Progressive supranuclear palsy (PSP): Clinical features and diagnosis

INTRODUCTION — 

Progressive supranuclear palsy (PSP) is a rare age-related neurodegenerative disorder and one of several atypical parkinsonian disorders that feature prominently in the differential diagnosis of Parkinson disease (PD). PSP takes its name from the characteristic eye movement abnormalities that develop in most patients over the course of the disease, often as a mid- to late-stage finding. Most commonly, patients with PSP come to medical attention due to progressive postural instability and unexplained falls out of proportion to other parkinsonian signs and symptoms.

PSP was originally described in patients with a characteristic syndrome of progressive supranuclear ophthalmoplegia, gait disorder, postural instability, dysarthria, dysphagia, rigidity, and frontal cognitive disturbance [1]. However, it is now recognized to encompass phenotypic variants that overlap with features of other neurodegenerative disorders. All PSP variants share common neuropathologic findings of tau-positive inclusions and neurofibrillary tangles; neuronal loss; and gliosis involving the basal ganglia, brainstem, cerebellum, and cerebral cortex.

This topic will review the epidemiology, pathology, clinical features, and diagnosis of PSP. Management and prognosis are reviewed separately. (See "Progressive supranuclear palsy (PSP): Management and prognosis".)

Other neurodegenerative parkinsonian syndromes are discussed separately. (See "Clinical manifestations of Parkinson disease" and "Corticobasal degeneration" and "Multiple system atrophy: Clinical features and diagnosis" and "Diagnosis and differential diagnosis of Parkinson disease", section on 'Differential diagnosis'.)

EPIDEMIOLOGY

●Incidence and prevalence – PSP is one of the most common degenerative forms of atypical parkinsonism, with an estimated prevalence of 5 to 7.1 per 100,000 person-years [2,3]. It is approximately two to three times more prevalent than corticobasal degeneration (CBD) and multiple system atrophy (MSA) but approximately ten times less common than Parkinson disease (PD) [2,4-6]. Males and females are affected in equal proportions [7-16].

In the few population-based studies that have been performed, the estimated annual incidence of PSP is 1 per 100,000 person-years [3,17-19]. The incidence increases with age, from 1.7 cases per 100,000 person-years at ages 50 to 59 years to 14.7 per 100,000 person-years at 80 to 89 years of age [20].

●Age of onset – The mean age of onset of PSP ranges from the late sixties to early seventies [19,21-24]. Virtually no cases of autopsy-confirmed PSP have been reported in patients younger than age 40 years [25].

●Risk factors – There are no established risk factors for PSP except age. Some studies have reported that education level or environmental exposures may be associated with increased risk, but the findings have been inconclusive [26-32]. Patients with PSP may have a higher prevalence of comorbidities than age-matched controls, including diabetes mellitus, cerebrovascular disease, hypertension, and polyneuropathies [33]. Whether these represent true risk factors requires further study.

●Genetic susceptibility – PSP is considered to be a sporadic disorder, but some observations suggest that genetic susceptibility has a role. Very rarely, patients have a positive family history of PSP or other parkinsonian disorders [34-37]. Pathogenic variants in microtubule-associated protein tau (MAPT), most commonly associated with frontotemporal dementia, can also manifest in a clinical phenotype of PSP, although these cases are a small minority of patients with PSP [38]. (See "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis", section on 'Microtubule-associated protein tau (MAPT) mutations'.)

Genome-wide association studies have identified rare variants in several genes as possible risk alleles for PSP, including MAPT, syntaxin 6 (STX6), eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3), and myelin-associated oligodendrocyte basic protein (MOBP) [39-42]. Subhaplotypes of MAPT are also of interest as mediators of risk, particularly based on the prominence of tau in the neuropathology of PSP, but more studies are needed [43-46].

PATHOLOGY AND PATHOGENESIS — 

PSP is a tauopathy associated with neuronal and glial degeneration involving basal ganglia, brainstem, cerebellum, and cortex. Although the neuropathology is well established, the etiology and pathogenic mechanisms remain poorly understood.

●Gross and microscopic pathology – Gross examination of the brain in patients with PSP reveals midbrain and, to a lesser extent, cerebral cortical atrophy, hypopigmentation of the substantia nigra and locus ceruleus, and enlargement of the third ventricle and Sylvian aqueduct [7,47].

Microscopic findings in PSP are distinctive and prominent. The most consistent sites of pathology are in the basal ganglia, particularly in the substantia nigra, subthalamic nucleus, and internal globus pallidus, in addition to the cerebellum, oculomotor complex, periaqueductal gray matter, superior colliculi, basis pontis, dentate nucleus, and prefrontal cortex [47]. Involvement of the cerebral cortex is also increasingly recognized [14]. PSP pathology has also been reported in the spinal cord, which may account for urinary disturbances [48].

●Histopathology – The histologic characteristics of PSP include neuronal loss, gliosis, and the presence of tau-positive filamentous inclusions in specific anatomic areas involving astrocytes, oligodendrocytes, and neurons (picture 1). Tau aggregates take several forms:

•Neuronal inclusions – Cytoplasmic tau-positive inclusions in surviving neurons, known as globose neurofibrillary tangles, are classically described in PSP but are not specific to PSP. Such tangles are also found in Alzheimer disease, postencephalitic parkinsonism, chronic traumatic encephalopathy, and the parkinsonism-dementia complex of Guam.

•Glial inclusions – Tau-positive cytoplasmic inclusions commonly seen in oligodendrocytes are called "coiled bodies." When seen in astrocytes, tau-positive inclusions are called "tufted astrocytes," and these are considered a hallmark of PSP [49,50].

•Peripheral nerve aggregates – Tau-positive deposits have been demonstrated in cranial and anterior spinal nerves of autopsy specimens of patients with PSP [51].

Different phenotypes of PSP are associated with varying distributions of oligodendroglial, astroglial, neuronal, and tau disease in different regions of the brain [52], which may be important in identifying the predominant subtype and may provide prognostic information [53].

●Microstructural changes – Abnormally phosphorylated tau protein is the major structural element of the neurofibrillary tangles in PSP. Tau is a protein that is involved in axonal transport and stabilization of neuronal microtubules. It is thought that abnormal phosphorylation of tau interferes with microtubule function, impairs axonal transport, and leads to tau aggregation into neurofibrillary tangles.

While tau filaments are seen in various neurodegenerative disorders, the microscopic structure of tau filaments in PSP is the same across all phenotypic variants and differs from other tauopathies [54]. Ultrastructurally, the neurofibrillary tangles of PSP are composed of single straight tau filaments, in contrast to the paired helical filaments that predominate in Alzheimer disease [55]. The tangles in PSP are predominantly of the globose (globular) type; in other neurodegenerative disorders with tau pathology, the tangles are flame shaped. When resolved under cryo-electron microscopy, the tau filaments in most cases of PSP have a three-layer folded conformation [54].

In addition to the neuronal and glial tau inclusions characteristic of PSP, other abnormal aggregated proteins (eg, amyloid-beta, alpha-synuclein, and TDP-43), termed copathologies, are commonly present in patients with a pathologic diagnosis of PSP [56].

The mechanisms underlying the propagation of tau pathology in PSP are unknown, but accumulating experimental evidence suggests that tau may spread in a cell-to-cell, prion-like manner. This phenomenon has been demonstrated in vitro, in transgenic mice, and in nonhuman primates [57-59]. In a study in which tau proteopathic seeds derived from post mortem samples of patients with PSP were injected into the supranigral area of rhesus macaques, pathologic hallmarks of PSP (eg, tau-positive globose and neurofibrillary tangles, tufted astrocytes) were identified near injection sites as well as in striatum, pallidum, and thalamus at 18 months, and parkinsonism and other behavioral abnormalities developed as early as six months after injection [59].

●Genetics – Normal brain tau contains six isoforms that are generated by the alternative splicing of a single tau gene (MAPT) on chromosome 17. Dominantly inherited pathogenic variants in the MAPT gene cause frontotemporal dementia with and without parkinsonism as well as PSP on rare occasions. Two particular variants of MAPT (Glu342Lys and Arg406Gln) have been associated with atypical features of classic PSP as well as features of Alzheimer disease and, for Glu342Lys, with features more common in alpha-synucleinopathies (autonomic dysfunction, dream enactment behavior) [60]. In both cases, increased tau aggregation was seen in the bilateral medial temporal lobes. (See "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis", section on 'Microtubule-associated protein tau (MAPT) mutations'.)

Whole genome sequencing in 1718 cases of PSP (a majority of which were autopsy confirmed) demonstrated several single nucleotide variants, some previously known (MOBP, STX6, SLCO1A2, DUSP10, and SP1) and some unknown (APOE epsilon 2, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1) [61]. There were also several structural variants, including H1/H2 haplotype region (17q21.31) and IGH, PCMT1, CYP2A13, and SMCP. These data would suggest that a larger genetic component exists in PSP, and further study is needed.

PSP also shares a degree of genotypic overlap with corticobasal degeneration (CBD), as both disorders are more frequently associated with homozygosity for the H1 tau haplotype, which is an inversion of 900 kb on chromosome 17 that includes the MAPT gene (an association also seen in Parkinson disease [PD], but with different subhaplotype) [62,63]. In addition, isoforms common to both PSP and CBD tauopathies are aggregates of the four-repeat (4R) microtubule-binding domains that occur because of splicing of exon 10, in contrast to other tau disorders, where the three-repeat (3R) form dominates in the aggregates [64]. The normal ratio of 3R and 4R tau is approximately equal.

●Neurochemical changes – The degenerative process in PSP involves dopaminergic neurons that innervate the striatum, as well as cholinergic interneurons and gamma-aminobutyric acid (GABA) efferent neurons in the striatum and other basal ganglionic and brainstem nuclei [65,66]. Post mortem studies of patients with PSP have demonstrated a marked reduction in striatal D2 receptors, whereas the striatal D1 receptors are relatively spared [67,68].

In the brainstem, degeneration of cholinergic neurons is observed in the Edinger-Westphal nucleus, rostral interstitial nucleus of Cajal, medial longitudinal fasciculus, superior colliculus, and pedunculopontine nucleus [69,70]. A reduction in the acetylcholine vesicular transporter potentially may differentiate PSP from other types of neurodegenerative disorders [71]. Glutamate is increased in the striatum, pallidum, nucleus accumbens, and occipital and temporal cortex [72]. One post mortem study demonstrated a 50 to 60 percent reduction of the GABA-ergic basal ganglia output neurons, which may, in part, explain the poor response to dopaminergic therapy in most patients who have this disorder [73].

CLINICAL FEATURES — 

PSP is heterogeneous, and there is a wide spectrum of clinical variability, particularly early in the course of disease. Clinicopathologic studies support a number of phenotypes in patients with tau pathology at autopsy in a pattern that is typical of PSP [74].

Classic (Richardson) phenotype — The "classic" phenotype of PSP, known as Richardson syndrome (PSP-RS), corresponds to original descriptions of the disease and accounts for about one-quarter of patients with PSP confirmed neuropathologically [21,22].

Most patients with PSP-RS present with gait disturbances resulting in backward falls, and nearly all patients eventually develop supranuclear ophthalmoparesis or ophthalmoplegia. Additional common features include dysarthria, dysphagia, pseudobulbar palsy, axial rigidity, bradykinesia, frontal cognitive abnormalities, and sleep disturbances.

Gait disorder, postural instability, and falls — Patients with classic PSP-RS have a stiff and broad-based gait, with a tendency to have their knees and trunk extended and arms slightly abducted. This posture contrasts with the flexed posture typically seen in patients with Parkinson disease (PD).

Patients demonstrate impulsivity, probably from frontal lobe involvement, and hence tend to jump out of the chair (Rocket sign), lurch, stagger, and sometimes spontaneously start going backwards. Step length is varied, as is base width. Instead of turning en bloc as seen in PD, they tend to pivot quickly, further compromising their balance and indicating an inability to take protective measures. This is sometimes referred to as the "drunken sailor gait."

Postural instability, which refers to decreased ability to prevent falling in any direction due to impairment of centrally mediated postural reflexes, is prominent. Postural instability is tested with the pull test, where the examiner stands behind the patient and exerts a gentle but firm tug backwards on the patient's shoulders. Patients with normal postural reflexes should be able to maintain their balance and take no more than two steps backwards to right themselves. Patients with PSP typically take multiple steps backwards in response to the pull test and may fall if not supported. Some make no attempt to correct for a pull backwards and fall "like a tree."

When postural instability and falls are the only features of PSP, an abnormal response to postural reflex testing (the pull test) may be the only abnormality on examination [75]. It is interesting to note that some patients in the earlier stages have a negative pull test despite having a history of daily falls. In this case, it is the impulsiveness that leads to falls.

When patients with PSP fall, they usually fall backwards. Over the course of the illness, such falls can result in a spectrum of injuries that include bruises, lacerations, bone/skull fractures, subdural hematomas, and sometimes death [76].

Cross-sectional studies reviewing objective measurements of gait and balance from wearable sensors and posturography demonstrate that patients with PSP have impairments in gait initiation, steady-state gait, and static and dynamic balance when compared with patients with PD and healthy controls [77].

Oculomotor findings — Supranuclear ophthalmoparesis or ophthalmoplegia is the hallmark of PSP, but it may take as long as 10 years to develop. The average is three to four years [78].

●Slow vertical saccades – The earliest manifestation is slowing of vertical saccades, tested by asking the patient to look straight ahead and then look upwards or downwards towards a visual target (eg, the examiner's thumb). Individuals with normal supranuclear control of eye movements can move the eyes swiftly and accurately from one target to another in one burst; in PSP, the eyes move more slowly to reach the target or reach the target in more than one step. Such findings are an important feature allowing earlier diagnosis.

●Restricted saccadic range – Slowing of vertical saccades typically progresses to involve a limitation of saccadic range, meaning that the eyes cannot voluntarily look fully upwards or downwards. Concomitant limitation of lateral gaze is often present but is less prominent. Pursuit movements of the eyes, tested by asking the patient to follow the examiner's finger as it moves slowly up and down and side to side, are slow, jerky, and hypometric with unstable fixation [79].

Downward vertical gaze impairment is often the most consequential in activities of daily living and commonly leads to problems with reading, spilling food while eating, and tripping while walking [76].

●Intact oculocephalic response – The ophthalmoparesis of PSP is initially overcome by the oculocephalic (doll’s eyes) maneuver, in which the patient is asked to fixate on the examiner’s nose as the patient's head is gently but quickly moved up and down and side to side. As the head is moved, the eyes can be seen to move more fully in the vertical and horizontal planes as fixation is maintained. As the disease progresses to involve the brainstem, vestibuloocular reflexes may be lost.

●Other eye findings – Other oculomotor findings in PSP include saccadic intrusions into fixation ("square wave jerks"), which can lead to alterations in saccade trajectory, "staircase saccades," and "round-the-houses" [80,81]. Loss of optokinetic nystagmus (particularly in the vertical direction), loss of convergence, blepharospasm, and eyelid-opening apraxia can also be seen [82,83].

●Characteristic facial expression – The combination of rare blinking, facial dystonia with eyelid retraction, and gaze abnormalities leads to the development of a classic facial expression of perpetual surprise or astonishment [75].

Parkinsonism — In addition to the classic gait and postural disturbances described above, patients with PSP-RS have a variety of additional motor manifestations related to parkinsonism.

●Bradykinesia – Bradykinesia with marked micrographia is a primary feature of parkinsonism in PSP and tends to be present in all phenotypic variants. Unlike the classic bradykinesia of PD with slowing and decrement of amplitude on a finger-tapping task, patients with PSP may show non-decrementing, very low-amplitude, fast tapping.

●Rigidity – Rigidity in patients with PSP is usually more apparent in axial muscles, especially the neck and upper trunk, than in limb muscles. It can be demonstrated on examination by resistance to passive movement of the neck.

●Dystonia – Retrocollis was emphasized as an important physical finding in the original description of the disorder [1] but is now estimated to occur in less than 25 percent of cases [84]. In addition to the retrocollis, other types of dystonia include blepharospasm and, more rarely, limb or hemidystonia [85-87].

Apraxia of eyelid opening (inability to voluntarily open the eyes) can be mistaken for typical blepharospasm but is distinguished by the absence of forced closure of the eyes. In many patients this is not a true apraxia but may be a form of blepharospasm due to isolated contraction of the pretarsal orbicularis oculi.

The face is stiff, immobile, and deeply furrowed (the look of surprise) due to dystonia [7].

A proportion of patients with PSP may show a moderate response to dopaminergic agents in the early stages of disease (generally the PSP with predominant parkinsonism [PSP-P] variant), but most do not [75]. In some, the gait and balance problems actually worsen with levodopa. (See "Progressive supranuclear palsy (PSP): Management and prognosis", section on 'Pharmacologic treatments'.)

Pyramidal signs — Approximately one-third of patients with PSP develop pyramidal signs, including hyperreflexia and Babinski signs. Facial and jaw jerks are exaggerated. The tongue is tightly contracted and movements are slow. Spastic dysarthria, dysphonia, and dysphagia are profound in the middle to later stages of disease.

Cognitive and behavioral abnormalities — The neuropsychological profile of PSP primarily involves frontal lobe dysfunction, with impaired abstract thought, decreased verbal fluency, motor perseveration, and frontal behavioral disturbances such as apathy, impulsivity, and disinhibition [75].

●Cognitive dysfunction – The presence of early and severe frontal cognitive (executive) deficits is a common finding in PSP [88-90]. Executive dysfunction may be the presenting symptom of PSP in some patients but is more characteristic of the middle to later stages of the disease.

In a cohort of 311 patients with PSP, global cognition was impaired in approximately 57 percent [91], while impairment for a single or multiple domains was observed in 40 percent each and frontal impairment was observed in 62 percent. Cognitive impairment was seen in the early stages in 50 percent. Ideomotor apraxia is seen in a proportion of patients with PSP, typically those manifesting features of corticobasal syndrome (referred to as PSP with predominant corticobasal syndrome or PSP-CBS). (See 'Variant phenotypes' below.)

●Neuropsychologic abnormalities – Behavioral abnormalities are also common in patients with PSP. Across studies, the most common symptoms are apathy (>90 percent), depression (27 to 60 percent), disinhibition (36 percent), obsessive-compulsive symptoms (24 percent), and anxiety (18 percent) [92-95].

Pseudobulbar palsy is another characteristic feature of PSP. Emotional incontinence is much less common than in other forms of pseudobulbar palsy [7], but patients with PSP commonly manifest a characteristically hoarse groaning voice along with moaning.

●Abnormal speech – Speech perseveration, stuttering, palilalia (involuntary repetition of words or phrases) and anomia, but not true aphasia, are common [75]. Some patients with PSP present with a variant of nonfluent aphasia (PSP with predominant speech/language disorder, or PSP-SL). (See 'Variant phenotypes' below.)

Sleep disturbances — Insomnia is common in PSP throughout the course of disease. Patients may experience difficulties with sleep onset, sleep maintenance, or both [96]. Marked rigidity may result in the inability to remain comfortable in bed, further contributing to the sleep complaints. Circadian rhythm abnormalities are also common [97].

In contrast with PD and multiple system atrophy (MSA), rapid eye movement sleep behavior disorder (RBD) is infrequently associated with PSP [98]. This negative finding, similar to the case of preserved olfaction (see 'Potential disease markers' below), can be helpful in differentiating PSP, a tau disorder, from PD and MSA, both of which are synucleinopathies and commonly associated with RBD.

Variant phenotypes — Many phenotypic variants of PSP exist, and they have considerable clinical overlap with other neurodegenerative disorders [21]. Importantly, clinical phenotype may vary over the course of the disease, and the variants below are primarily based on early and predominant features. The development of these clinical subtypes is likely an expression of the distribution of tau pathology in early disease [99]. Approximately 40 percent of patients with PSP transition from one clinical phenotype to another when examined serially, primarily within the first four years after diagnosis [100]. Distinctions among variants often fade with disease progression and development of more classical features.

The recognized phenotypes of PSP include the following [25]:

●PSP with Richardson syndrome (PSP-RS) – (See 'Classic (Richardson) phenotype' above.)

●PSP with predominant parkinsonism (PSP-P) – PSP-P is characterized by asymmetric onset of limb symptoms, including tremor, and a moderate initial therapeutic response to levodopa [101-103]. These cases are frequently misdiagnosed as PD during early stages of disease. PSP-P has a slower rate of disease progression than PSP-RS [104]. Falls and cognitive impairment occur later in PSP-P than in PSP-RS.

●PSP with predominant oculomotor dysfunction (PSP-OM) – PSP-OM is characterized by presentation with oculomotor features of PSP (eg, vertical supranuclear gaze palsy, slow velocity of vertical saccades, "square wave jerks") and minimal or no evidence of postural instability, akinesia, or cognitive dysfunction [21,22,78].

●PSP with predominant postural instability (PSP-PI) – PSP-PI is characterized by presentation with postural instability and delayed development of oculomotor dysfunction [22,105].

●PSP with progressive gait freezing (PSP-PGF) – PSP-PGF (or primary progressive freezing of gait [PPFG]) is characterized by early (initial feature or frequently present in the first year) gait freezing, bradykinesia, rigidity, and unresponsiveness to dopaminergic medications [21,106-109]. However, this syndrome can be the result of several underlying neurodegenerative disorders [110], as shown in a prospective study of nine patients with progressive gait freezing who were followed for 6 to 16 years [109]. Three were ultimately diagnosed clinically with PSP, one was diagnosed on clinical grounds with corticobasal syndrome (which could have been a variant phenotype of PSP), and one patient each was diagnosed pathologically with dementia with Lewy bodies and pallidonigroluysian degeneration.

●PSP with predominant frontal presentation (PSP-F) – PSP-F is characterized by cognitive impairment or behavioral change attributed to frontal lobe dysfunction, including behavioral variant frontotemporal dementia [78,111-113]. The most common PSP-F syndrome encompasses features such as apathy, bradyphrenia, executive dysfunction, decreased verbal fluency, disinhibition, impulsivity, and perseveration [21].

●PSP with predominant speech/language disorder (PSP-SL) – PSP-SL presents with the nonfluent/agrammatic variant of primary progressive aphasia or with progressive apraxia of speech [114-118].

●PSP with predominant corticobasal syndrome (PSP-CBS) – PSP-CBS is characterized by progressive asymmetric apraxia, dystonia, cortical sensory loss, alien limb syndrome, and levodopa unresponsiveness [119-124]. PSP-CBS is a rare presentation of PSP pathology and was only present in 6 of 179 pathologically diagnosed PSP cases in the Queen Square Brain Bank series [123]. Nevertheless, among the causes of CBS, PSP is second only to corticobasal degeneration (CBD). (See "Corticobasal degeneration".)

●PSP with predominant cerebellar ataxia (PSP-C) – PSP-C is characterized by cerebellar ataxia as the initial and principal symptom before developing the cardinal features of PSP-RS [125-129].

●PSP with predominant primary lateral sclerosis (PSP-PLS) – PSP-PLS is characterized by upper motor neuron disease and degeneration of the corticospinal tracts [130,131].

Neuroimaging — Common magnetic resonance imaging (MRI) findings that can be appreciated on structural imaging in patients with PSP, particularly when disease is longstanding, include:

●Generalized and brainstem atrophy, most pronounced in the midbrain

●Hummingbird sign (image 1), also called the "penguin silhouette" sign, on midsagittal MRI resulting from prominent midbrain atrophy with a relatively preserved pons [132-134]

●Superior cerebellar peduncle atrophy [135]

●Concavity of the lateral margin of the midbrain tegmentum on axial T2-weighted MRI resulting from profound midbrain atrophy ("morning glory" flower sign) [136]

When quantitative techniques are applied, such as voxel-based morphometry and volumetric analysis, degeneration and atrophy can also be appreciated in the pons, thalamus, and striatum, as well as in frontal, prefrontal, insular, premotor, and supplementary motor areas [137]. Such studies have attempted to define a specific pattern of atrophy that distinguishes PSP from other neurodegenerative disorders like PD and MSA with varying success [137-144]. Analysis of longitudinal brain maps is a promising technique to measure in vivo progression of atrophy in PSP [145].

Positron emission tomography using 18-F fluorodeoxyglucose (FDG-PET) in patients with PSP reveals decreased glucose metabolism in the midbrain as the earliest sign [146], similar to structural changes appreciated on MRI. Decreased metabolic activity in the caudate, putamen, and prefrontal cortex can also be appreciated as the disease progresses [147-150].

Striatal dopamine transporter imaging (eg, DaTscan) in patients with PSP generally shows reductions in caudate and putamen dopamine transporter density, similar to findings in other atypical parkinsonian disorders [151]. Combinations of advanced imaging techniques may prove more useful in differentiating PSP from other disorders [152]. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'DaTscan'.)

EVALUATION AND DIAGNOSIS

Clinical suspicion — The diagnosis of PSP during life is based upon the clinical features. Suspicion for PSP is raised when new-onset neurologic, cognitive, or behavioral deficits progress in absence of other identifiable causes in a patient ≥40 years of age. The core clinical features include:

●Early postural instability with falls

●Oculomotor deficits, especially slowing of vertical saccades followed by a vertical gaze palsy

●Akinesia/parkinsonism

●Frontal lobe impairments, including speech and language problems and behavioral change

●Lack of response to levodopa

However, early diagnosis is difficult, as the disease varies quite a lot clinically.

Evaluation and testing — No laboratory or imaging studies are diagnostic, and their primary role is to rule out reversible causes of decline. Imaging can be supportive if there is predominant midbrain atrophy on MRI, but the absence of this feature does not rule out the diagnosis of PSP, especially in patients at the earliest stages or presenting with a non-Richardson syndrome phenotype.

A levodopa trial in patients with parkinsonism and suspected PSP should be performed and can assist with the diagnosis. A poor or unsustained response to levodopa therapy is generally observed in patients with PSP and can help to distinguish PSP from Parkinson disease (PD). Responsiveness is typically tested by administering carbidopa-levodopa in escalating doses up to 1000 mg of levodopa daily as necessary and tolerated over several months, as reviewed separately. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'Response to dopaminergic therapy'.)

Diagnostic criteria — In 2017, the Movement Disorder Society (MDS) proposed new diagnostic criteria for PSP [25]. The MDS-PSP criteria include the following components:

●Basic features (inclusion and exclusion criteria) necessary for the diagnosis (see 'Inclusion and exclusion criteria' below)

●Four core functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as characteristic manifestations of PSP (table 1) (see 'Core features' below)

●Supportive clinical features that increase diagnostic confidence (see 'Supportive features' below)

●Operationalized definitions for the core features and supportive features (see 'Operationalized definitions' below)

●Four levels of diagnostic certainty (table 2) (see 'Certainty levels' below)

Inclusion and exclusion criteria — Basic features for the diagnosis of PSP of any phenotype and at any stage include mandatory inclusion criteria, mandatory exclusion criteria, and context-dependent exclusion criteria [25].

●Mandatory inclusion criteria:

•Sporadic occurrence

•Age 40 years or older at onset of first PSP-related symptom

Consider any new-onset neurologic, cognitive, or behavioral deficit that subsequently progresses during the clinical course in absence of other identifiable cause as a PSP-related symptom. Note that rare variants (mutations) of the MAPT gene may lead to inherited phenocopies of sporadic PSP.

●Mandatory clinical exclusion criteria:

•Predominant, otherwise unexplained impairment of episodic memory, suggestive of Alzheimer disease

•Predominant, otherwise unexplained autonomic failure (eg, orthostatic hypotension suggestive of multiple system atrophy [MSA] or dementia with Lewy bodies [DLB])

•Predominant, otherwise unexplained visual hallucinations or fluctuations in alertness, suggestive of DLB

•Predominant, otherwise unexplained multisegmental upper and lower motor neuron signs, suggestive of motor neuron disease (pure upper motor neuron signs are not an exclusion criterion)

•Sudden onset or stepwise or rapid progression of symptoms, in conjunction with corresponding imaging or laboratory findings, suggestive of vascular etiology, autoimmune encephalitis, metabolic encephalopathies, or prion disease

•History of encephalitis

•Prominent appendicular ataxia

•Identifiable cause of postural instability (eg, primary sensory deficit, vestibular dysfunction, severe spasticity, or lower motor neuron syndrome)

●Mandatory imaging exclusion criteria:

•Severe cerebral leukoencephalopathy

•Relevant structural abnormality (eg, normal pressure or obstructive hydrocephalus; basal ganglia, diencephalic, mesencephalic, pontine, or medullary infarctions, hemorrhages, hypoxic-ischemic lesions, tumors, or malformations)

●Context-dependent imaging exclusion criteria:

•In syndromes with sudden onset or stepwise progression, exclude stroke, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) or severe cerebral amyloid angiopathy, evidenced by diffusion-weighted imaging (DWI), fluid-attenuated inversion recovery (FLAIR), or T2* MRI

•In cases with very rapid progression, exclude cortical and subcortical hyperintensities on DWI-MRI suggestive of prion disease

●Context-dependent laboratory exclusion criteria:

•In patients with PSP with predominant corticobasal syndrome (PSP-CBS), exclude primary Alzheimer disease pathology (typical cerebrospinal fluid [CSF] constellation [ie, both elevated total tau and phospho-tau protein and reduced beta-amyloid 42] or pathologic beta-amyloid positron emission tomography [PET] imaging)

•In patients <45 years of age, exclude:

-Wilson disease

-Niemann-Pick disease, type C

-Hypoparathyroidism

-Neuroacanthocytosis

-Neurosyphilis

•In rapidly progressive patients, exclude:

-Prion disease

-Paraneoplastic encephalitis

-In patients with suggestive features (ie, gastrointestinal symptoms, arthralgias, fever, younger age, and atypical neurologic features such as myorhythmia), exclude Whipple disease

●Context-dependent genetic exclusion criteria:

•MAPT rare variants (mutations) are not an exclusion criterion, but their presence defines inherited, as opposed to sporadic, PSP

•MAPT H2 haplotype homozygosity is not an exclusion criterion but renders the diagnosis unlikely

•Leucine-rich repeat kinase 2 (LRRK2) and parkin RBR E3 ubiquitin protein ligase (PRKN) rare variants have been observed in patients with autopsy-confirmed PSP, but their causal relationship is unclear so far

•Known rare variants in other genes are exclusion criteria because they may mimic aspects of PSP clinically but differ neuropathologically; these include:

-Non-MAPT-associated frontotemporal dementia (eg, C9orf72, GRN, FUS, TARDBP, VCP, CHMP2B)

-PD (eg, SYNJ1, GBA)

-Alzheimer disease (APP, PSEN1, PSEN2)

-Niemann-Pick disease, type C (NPC1, NPC2)

-Kufor-Rakeb syndrome (ATP13A2)

-Perry syndrome (DCTN1)

-Mitochondrial diseases (POLG, mitochondrial rare variants)

-Dentatorubral pallidoluysian atrophy (ATN1)

-Prion-related diseases (PRNP)

-Huntington disease (HTT)

-Spinocerebellar ataxia (ATXN1, 2, 3, 7, 17)

Core features — Four core functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) are the characteristic manifestations of PSP [25]. Within each domain, there are three characteristic clinical features (table 1), which are stratified and listed in descending order of presumed level of certainty from highest to lowest.

●Ocular motor dysfunction:

•Vertical supranuclear gaze palsy

•Slow velocity of vertical saccades

•Frequent macro square wave jerks or "eyelid-opening apraxia"

●Postural instability:

•Repeated unprovoked falls within three years

•Tendency to fall on the pull test within three years

•More than two steps backward on the pull test within three years

●Akinesia:

•Progressive gait freezing within three years

•Parkinsonism, akinetic-rigid, predominantly axial, and levodopa resistant

•Parkinsonism, with tremor and/or asymmetric and/or levodopa responsive

●Cognitive dysfunction:

•Speech/language disorder (ie, nonfluent/agrammatic variant of primary progressive aphasia or progressive apraxia of speech)

•Frontal cognitive/behavioral presentation

•Corticobasal syndrome

Supportive features — Supportive features can increase diagnostic confidence but do not qualify as diagnostic features [25]. They are divided into clinical clues and imaging findings, with individual features listed in descending order from highest to lowest contribution to diagnostic certainty.

●Clinical clues:

•Levodopa resistance

•Hypokinetic, spastic dysarthria

•Dysphagia

•Photophobia

●Imaging findings:

•Predominant midbrain atrophy or hypometabolism

•Postsynaptic striatal dopaminergic degeneration

Operationalized definitions — The MDS-PSP criteria provide detailed descriptions (table 1) for each of the core features and supportive features to standardize the application of the diagnostic criteria [25].

Certainty levels — The MDS-PSP criteria specify four levels of diagnostic certainty (table 2), which are derived by combinations of core clinical features and clinical clues [25].

●Definite PSP, the gold standard, can be diagnosed only post mortem by neuropathologic examination.

●Probable PSP is diagnosed when clinical features with a high specificity are present.

●Possible PSP is diagnosed in the presence of clinical features considered to substantially increase the sensitivity for PSP.

●Clinical syndromes suggestive of PSP encompass syndromes with features that may constitute early or subtle evidence for PSP.

Predominance types — The MDS-PSP criteria determine clinical predominance types (table 2) based upon the combination of clinical features [25]. Recognized predominance types correspond to the variant phenotypes discussed previously (see 'Variant phenotypes' above):

●PSP with Richardson syndrome (PSP-RS)

●PSP with predominant parkinsonism (PSP-P)

●PSP with predominant oculomotor dysfunction (PSP-OM)

●PSP with predominant postural instability (PSP-PI)

●PSP with progressive gait freezing (PSP-PGF)

●PSP with predominant frontal presentation (PSP-F)

●PSP with predominant speech/language disorder (PSP-SL)

●PSP with predominant corticobasal syndrome (PSP-CBS)

The MDS-PSP diagnostic criteria omitted two other recognized but rare variant phenotypes (PSP with predominant cerebellar ataxia [PSP-C] and PSP with predominant primary lateral sclerosis [PSP-PLS]) because the sparse clinicopathologic evidence about them was inadequate for devising clinical diagnostic criteria with sufficient specificity [25].

Neuropathologic diagnosis — Neuropathologic examination remains the gold standard for its definitive diagnosis. The pathologic diagnosis of PSP is based upon the identification of neurofibrillary tangles in a distribution considered typical for PSP [153]. The diagnosis requires a high density of neurofibrillary tangles and neuropil threads in the basal ganglia and brainstem [47]. Astrocytic plaques and tau-positive tufts of abnormal fibers are highly characteristic of typical PSP [154]. (See 'Pathology and pathogenesis' above.)

Potential disease markers — There are no established laboratory or imaging markers for the diagnosis of PSP. However, imaging findings of predominant midbrain atrophy, midbrain hypometabolism, and postsynaptic striatal dopaminergic degeneration are supportive features (see 'Supportive features' above) that increase diagnostic confidence [25]. (See 'Neuroimaging' above.)

Routine investigations of CSF in PSP are normal. Potential markers of PSP include levels of neurotransmitters and brain metabolites in the CSF, but these are not validated for routine use. Tau quantification from skin biopsies may be a potential diagnostic tool in the future [155,156].

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of PSP based on common clinical symptoms and signs is listed in the table (table 3). The disorders that are the most difficult to differentiate from PSP are the other neurodegenerative parkinsonian disorders such as Parkinson disease (PD), corticobasal degeneration (CBD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), as well as vascular parkinsonism.

Parkinsonism — Considerations regarding the three most overlapping neurodegenerative disorders commonly resulting in parkinsonism are as follows:

●PSP versus PD – Unsteady gait and freezing of gait appear early in the course of PSP with Richardson syndrome (PSP-RS) and PSP with progressive gait freezing (PSP-PGF) compared with PD. The parkinsonism of PSP-RS differs from that of PD in other ways as well: resting tremor is rare, and rigidity tends to be much more pronounced in the neck than the limbs. Absent, poor, or rapidly waning response to levodopa suggests PSP over PD. In addition, the relative preservation of olfaction in PSP can help distinguish it from PD, which is characterized by hyposmia early in the course. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'Olfactory testing'.)

The initial clinical presentation of PSP with predominant parkinsonism (PSP-P) may resemble PD, and the two disorders can be difficult to distinguish early on. However, with disease progression, symptoms such as levodopa-induced dyskinesia, autonomic dysfunction, and visual hallucinations are much less common in PSP-P, which can help distinguish it from PD [104]. Furthermore, patients with early PSP-P often lose their levodopa response and develop other more typical clinical features of PSP (eg, oculomotor abnormalities).

●PSP versus CBD – PSP with predominant corticobasal syndrome (PSP-CBS) refers to the clinical CBS phenotype of neuropathologically defined PSP, characterized by a variable combination of progressive asymmetric limb rigidity and dystonia, apraxia, cortical sensory loss, alien limb, and bradykinesia that is unresponsive to levodopa. PSP-CBS is the second most common cause of CBS after CBD, and distinguishing between the two disorders during life is sometimes impossible.

●PSP versus MSA – PSP and MSA are the most likely causes of unexplained postural instability and falls occurring within the first year of symptom onset [75]. Compared with PSP, MSA has a younger mean age of onset (sixth decade). In addition, early and prominent autonomic symptoms such as orthostatic hypotension are more suggestive of MSA than PSP [157]. Nevertheless, these disorders overlap enough (including the presence of gaze-evoked nystagmus in PSP) that clinical differentiation may be difficult, especially in the early course of illness. (See "Multiple system atrophy: Clinical features and diagnosis".)

Rare cases of autoimmune encephalitis have been described with a clinical phenotype similar to that of PSP, including anti-IgLON5 encephalitis and anti-Ma2 encephalitis, although with a more subacute rather than chronic presentation [158-160]. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Anti-IgLON5 disease' and "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Ma2-associated encephalitis'.)

Supranuclear gaze palsy — Supranuclear gaze palsy is a distinguishing feature of PSP but may occasionally be present in other disorders, such as DLB, Alzheimer disease, PD, vascular parkinsonism, MSA, prion disease (eg, Creutzfeldt-Jakob disease), Whipple disease, and CBD [75,161,162].

In some cases, specific features of the gaze palsy are distinctive. In PSP, the vertical supranuclear palsy precedes the development of the horizontal gaze palsy, but in CBD, oculomotor apraxia usually precedes the supranuclear gaze palsy, which usually affects both the horizontal and vertical gaze [75]. The saccades in CBD have increased latency but normal speed and are similarly affected in the vertical and horizontal plane, whereas in MSA, the saccades have normal speed and latency. Blink rate, diminished in PD and MSA, is usually less impaired in PSP. In addition, the upward gaze palsy, which may be the first indication of an ocular motor abnormality, should be differentiated from the limitation of upward gaze observed in healthy older adult patients, in whom saccades have normal speed [75].

Accompanying neurologic signs are also clues. A midbrain or third ventricular tumor could cause vertical gaze palsy, extensor truncal rigidity, and pyramidal symptoms and/or incoordination [1,163]. A tumor of the pineal gland can produce the so-called Parinaud syndrome characterized by limited upgaze, sluggishly reactive and large pupils, and retraction nystagmus.

Cognitive dysfunction — Because patients with PSP often exhibit early frontal lobe cognitive disturbances and sometimes frank dementia, which can be the presenting features, they can be misdiagnosed as having cortical dementias such as frontotemporal dementia or Alzheimer disease. Pseudobulbar palsy, especially early in the disease course, can be mistaken for depression and other psychiatric illnesses. In cases of PSP with rapidly progressive moderate to severe dementia, Creutzfeldt-Jakob disease might be suspected.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Parkinsonian syndromes".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Progressive supranuclear palsy (PSP) is a sporadic, age-related neurodegenerative disorder with a mean age of onset in the late sixties to early seventies. Although rare, it is one of the most common atypical parkinsonian degenerative disorders. There are no established risk factors except age. (See 'Epidemiology' above.)

●Pathology and pathogenesis – PSP is a tauopathy characterized by neuronal and glial degeneration involving basal ganglia, brainstem, cerebellum, and cortex. Tau-positive inclusions are observed in neurons, astrocytes, and oligodendrocytes (picture 1). Despite well-described neuropathologic changes, the etiology and pathogenic mechanisms remain poorly understood. (See 'Pathology and pathogenesis' above.)

●Clinical features – PSP is heterogeneous, and multiple clinical phenotypes are recognized in patients with PSP confirmed neuropathologically. (See 'Clinical features' above.)

•The "classic" phenotype of PSP, known as Richardson syndrome (PSP-RS), usually presents with gait disturbances and postural instability resulting in falls. Nearly all patients eventually develop supranuclear ophthalmoparesis or ophthalmoplegia. Additional common features include dysarthria, dysphagia, pseudobulbar palsy, rigidity, bradykinesia, frontal cognitive abnormalities, and sleep disturbances. (See 'Classic (Richardson) phenotype' above.)

•PSP with predominant parkinsonism (PSP-P) is another common phenotype characterized by asymmetric onset of parkinsonism involving the limbs, including tremor, and relatively later onset of falls and cognitive impairment compared with PSP-RS. (See 'Variant phenotypes' above.)

•A number of additional phenotypes have overlapping clinical features with other neurodegenerative disorders, including frontotemporal dementia, corticobasal degeneration (CBD), and upper motor neuron disease. (See 'Variant phenotypes' above.)

●Neuroimaging – Common MRI findings in patients with PSP include generalized and brainstem atrophy that is most pronounced in the midbrain. The hummingbird sign on midsagittal MRI (image 1) results from prominent midbrain atrophy with a relatively preserved pons. (See 'Neuroimaging' above.)

●Diagnosis – PSP should be suspected in older adults with a progressive neurologic syndrome sharing some or all of the following core clinical features (see 'Evaluation and diagnosis' above):

•Postural instability and falls

•Oculomotor deficits, especially vertical gaze palsy

•Akinesia/parkinsonism that is poorly responsive to levodopa

•Frontal lobe impairments, including speech and language problems and behavioral change

The diagnosis during life is based on clinical diagnostic criteria (table 1). There are no diagnostic laboratory or imaging biomarkers.

●Differential diagnosis – The disorders that are the most difficult to differentiate from PSP are Parkinson disease (PD), CBD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and vascular parkinsonism (table 3). (See 'Differential diagnosis' above.)