Introduction
Progressive supranuclear palsy (PSP) is a rare, progressive neurological disorder. It affects an estimated 5000 individuals in the UK and typically occurs over the age of 60, with a slightly higher prevalence in people assigned male at birth. The disorder is caused by the aggregation of tau proteins in the brain, affecting balance, vision, speech, swallowing, and cognition.1,2
Diagnosis is based on neurological examination and neuroimaging but may take up to 3 years, and misdiagnosis is common. With an average survival of 7 years, timely diagnosis and treatment are essential to manage the rapid progression of symptoms and prevent serious complications.3,4 Treatment is not curative but multidisciplinary and tailored to the individual’s symptoms.
What causes PSP?
PSP is caused by changes to tau proteins in the cells of the central nervous system. This is due to a number of genetic, epigenetic and environmental factors.1,5,6 Tau proteins occur naturally in the body. Their role is to stabilise and regulate microtubules, which are cellular components essential for cell division and structure.7
There are six types of tau proteins, called isoforms. Individuals with PSP have too many 4R isoforms in the brain.6 All six tau isoforms are coded for by the MAPT gene. However, 99% of cases are sporadic, meaning they are not inherited.5,6
In PSP, tau proteins undergo structural modifications, causing them to detach from the microtubules.1,3,5,6,8 The modified tau are insoluble, so do not break down normally, and aggregate into small fibres in cells such as neurons.3,6,9
This build-up of tau proteins causes cell death and atrophy (shrinkage) of the midbrain, the area of the brain responsible for:1,3,10
- Regulation of movement
- Muscle control
- Eye movement
- Pain
- Mood
Shrinkage also affects the frontal lobe, an area of the brain responsible for memory, behaviour, attention and language.3,11 The range of symptoms depends on where these proteins accumulate in the brain, making the different variants of PSP hard to diagnose.5,12
Diagnosis
Early diagnosis is important to ensure that symptoms are managed as soon as possible and prevent serious complications. This may be based on some, or all, of the symptoms below.
Symptoms
| Muscle and motor problems | - Repeated, unprovoked falls, usually backwards, within the first year13 - Postural instability: difficulty balancing - Akinesia: loss of voluntary movement14 - Dysphagia: difficulty swallowing usually develops after 3-4 years. It can lead to severe complications such as choking, weight loss or chest infections13,15 - Decreased facial expressions: fixed smile or grimace13 - Symmetrical muscle stiffness: particularly in the neck, leading to headaches |
| Visual difficulties | - Vertical supranuclear gaze palsy: difficulty looking up and down - A fixed glare - Reduced blinking, causing irritation or dryness13 - Eyelid apraxia: difficulty opening eyes13 - Tunnel vision, blurred or double vision - Photophobia: sensitivity to light |
| Speech difficulties | - Progressive apraxia: difficulty producing speech sounds and regulating speech rhythm, leading to slow, slurred speech4,13 - Low-pitch and nasal sounding voice - Progressive aphasia: difficulty finding and understanding spoken and written language14 |
| Cognitive and behavioural changes | - Impaired judgement and impulsive behaviour - Mood changes such as irritability, apathy or stubbornness - Sudden outbursts of tears or laughter - Fatigue and sleep disturbances - Mild memory difficulties13 |
| Bladder and bowel changes | Constipation, urinary urgency, frequent urination and/or incontinence are common as the disorder advances.13 |
Diagnostic tests
| Neurological examination | May be carried out by a neurologist and involves testing motor reflexes, balance, vision, cognition and behaviour.16 Symptoms are graded in terms of the MDS-PSP criteria (2017) by the International Parkinson and Movement Disorder Society.14 Diagnosis is based on four categories:14 - Motor dysfunction (visual disturbances). - Postural instability (balance) - Akinesia (voluntary movement) - Cognitive dysfunction |
| Neuroimaging | Neuroimaging is used in conjunction with physical examination to support PSP diagnosis and exclude the presence of other conditions, such as Parkinson’s disease, vascular dementia, leukodystrophy, normal pressure hydrocephalus and frontal lobe lesions.13,17 This may include: - Magnetic resonance imaging (MRI scan): Images are produced using a strong magnetic field and radio waves, which can help to identify changes associated with PSP, such as atrophy (shrinkage) of the midbrain and/or frontal lobe.6,10 The hummingbird sign refers to the pattern of shrinkage seen in PSP 18 - Positron emission tomography (PET) scan: A substance that emits radiation is injected, and used to produce three-dimensional images of the body. Fluorodeoxyglucose positron emission tomography (FDG-PET) may be used to show the metabolism of glucose, which is decreased in the frontal and mid-brain regions of individuals with PSP 17,19 - Dopamine active transporter (DaT) scan: Also known as SPECT imaging, it involves the injection of a radioactive substance, which emits gamma rays, detected by a gamma camera. PSP causes reduced uptake of the substance in the striatum, another area in the midbrain responsible for voluntary movement.17 |
| Neuropsychological tests | Neuropsychological tests such as the frontal assessment battery may be conducted to assess memory, attention, concentration, language, and visual processing.20 |
Differential diagnosis
Due to the lack of definitive tests for PSP, diagnosis often involves the elimination of other conditions, including:
- Parkinson’s disease: Both conditions affect the substantia nigra, an area of the mid brain which controls movement, affecting balance, coordination, and vision. However, PSP can be distinguished by vertical supranuclear gaze palsy (difficulty looking downwards), poor response to levodopa, a medication used to treat Parkinson’s, and the absence of tremor14,21
- Corticobasal degeneration (CBD): CBD is also caused by the aggregation of tau proteins. However, symptoms such as stiffness or clumsiness are usually one-sided in CBD
- Multiple system atrophy (MSA): MSA also affects the brain stem, causing difficulties with balance and coordination. However, MSA is associated with autonomic symptoms such as low blood pressure or respiratory difficulties5,17,22
Coping with the diagnosis
Being diagnosed with PSP can be challenging and scary. It is normal to feel a range of emotions, from relief to distress. Support is available from the PSP Association on 0300 011 0122.
Treatment
There is no curative treatment currently available for PSP, and individuals with the disorder require significant care and support from a multidisciplinary team, including:13
- A doctor
- Specialist nurses
- District nurses
- Physiotherapist
- Occupational therapist
- Dietician
- Speech and language therapist
- Community mental health team
- Social worker
- Palliative care team
Treatment is holistic and focused on symptom relief and risk management, such as:
Symptom management
| Muscle and motor issues | - Physiotherapists provide exercises and techniques for fall prevention, postural stability and gait - Occupational therapists provide home modifications/ adaptations, such as grab rails - Medication such as levodopa, amantadine or rotigotine for rigidity and mobility13 - Topical non-steroidal anti-inflammatory drugs for muscle spasms - Vitamin D for bone strength, to prevent injury due to falls13 |
| Pain management | - NSAIDs such as paracetamol - Muscle relaxants such as baclofen or clonazepam for muscle spasticity or spasms - Gabapentin or pregabalin for neuropathic pain - Botulinum toxin injections (botox) for painful muscle spasms - Non-pharmacological interventions: heat patches, massage, gentle exercises - Referral to a specialist pain clinic23 |
| Visual difficulties | - Botulinum toxin injections (botox) for eyelid opening difficulties13,17 - Prism glasses – multiple reflective surfaces to facilitate looking up/down - Wraparound sunglasses and tinted lenses for photophobia - An eye patch for double vision - Eye sprays and drops for dry eyes - Referral to an orthoptist or ophthalmologist23 |
| Swallowing and speech difficulties | - Speech and language therapists (SALT) help individuals to develop swallowing techniques, alter dietary consistency, offer thickening fluids, and work with dieticians to modify meal plans. - Percutaneous endoscopic gastrostomy (PEG) tube feeding involves the surgical insertion of a feeding tube through the abdominal wall into the stomach - Drooling caused by dysphagia may be treated using oral atropine drops or dietary changes - Speech applications, alphabet boards, voice amplifiers and communication charts to assist with communication13 |
| Bladder and bowel issues | - Bladder issues may be treated with medication such as Mirabegron - Dietary changes, such as getting enough fibre and plenty of fluids, are advised to avoid constipation - Continence nurse advisor13 |
| Cognitive difficulties | - Antidepressants may help to stabilise mood and manage apathy13,17 - Caregiver education and support can improve communication and quality of life 20 - Community psychiatric nurse, psychologist or psychiatrist |
| Sleep disturbances | May be caused by other symptoms, such as muscle stiffness, pain, mood disturbances and medication. Treatment involves sleep hygiene advice, and medication such as mirtazapine if needed.13, 20 |
Advanced stages treatment
It is important for treatment and care preferences to be discussed early, as individuals typically need significant support in the advanced stages.
- Advanced directives: An advanced directive, or statement, can help to ensure that decisions made on behalf of the individual are in their best interest. This may cover spiritual or religious beliefs, preferences for care settings, practical issues such as pets, or personal preferences
- Palliative care treatment: Palliative care offers physical, psychological, and spiritual support at home, in a hospital, or in a hospice setting. This may involve advanced care planning, family support, counselling, symptom management, day centres or respite.13 Early involvement can ease anxiety around symptom progression
Future treatment development
The development of treatments currently focuses on targeting tau proteins, including:
- Microtubule stabilising agents: support and strengthen the microtubules, weakened by the dysfunctional tau proteins17,24
- Anti-tau monoclonal antibodies: stop/slow the spread of pathogenic tau protein24
- Tau acetylation inhibitors: stop the modification of tau proteins17
- Tau vaccines: produces antibodies that target part of the tau protein to prevent aggregation24
Summary
PSP is a rare, progressive neurological disorder caused by the aggregation of Tau proteins in the brain. It affects vision, movement, swallowing, and cognition, and individuals require significant care. Diagnosis is based on neurological examination, neuroimaging, and the exclusion of similar conditions. Treatment is not curative and requires a multidisciplinary approach, including palliative care. Research into future treatments involves targeting tau proteins.
References
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