Progressive supranuclear palsy (PSP) is an atypical parkinsonian syndrome characterized by parkinsonism, supranuclear gaze impairment, prominent and early postural instability with falls, axial greater than appendicular rigidity, and cognitive decline.

• PSP
• Steele-Richardson-Olszewski syndrome

While there are several subtypes of PSP, the majority of patients present with the following core features:

• •Early postural instability and retropulsion leads to frequent backward falls. In severe cases, patients could fall backward just by sitting on the floor, and the falls frequently occur within the first yr.
• •Akinesia and atremulous parkinsonism with early gait freezing within the first 3 yr or an akinetic-rigid axial parkinsonism. Although sometimes confused for idiopathic Parkinson disease (PD), gait freezing within the first 3 yr and symmetry of symptoms are atypical for PD.
• •Supranuclear gaze palsy is often preceded by slowing of vertical saccades, and patients might report difficulty with tasks that require downward gaze eye movement, such as reading. Square wave jerks are another common but nonspecific finding to PSP, as they can also manifest in cerebellar ataxia. The term "supranuclear" implies that the integrity of third, fourth, and sixth nerve nuclei. Thus, the standard way of examining its supranuclear nature is to conduct the oculocephalic maneuver (Fig E1), the response to which remains normal in PSP.
• •Dystonia of the frontalis and procerus muscles gives the PSP patient a "surprised" or "frightened" expression (Fig. E1) as opposed to the hypomimia of PD (Fig. E2). Of note, blepharospasm, a focal dystonia of eyelid closure, and eyelid open apraxia could also manifest in PSP.
• •At the neuropathology level, PSP belongs to frontotemporal lobar degeneration. Thus frontal lobar dysfunction and its related symptoms are commonly seen in PSP, including, but not limited to, the following:
  1. 1.Speech apraxia: While not universally presenting in every person with PSP, speech apraxia is one of the main features of PSP. Speech is effortful, distorted, groping, and halting, as opposed to the hypophonia seen in PD.
  2. 2.Pseudobulbar affect can be seen, typically presenting with inappropriate and involuntary crying or laughter without a preceding trigger or with a trigger that is disproportionate to the emotional response.
  3. 3.Early cognitive impairment and behavioral disturbance, including apathy and/or impulsivity. Impulsivity has been identified as one of the main factors for falls in PSP, in addition to the motor symptoms.
  4. 4.Applause sign (the inability to execute the same amount of claps as performed by the examiner) can be seen in PSP as well as other neurodegenerative disorders, especially later in the disease course.³
• •There are multiple subtypes of PSP by clinical presentation, and there is significant variability in the correlation between clinical presentation and neuropathology.^1,3,4 The majority of PSP subtypes belong to Richardson syndrome (PSP-RS), the classic PSP with constellations of above-mentioned features exhibiting early in the stage. PSP with predominant parkinsonism (PSP-P) demonstrates slower progression and better response to carbidopa/levodopa compared to other PSP subtypes. Depending on the predominant and early clinical features, patients can be further categorized into PSP with predominant oculomotor dysfunction (PSP-OM), postural instability (PSP-PI), progressive gait freezing (PSP-PGF), frontal presentation (PSP-F), or speech/language disorder (PSP-SL). Of note, while the cerebellum and upper motor neuron systems have been traditionally thought to be less involved in PSP, cerebellar ataxia (PSP-C) and upper motor neuron (PSP-PLS) system involvement can be the principal and initial symptoms in PSP, as reported from pre- and postmortem studies.^5-7

PSP is a tauopathy characterized by widespread atrophy and neuronal degeneration of nuclei in the brain stem and basal ganglia as a result of abnormal tau protein accumulation in tufted astrocytes and neurofibrillary tangles. While sharing the features of MAPT H1 haplotype and four-repeat tau isoforms, the cytopathology of corticobasal degeneration is astrocytic plaque not tufted astrocytes.⁸

• •PD: While severe postural instability and hypomimia could occur early in PD, most PD cases respond robustly to levodopa, progress more slowly, start asymmetrically, and lack "red flag" symptoms listed previously
• •Corticobasal degeneration: A 4-repeat tauopathy like PSP but associated with early parietal lobe syndrome (e.g., ideational and ideomotor apraxia, cortical sensory loss/astereognosis), prominent asymmetric dystonia, and myoclonus, and sometimes an "alien hand" syndrome
• •Multiple system atrophy: Distinguished by dysautonomia (particularly orthostatic hypotension), cerebellar ataxia, and inspiratory stridor
• •Dementia with Lewy bodies: A syndrome of coinciding dementia and parkinsonism that usually co-occur within 1 yr, with vivid visual hallucinations and fluctuating mental status

• •PSP remains primarily a clinical syndrome-based diagnosis, best made by a neurologist familiar with the disorder, such as a movement disorders specialist. Of note, immunohistochemical analysis of a skin biopsy using monoclonal antibodies to detect phosphorylated alpha-synuclein is an emerging technique that aids in the pathologic differential diagnosis between PD and other synucleinopathies from PSP, particularly in cases where the clinical presentation makes a definitive diagnosis challenging.^9,10
• •A robust response to levodopa may lead consideration away from PSP. ∼30% of patients will have a mild initial response to levodopa but not the marked response seen in PD.^1,2
• •Brain MRI (see "Imaging Studies") can be helpful.
• •Histopathologically, the degenerative process involves mainly the basal ganglia, diencephalons, and brain stem. Pathologic findings include neuronal loss, gliosis, neurofibrillary tangles, and granulovacuolar degeneration in neurons of the brain stem. There are tufted astrocytes in the motor cortex and the striatum, and the typical neuronal lesion is the globose neurofibrillary tangle, made up of hyperphosphorylated four-repeat tau protein filaments (Fig. E3).

There are no diagnostic laboratory tests.

• •Dorsal midbrain atrophy is commonly seen on MRI and is referred to as the "hummingbird sign" on sagittal view due to the elongated beak appearance seen on the midsagittal plane. "Mickey Mouse" or "morning glory" sign due to the larger ear appearance on axial view of the midbrain. Given that these intriguing neuroimaging features can be overtly subjective, the midbrain to pons ratio measurement was proposed to establish the objective measurement for diagnosis as opposed to the naked eyes.¹¹
• •Dopamine transporter imaging (DaT scan with [¹²³I]β-CIT SPECT) shows reduced uptake in PSP, as well as in PD, frontotemporal dementia, and corticobasal degeneration. Overall, the DaT scan is useful to determine if there is any reduced dopamine uptake but not useful in differentiating PSP from other parkinsonian disorders, including PD, multiple system atrophy, and corticobasal degeneration.

• •Physical and occupational therapy are essential for avoiding the morbidity associated with frequent falls. Assistive devices such as a U-step walker or wheelchair should be encouraged due to frequency of falls present within the first yr.
• •Dysphagia is a common finding that should be monitored closely in conjunction with early speech therapy referral. Weight loss and aspiration are common. Percutaneous endoscopic gastrostomy (PEG) tube placement for tube feeding should be reserved only for severe cases, and the decision-making process should heavily focus on the goals of care discussions, including quality of life and ethical considerations, with a palliative team involved.¹⁰
• •Prisms may be helpful to compensate for misalignment and diplopia resulting from the eye movement abnormalities; however, benefits, if noted, tend to be short-lived as the disease progresses.
• •Newly listed in the PSP Best Practice Guideline, palliative care referral should be actively considered and provided. Recent research studies, including a randomized trial, have shown that palliative care involvement can improve the quality of life, especially in the early stage of disease.¹²

• •All patients, if no contraindications, should attempt the levodopa trial.^1-3 Although classically thought to be unresponsive to levodopa, there is often a transient but meaningful response to higher doses of levodopa (1200 mg/day), and some patients (PSP-P) may respond well to levodopa. The poor response to levodopa is most likely due to the loss of postsynaptic dopamine receptors.
• •Pure or strong anticholinergic medications, such as amitriptyline, benztropine, and trihexyphenidyl should be avoided, as they might further impact the gait and induce neuropsychiatric features. On the other hand, although amantadine also has an anticholinergic effect, it might improve gait and freezing, so it can be considered (less than 100 mg tid).
• •Blepharospasm and cervical dystonia can be effectively treated with botulinum toxin injections.
• •Pseudobulbar effect is common and can be effectively treated with dextromethorphan/ quinidine (Nuedexta) or citalopram 10 to 20 mg.
• •Apathy is more common than depression. Can consider selective serotonin reuptake inhibitor such as citalopram because it helps with pseudobulbar affect and impulsivity.
• •Mirtazapine can be considered for insomnia and increased appetite.
• •Urinary urgency/frequency can be treated with mirabegron after ruling out other confounders such as prostate enlargement, diuretic, and caffeine. Will need to watch for hypertension while on this medication.

Median latency from symptom onset to wheelchair-bound state is 5 yr and to death is 7 yr in PSP-Richardson syndrome (classically described phenotype earlier). Lifespan improves to 10 to 12 yr in the PSP-parkinsonism variant.^1,3,4

Referral to a movement disorders center, preferably one with a CurePSP Center of Care designation, is appropriate (https://www.psp.org/centers-of-care).

Consider PSP in a parkinsonian patient with the onset of falls within 1 yr of diagnosis, vertical eye movement abnormalities, early cognitive impairment, pseudobulbar affect, frontonasal dystonia, or poor response to levodopa.

PSP patients are highly sensitive to developing psychosis and agitation with medications and stress. Patients and families need to be educated on avoiding anticholinergics and opiates and know that any infection or stress may cause altered mental status. The antipsychotics of choice that will not further impact parkinsonian symptoms significantly are quetiapine and clozapine. Olanzapine is the next drug of choice, but it may further affect parkinsonism more than quetiapine and clozapine. Other antipsychotics, such as haloperidol and risperidone should be avoided.

Patient and caregiver information and resources can be found through CurePSP at https://www.psp.org/ineedsupport. You may also refer to specific pamphlets designed by the CurePSP,¹³ which can be obtained at every CurePSP Center of Care.

Parkinson Disease (Related Key Topic)