalance.[55]

Imbalanced, slow, lurching walking on a wide base is reminiscent of a 'drunken sailor'.[10]
In contrast to the en bloc turning typical of PD, patients with PSP may pivot carelessly and retropulse, with a risk of falling backwards.[10]
Evaluate postural instability with the pull test.[3][10] This involves the examiner standing behind the patient and first gently pulling both shoulders, then doing so more vigorously a second time to disturb the patient’s balance.[55] An abnormal pull test is confirmed if the patient needs to take more than two steps backwards to regain balance or if they need to be caught.[3]
A sit-to-stand test may reveal altered sequencing due to lack of trunk flexion and anterior weight shift.[10]
Tendency to fall on pull test
Iankova V, et al; Movement Disorder Society-endorsed PSP Study Group. Parkinsonism Relat Disord 2020 Sep;78:200-3; used with permission

Oculomotor signs

The characteristic slowing of vertical saccades, which is a crucial feature for diagnosing PSP, is not an early sign, often taking 2-3 years to manifest.[28]

Oculomotor dysfunction typically starts with frequent square wave jerks, progressing to slowing of vertical saccades and then to the cardinal sign of vertical supranuclear gaze palsy.[3]

This delay in the appearance of abnormal eye movements is a factor in delayed diagnosis of PSP. Moreover, early signs are subtle and might be missed in initial evaluations if not specifically tested.
A valuable sign that is not part of the formal diagnostic criteria but can be seen before restriction and slowing of saccades is a curvilinear path on downwards saccades (the 'round-the-houses' sign).[42]
[Figure caption and citation for the preceding image starts]: The “round-the-houses” sign, which can often be seen before restriction and slowing of saccades. Note the lateral curvature of downward path of eye movement (yellow arrows)Rowe JB, et al. Practical Neurology 2021; 21: 376-83; used with permission [Citation ends].

To assess the saccades, instruct the patient to shift their gaze between two fixed visual points (such as the index finger and thumb) positioned on the right/left or top/bottom of their visual field.

First evaluate the horizontal saccades and then proceed to examine the vertical saccades. Normally, the trajectory of the eyeball is so fast that it can hardly be seen to be moving, whereas in PSP the speed of the eyeball movement is so slow that the trajectory can be easily seen.[28] In patients with PSP, this slowing is seen to affect vertical eyeball movements both earlier than, and to a greater degree than, horizontal eyeball movements.[3][28]
Reduction or loss of the optokinetic nystagmus (OKN), typically tested with OKN strips, confirms the loss of saccades.[10]
Restriction of the vertical range (as opposed to speed) of voluntary eye movements occurs later, with low amplitude of the voluntary vertical gaze.
Use the doll’s head manoeuvre to activate the vertibulo-ocular reflex, thereby confirming the supranuclear nature of gaze palsy (i.e., involuntary vertical eye movements are preserved whereas voluntary eye movements are impaired).[3] This involves asking the patient to fix the eyes on a target while the head is passively moved up and down.
Slow vertical saccades
Iankova V, et al; Movement Disorder Society-endorsed PSP Study Group. Parkinsonism Relat Disord 2020 Sep;78:200-3; used with permission
Vertical supranuclear gaze palsy with demonstration of doll’s head manoeuvre
Iankova V, et al; Movement Disorder Society-endorsed PSP Study Group. Parkinsonism Relat Disord 2020 Sep;78:200-3; used with permission

Ask the patient to fixate on a near target with eyes in the primary position. Macro square wave jerks can frequently be seen in patients with PSP and are often an early sign of oculomotor dysfunction.[3]

Jerky involuntary movements of small amplitude will be seen that momentarily move the eyes horizontally away from the target, followed by returning to the target after an interval of less than a second.
These are not specific to PSP but tend to be more frequent, larger movements in PSP than in other conditions in which square wave jerks can occur (e.g., other parkinsonian conditions, Friedreich’s ataxia, Huntington’s chorea, and multiple sclerosis.[10][56][57] Square wave jerks can also occasionally be seen in healthy older adults.
Macro square wave jerks
Iankova V, et al; Movement Disorder Society-endorsed PSP Study Group. Parkinsonism Relat Disord 2020 Sep;78:200-3; used with permission

Cognitive dysfunction

Evaluate the patient’s cognitive function. Cognitive impairment frequently occurs in PSP and predominantly involves frontal executive function and verbal fluency.[10][37][58]

Use a screening scale to evaluate cognition. The Montreal Cognitive Assessment (MoCA) scale is preferred over the Mini Mental State Examination (MMSE) because it is more sensitive in detecting executive dysfunction.[59] MoCA test: digital tools Opens in new window MoCA test: paper versions Opens in new window

Speech/language impairment

Free speech will reveal most speech and/or language deficits. Language disturbances in PSP are characterised by:[3][36][60]

Apraxia of speech (difficulty planning and coordinating the movements necessary for speech production, resulting in effortful, halting speech with inconsistent sound errors and distortions, or slow speech with syllables segmented)
Non-fluent aphasia (reduced fluency and difficulty in generating speech and forming coherent sentences).
Apraxia of speech
Iankova V, et al; Movement Disorder Society-endorsed PSP Study Group. Parkinsonism Relat Disord 2020 Sep;78:200-3; used with permission
nfa PPA spontaneous speech
Iankova V, et al; Movement Disorder Society-endorsed PSP Study Group. Parkinsonism Relat Disord 2020 Sep;78:200-3; used with permission

Bulbar signs

Dysarthria eventually affects almost all patients with PSP and has a hypokinetic and/or spastic feature, often accompanied by a strained-strangled or breathy voice quality.[61][62]

Swallowing impairment is frequent in PSP.[3][10]

Choking or coughing on liquids and later on solid food are indicative symptoms, along with drooling.
If not apparent from the history, swallowing function can be evaluated by a water swallow test.

Pseudobulbar affect (PBA), sometimes classified as a behavioural symptom, affects many patients with PSP.

PBA is a representation of bulbar upper motor neuron involvement and is usually accompanied by a spastic dysarthria.[63] It presents with labile facial expression of emotions that might not be congruent with the patient’s mood.

Dystonia

Limb dystonia is usually unilateral, involving an upper limb or one side of the body.

It occurs most frequently in the corticobasal syndrome variant of PSP (PSP-CBS) but is also seen in up to one third of PSP-RS cases.[64]

Neck dystonia, although less frequent, is more specific to PSP (mainly PSP-RS).[3]

It may present with retrocollis (with the neck extended and the head pulled back) and can significantly accentuate imbalance and increase risk of falls.

Facial dystonia can sometimes present in patients with PSP, resulting in deep nasolabial folds and a furrowed brow, giving the appearance of surprise or concern (referred to as the Procerus sign).[3][65]

Disturbances in eyelid motion are frequent, including severely decreased blinking, lid retraction (resulting in a staring appearance), blepharospasm, and eyelid-opening apraxia. Blepharospasm and eyelid-opening apraxia both result in involuntary eyelid closure. Blepharospasm is caused by active contraction in the orbicularis oculi muscles, which may be amenable to treatment with botulinum toxin, whereas apraxia of eyelid opening is caused by an inability to open the eye due to central mechanisms and is far more difficult to treat.
Eyelid opening apraxia
Iankova V, et al; Movement Disorder Society-endorsed PSP Study Group. Parkinsonism Relat Disord 2020 Sep;78:200-3; used with permission

Other signs

Neurological examination will reveal apraxia in many patients with PSP.[66]

Apraxia is defined as a disorder of skilled action and tool use despite adequate sensorimotor and cognitive function. It is one of the defining features in the PSP-CBS phenotype, but is also frequently seen in PSP-RS (if the degree of motor impairment allows for appropriate testing).[67]
Bedside tests include asking the patient to copy gestures (e.g., a peace sign or OK sign) or asking the patient to mime how they would use a tool to perform a task (e.g., brushing teeth or stirring coffee).

Myoclonus is an important feature of the CBS phenotype that rarely occurs in PSP-RS.[3]

Because the myoclonus in these patients is usually action-induced, it might not be apparent on observation but can be provoked by slightly tapping on outstretched fingers.

Pyramidal signs such as brisk muscle stretch reflexes, Babinski sign, Hoffmann sign, or exaggerated jaw jerk are occasionally present in patients with various phenotypes of PSP.[68]

Initial investigations

Imaging

Request a brain magnetic resonance imaging (MRI) in any case where PSP is suspected.[3][69]

Although PSP is diagnosed clinically, an initial brain MRI helps to rule out other differential diagnoses such as normal pressure hydrocephalus, midbrain or third ventricular tumour, pineal gland tumour, frontal mass lesions, multiple small vessel infarcts, and vascular parkinsonism.
Demonstration of the characteristic features of PSP can increase diagnostic confidence in a patient who has been diagnosed based on clinical features, meaning the patient qualifies for an 'imaging supported diagnosis'.[3] MRI in PSP is characterised by significant mesencephalic atrophy. Atrophy of midbrain and superior cerebellar peduncles strongly supports PSP.[3][14][70] This feature can result in various radiographic signs, including 'hummingbird', 'Mickey Mouse', and 'morning glory' signs in the midsagittal and axial planes.[14] While this pattern is very frequent in PSP-RS, it is unclear how early this feature 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].

The European Association of Nuclear Medicine/European Academy of Neurology and the American College of Radiology recommend fluorodeoxyglucose positron emission tomography (FDG-PET) imaging as potentially helpful in distinguishing PSP (in particular, the PSP-RS phenotype) from PD, particularly in the first 2 years of symptom onset.[69][75]

In PSP-RS, hypometabolism is typically seen, whereas patients with PD generally show normal or even increased striatal metabolism.[75]

Therapeutic trial

A trial of levodopa (in the form carbidopa/levodopa) is strongly recommended for patients who are affected by parkinsonism. Minimal or no response supports a diagnosis of PSP.[3][10]

Progressively increase the dose to the recommended range.
Continue the highest tolerated dosage for at least 1 month before determining the response.
Levodopa resistance sufficient to support a diagnosis of PSP is defined as ≤30% improvement on the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS).[3]
The parkinsonism subtype of PSP (PSP-P) may be an exception where levodopa will elicit a more robust response.

Other investigations

Other investigations can be ordered based on clinical clues to rule out differential diagnoses that might mimic PSP.

A tilt table test can identify neurogenic orthostatic hypotension, which would point towards a diagnosis of multiple system atrophy (MSA) or Lewy body dementia rather than PSP.[3] In practice, consider performing an active stand test first, with measurement of blood pressure (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.
Consider requesting polysomnography (where available) if a patient with parkinsonism has a clear history of dream enactment, obtained from a bed partner. It may occasionally be helpful in distinguishing PSP from PD, dementia with Lewy bodies (DLB), and 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]
Several treatable disorders can present with vertical supranuclear gaze palsy. Specific diagnostic tests can help to differentiate these disorders from PSP. These include:
- For Neimann-Pick disease type C (NPC): bone marrow biopsy or skin biopsy with fibroblast culture and filipin test
- For Whipple's disease: polymerase chain reaction (PCR) for Tropheryma whippelii on a cerebrospinal fluid (CSF) sample or intestinal biopsy[76]
- For Wilson’s disease: a 24-hour urine copper may suggest the diagnosis, warranting further investigation
- For autoimmune/paraneoplastic encephalitis: serum and CSF paraneoplastic antibody panel.
If disease progression is particularly rapid, CSF biomarkers to exclude prion disease may be indicated.[3]

Emerging investigations

Biomarkers are being developed that can help differentiate PSP from other neurodegenerative parkinsonian disorders including corticobasal degeneration, frontotemporal lobar degeneration, multiple system atrophy, Lewy body dementia, and even Alzheimer’s disease.[14]

For example, if Alzheimer’s disease is suspected, beta-amyloid or tau PET scan can help rule out this disorder.[3]
However, even where available these biomarkers are not routinely used in clinical practice because an exact pathological diagnosis does not change the clinical management in most cases due to the lack of specific disease-modifying treatments.

Certainty of diagnosis

The formal diagnostic criteria for PSP are complex and categorise the patient as having probable, possible, or suggestive PSP according to a range of factors. A definitive diagnosis requires postmortem neuropathological examination.

The 2017 Movement Disorder Society (MDS) diagnostic criteria for the full spectrum of PSP phenotypic subtypes cover basic features that must be present, a wide range of exclusion criteria that rule out PSP, clinical and imaging clues that can support a PSP diagnosis, and a table of core clinical features for different symptom domains (ocular motor dysfunction/postural instability/akinesia/cognitive dysfunction). The criteria are used to determine the level of likelihood that a patient has PSP (probable/possible/suggestive) and the phenotypic subtype.[3]
Prior to publication of the 2017 MDS criteria, the 1996 criteria published by the National Institute of Neurological Disorders and Stroke/Society for PSP (NINDS/SPSP criteria) were used.[28] These have excellent specificity but limited sensitivity for non-Richardson's syndrome PSP subtypes.[3]
See Criteria.

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