Krishe Menezes, MD, DM, DNB
Lawrence W. Elmer, MD, PhD
DESCRIPTION 
- Progressive supranuclear palsy (PSP) is one of the Parkinson plus syndromes. Despite clinical similarities, however, the basic neuropathological processes are significantly different from idiopathic Parkinson's disease (IPD). Clinically, PSP is regarded as one of the akinetic-rigid syndromes. Pathologically, however, it falls more in the class of tauopathies, which include, but are not limited to, Alzheimer's disease, frontotemporal dementias including Pick's disease, corticobasal degeneration (CBD), and others.
- Characterized by early gait disturbance, bradykinesia, rigidity, and occasionally tremor, it is most commonly misdiagnosed as IPD early in its onset. Relentlessly progressive, PSP usually leads to significant motor and cognitive decline in 5–8 years, resulting in institutionalization and death.
- Like many of the Parkinson plus syndromes, PSP shares the clinical characteristic of being poorly responsive or totally unresponsive to dopaminergic stimulation.
- Synonym: Steele–Richardson–Olszewski syndrome
EPIDEMIOLOGY
Incidence
- PSP represents approximately 1% of all cases of parkinsonism, while IPD represents at least 85%.
- Incidence rates of PSP increase with age and have been estimated at <2 new cases per year in the 6th decade up to nearly 15 per year in the 9th and later decades per 100,000 individuals.
Prevalence
Prevalence rates in the UK may approach 6–7 cases per 100,000 population.
RISK FACTORS
- Race: No known ethnic predilection.
- Age: The median age of diagnosis is mid-to-late 50s to early 60s, slightly earlier than IPD.
- Sex: Some authors suggest a male predominance, while other studies have found no gender differences.
Genetics
- PSP is one of the 4R tauopathies, characterized by accumulation of this specific isoform of tau with 4 repeats in the microtubule-binding domain.
- Rare cases of autosomal dominant, familial clusterings have been reported but the gene has not been identified yet. Recent evidence suggests that homozygous carriers of mutations affecting the tau gene may be at increased risk of developing PSP.
PATHOPHYSIOLOGY
- Prominent neurofibrillary tangles, neuronal loss along with astrocytic tufts and oligodendroglial inclusion bodies that stain immunocytochemically for tau proteins in pallidum, subthalamic nucleus, red nucleus, substantia nigra, pontine tegmentum, striatum, oculomotor nucleus, medulla, and dentate nucleus. In addition, there is frequently neuronal and glial pathology in the precentral gyrus (primary motor cortex).
ETIOLOGY
The cause of PSP is unknown. The possibility of infection has been raised due to similarities between PSP and post-encephalitic parkinsonism.
[Outline]
HISTORY
The earliest symptoms of PSP include frequent falling with profound postural instability (usually affecting >95% of patients at time of diagnosis), frequently accompanied by bilateral bradykinesia, i.e., masked facies, paucity of spontaneous limb movement, slowness, and shuffling of the gait.
PHYSICAL EXAM
- Patients occasionally have a resting tremor and may have complicating postural and intention tremors. The distribution of increased resistance to passive manipulation is predominantly axial, affecting neck and trunk more than the limbs. This pattern is typically opposite of that seen in IPD. Bradykinesia and rigidity are also typically more symmetric at onset in PSP, differentiating it from the largely asymmetric onset of signs and symptoms in IPD.
- The classic neuro-ophthalmologic features of PSP, while sometimes delayed relative to the gait disturbance, include loss of voluntary vertical gaze followed by loss of voluntary horizontal gaze. This “supranuclear” ophthalmoplegia can be overcome by doll's eyes maneuvers, confirming intact brainstem nuclei and their connections. Patients may have a neck dystonia with retrocollis, eyelid retraction, and wrinkling of the forehead, resulting in a prominent “staring/startled” appearance or the Procerus sign. Other neuro-ophthalmologic hallmarks include gaze impersistence, loss of optokinetic nystagmus (first in vertical, then in horizontal planes), and square wave jerks with ocular fixation.
- Other frequent symptoms include dysarthria, dysphagia, disinhibition, and frontal lobe symptoms such as perseveration, impulsivity, grasping, apathy, and/or depression.
- Three general clinical phenotypes of brainstem PSP have been described:
- PSP-Richardson (PSP-R) presents with classic symptoms as outlined in the NINDS criteria, axial greater than limb rigidity, usually with little or no responsiveness to levodopa, and have the poorest prognosis.
- PSP-parkinsonism (PSP-P) may mimic IPD more closely than other forms of PSP with asymmetric limb greater than axial rigidity and early, partial responsiveness to levodopa therapy. Prognosis is typically better than PSP-R, but response to levodopa therapy is usually less than that seen in IPD and wanes over 1–2 years.
- PSP-pure akinetic gait freezing (PSP-PAGF) presents with axial greater than limb rigidity, isolated freezing of gait, and little or no response to levodopa. Prognosis for PSP-PAGF is typically better than PSP-R.
- There are cortical variants of PSP, but these are discussed in the chapter on CBD.
Diagnostic Criteria (NINDS)/Society for PSP
- Criteria for possible PSP are as follows:
- Gradually progressive disorder with onset when the individual is aged 40 years or older.
- Either vertical supranuclear palsy or both slowing of vertical saccades and prominent postural instability with falls in the first year of onset.
- No evidence of other diseases that can explain the clinical features.
- Probable PSP modifies the “possible” criteria by requiring both a supranuclear vertical gaze palsy and prominent postural instability with falls in the first year of onset.
- Definite PSP can only be diagnosed histopathologically at autopsy. Not having the above-mentioned features does not exclude the diagnosis.
- There are numerous mandatory exclusionary criteria and supportive criteria.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
Bloodwork: There are no specific blood tests to diagnose PSP, but the following tests should be considered to identify potential underlying secondary causes of parkinsonism: Serum vitamin B12 level, thyroid function tests, serum ceruloplasmin, 24-hour urine copper excretion.
Imaging
- Functional neuroimaging using PET and SPECT scanning using markers for neuronal activity (fluorodeoxyglucose), dopaminergic terminals (beta-CIT, DTBZ, and others), and dopamine receptors (IBZD) may distinguish PSP from IPD, but does not distinguish from other Parkinson plus syndromes. These methods are not being widely implemented.
- There is no evidence to suggest that structural imaging studies (CT, MRI) can assist in the diagnosis of PSP. MRI imaging may reveal evidence of other causes of parkinsonism, such as vascular insults, mass lesions, calcium or iron deposition in the striatum, atrophy in the posterior fossa suggestive of multiple system atrophies, and cortical atrophy patterns suggestive of other dementing illnesses.
Diagnostic Procedures/Other
Studies of cardiac innervations utilizing131I-labelled meta-iodobenzylguanidine are normal in PSP versus abnormal in IPD although this study is rarely performed.
Pathological Findings
See “Pathophysiology”
DIFFERENTIAL DIAGNOSIS
- Corticobasal degeneration
- Dementia with Lewy bodies
- Drug-induced parkinsonism (e.g., anti-psychotics, anti-emetics, and other dopamine-blocking agents)
- Multiple system atrophy (MSA)
- Vascular parkinsonism
- Parkinsonism dementia complex of Guam
- Progressive non-fluent aphasia
- Post-encephalitic parkinsonism
- Post-traumatic parkinsonism
- Wilson's disease
- Frontotemporal dementia with parkinsonism
[Outline]
MEDICATION
- Rarely, patients with PSP will transiently respond to carbidopa/levodopa therapy at the beginning of the disease process. This response is usually minimal and short-lived. Antidepressants, especially amitriptyline and trazodone, have helped ameliorate some of the symptoms of rigidity, bradykinesia, and gait disturbance. Botulinum toxin injections have been useful for severe dystonias.
- Contraindications: Individuals with a history of cardiac arrhythmias or orthostatic hypotension may have adverse effects when prescribed tricyclic antidepressants.
- Precautions: The use of high doses of carbidopa/levodopa and other dopaminergic therapies may be associated with confusion, hallucinations, and agitation, especially in individuals with advanced symptoms of PSP.
ADDITIONAL TREATMENT
General Measures
There is no effective treatment for PSP. Management is aimed at alleviating consequences of the motor changes including dysphagia and cognitive impairment.
Issues for Referral
PSP is rarely seen in general neurology practices and even more rarely in primary care. Once a patient demonstrates atypical parkinsonism, referral to a dedicated movement disorders specialist is indicated.
Additional Therapies
The primary symptom of gait instability may be overcome by the use of 4-wheeled walkers, although the predominant tendency of patients with PSP to fall backwards usually limits the effective duration of this intervention. Dysarthria and dysphagia may benefit from speech pathology intervention. Exposure keratitis may be prevented by frequent administration of artificial tears.
COMPLEMENTARY AND ALTERNATIVE THERAPIES
Co-enzyme Q10 is frequently prescribed by specialists for people with PSP at a dose of 100–400 mg 3 times daily. No controlled clinical trials in PSP have been completed with CoQ10.
SURGERY/OTHER PROCEDURES
Percutaneous endoscopic gastrostomy (PEG) may be performed to provide life-sustaining nutrition.
IN-PATIENT CONSIDERATIONS
Admission Criteria
PSP is usually managed in an outpatient setting. Rarely, concomitant illnesses, especially aspiration pneumonia, can lead to an acute exacerbation of PSP symptoms, requiring hospitalization for dysphagia, airway management, and issues of decreased mobility. Psychosis symptoms may precipitate hospitalization and/or institutionalization.
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FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
PSP is a relentlessly progressive illness, typically leading to death within 6–10 years. Patients are monitored in the outpatient setting, usually at 4–6 month intervals. Judicious use of antidepressant medications and timely discussion of PEG tube placement are recommended to assist patients and their families prepare for future decline.
DIET
As dysphagia develops, use of pureed foods may be indicated to avoid aspiration pneumonia. As mentioned previously, patients may require PEG tube placement in order to maintain nutritional status.
PATIENT EDUCATION
The severe gait instability in PSP prevents the use of ambulatory exercise, although stretching and strengthening exercises in a sitting position may be useful. Aqua therapy with close supervision may help forestall some of the immobility issues associated with this illness. Speech therapy is useful for speech and swallowing disturbances. National organizations provide information to patients and their families.
PROGNOSIS
Due to its progressive nature, the symptoms of PSP always worsen with time. Death usually occurs as a consequence of pulmonary embolism or aspiration pneumonia.
COMPLICATIONS
PSP frequently leads to aspiration pneumonia and/or complications of falling. Due to impulsivity, patients with PSP will frequently force food into their mouth incessantly.
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ICD9
333.0 Other and unspecified extrapyramidal diseases and abnormal movement disorders
The clinical characteristic of patient falling in PSP is almost always backward in contrast to IPD, which is usually reported as falling forward.