Progressiv supranukleär pares

Synonym: Steele-Richardson-Olszewski syndrome

Progressive supranuclear palsy (PSP) is a neurodegenerative syndrome which was first described in 1964¹. It affects cognition, eye movements and posture. Characteristics include supranuclear, primarily vertical, gaze dysfunction accompanied by extrapyramidal symptoms and cognitive dysfunction. The cause is unknown.

PSP is the most common atypical Parkinsonian syndrome. It is increasingly recognised to encompass a spectrum of clinical phenotypes involving behavioural, language and a range of movement abnormalities. There are eight main clinical subtypes¹:

• Richardson's syndrome (PSP-RS): prominent postural instability, supranuclear vertical gaze palsy and frontal dysfunction.

• PSP-Parkinsonism (PSP-P): asymmetrical onset, tremor and moderate initial therapeutic response to levodopa.

• Pure akinesia with gait freezing is now referred to as PSP with progressive gait freezing (PSP-PGF): it initially presents with an isolated gait disorder years before developing other features of PSP-RS.

• PSP-corticobasal syndrome (CBS) is characterised by progressive asymmetric limb rigidity, apraxia, cortical sensory loss, alien limb, dystonia and bradykinesia unresponsive to levodopa. Clinically and genetically there is considerable overlap with corticobasal degeneration.

• PSP-speech language (PSP-SL): this is characterised by halting speech or distortions of language - sometimes known as apraxia of speech (AOS).

• PSP with frontal presentation (PSP-F): this presents with early and progressive deterioration of personality, social comportment, behaviour and cognition.

• PSP with predominant cerebellar ataxia (PSP-C): this presents with cerebellar ataxia as the initial symptom, eventually accompanied by cardinal features of RS.

• PSP with mixed pathology: a subset of patients with PSP develop other pathologies such as Alzheimers sjukdom, Parkinson's disease and other rarer conditions.

Diagnos

The diagnostic process, once entirely clinical, has been significantly advanced by the development of the International Parkinson's and Movement Disorder Society (MDS) Criteria, introduced in 2017. The diagnostic process is supplemented genetic testing, laboratory studies and imaging.

Kliniska egenskaper

Four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) were identified as clinical predictors of PSP. Within each of these domains, three clinical features were proposed, stratified by three degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP).

The criteria are complex and too detailed to be reproduced here. However, they can be accessed by referring to the original published paper².

Gene studies

It is now known that PSP is strongly associated with tau pathology (tauopathy)³. Tau is a protein whose role is to stabilise microtubules in neurones. However, in PSP, neurofibrillary tangles (NFTs) or neuropil threads (now recognised to be composed of tau protein), or both, form in the basal ganglia and brain stem. The distribution of tauopathy determines the subtype of PSP. The gene for tau itself, microtubule-associated protein tau (MAPT) is strongly associated with PSP. Familial mutations and other variants are occasionally encountered. Genetic studies demonstrating the presence of these genotypes are sometimes contributory to the diagnosis of PSP².

Laboratory studies

Ongoing research has identified a number of biomarkers which may be contributory in the diagnosis of early or variant PSP. These include tau protein levels in cerebrospinal fluid and plasma neurofilament light chain (Nfl)⁴.

Bilddiagnostik

• MRI - atrophy of the midbrain and superior cerebellar peduncles (SCPs) is a useful marker in differentiating PSP-RS from other Parkinsonian syndromes.

• Typically a sagittal view demonstrates the hummingbird sign: the atrophy of the midbrain results in a profile of the brain stem in which the preserved pons forms the body of the bird, and the atrophic midbrain the head, with beak extending anteriorly towards the optic chiasm. The morphology of the midbrain in patients with vertical supranuclear gaze palsy resembles the morning glory flower, thus termed the morning glory sign. Whilst these signs are oft quoted in the literature, they are of low sensitivity, particularly in early cases⁵.

• Resting-state functional MRI (fMRI) using biomarkers shows disruption in intrinsic connectivity network activity in the midbrain region in PSP⁶.

• Positron-emission tomography (PET) - tau-specific PET imaging has been used to successfully demonstrate areas of tau pathology in PSP patients. Other tau-specific imaging agents are being developed⁷.

• Single-photon emission computed tomography (SPECT) - dopamine-transporter SPECT shows reduced tracer uptake in the striatum which helps to differentiate PSP from similar conditions such as cerebrovascular disease and normal pressure hydrocephalus⁸.

Epidemiologi¹⁹

• The mean age of onset is 65 years. Virtually no autopsy-confirmed cases have been confirmed earlier than 40 years.

• PSP is a rare disease. However, prevalence estimates have risen over time as diagnostic techniques have improved. A recent UK study found a peak prevalence between the ages of 70-74 of approximately 18 cases per 100,000⁹.

• The estimated annual incidence is 5.3 per 100,000 in Europe¹⁰.

• PSP is as common as motor neurone disease or multiple system atrophy but may be incorrectly diagnosed as Parkinson's disease, corticobasal degeneration or Alzheimer's disease.

Presentation

• Variable presentation, depending on subtype.

• The main clinical features of the most common types are supranuclear ophthalmoplegia, pseudobulbar palsy, prominent neck dystonia, Parkinsonism, and behavioural, cognitive and gait disturbances that cause imbalance and frequent falls.

• Vertical gaze palsy is the most distinctive single clinical feature.

Symptom

• The onset is insidious and usually begins with a prolonged phase of vague fatigue, headaches, arthralgias, dizziness and depression. Patients also develop subtle personality changes, memory problems and pseudobulbar symptoms.

• Common symptoms at disease onset include postural instability and falls, dysarthria, bradykinesia and visual disturbances such as diplopia, blurred vision, burning eyes, and light sensitivity.

• Dysarthria, dysphagia and visual symptoms develop as the disease progresses.

• Convergent eye movements are often impaired, and convergence insufficiency may produce episodic diplopia at near distances.

• Cognitive dysfunction and personality change are common, with apathy, disinhibition, dysphoria and anxiety.

• Micturition disturbances, including urininkontinens, are common in the later stages.

Skyltar

• The classic gaze palsy usually involves looking down before looking up. It affects horizontal, as well as vertical, eye movements. Complete ophthalmoparesis may develop late in the disease course.

• Nearly continuous square wave eye jerks are common. They consist of small horizontal movements that take both eyes off target and then return the eyes to the target after a very brief pause.

• Eyelid signs include lid retraction, blepharospasm and lid lag.

• Bradykinesia with masked facies and a startled expression are frequent findings.

• Increased rigidity that is not cogwheel in nature. Resting tremor is unusual.

Differentialdiagnos

Andra orsaker till demens, and other movement disorders - eg, Parkinsons sjukdom.

Atypical Parkinsonian disorders include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and dementia with Lewy bodies. Clinical differentiation between these can be difficult in the early stages of the disease but advances in diagnostic techniques as described above may make this process easier¹¹.

Ledning¹

• There is currently no proven effective therapy.

• Patients with PSP-P and a more limited number of patients with PSP-RS often experience initial symptomatic relief with levodopa therapy. However, responses often are short-lived and incomplete. There is currently no effective medication for halting the progression of the disease.

• Chronic conjunctivitis is common because of the reduced blink rate and often requires treatment.

• Botulinum toxin A may be useful in the treatment of blepharospasm associated with PSP-RS.

• Physical therapy has been found to be helpful.

• Therapeutic approaches aimed at disease modification by targeting tau or mitochondrial dysfunction are currently being studied (eg, riluzole, tideglusib, davunetide). To date, none of the trials has demonstrated clinically satisfactory endpoints, but this may be due to lack of a pharmacodynamic biomarker that could demonstrate that the experimental agent engaged its physiological target and produced its hypothesised biological effect. Furthermore, because these conditions are rare, there are considerable challenges in obtaining statistically significant results.

Komplikationer

• Complications are mainly due to impaired balance, reduced cognition and immobility late in the disease process.

• Complications related to falls may cause significant injuries.

• Immobility in late disease leads to an increased risk of infection, especially pneumonia, urinary tract infection and skin infection.

Prognos

• Although the clinical course is variable, the typical presentation is usually associated with mortality 2.9-9.1 years after diagnosis⁹.

• The main cause of death is infection.

• The loss of independent gait and the inability to stand unassisted occurs less than three years after disease onset¹⁰.