Approach

​Treatment of progressive supranuclear palsy (PSP) is mainly focused on symptomatic management and rehabilitation, with the objective to avoid complications and to delay disability and perhaps death.[10]

  • Despite multiple clinical trials, there is as yet no disease-modifying treatment available for PSP.[10][97]

  • Note that high-quality evidence is lacking for most treatment options, hence many treatment recommendations are based on clinical experience.

  • The recommendations that follow are based on a 2021 best practice synopsis that summarized the scarce evidence and outlined the consensus opinion of the directors of 25 North American specialist centers for PSP.[10]

​PSP is best managed by a multidisciplinary team, including a social worker or a case manager, with care based on a case management approach drawing on the expertise of multiple specialties. Other key team members are a neurologist (ideally a movement disorder specialist), a physical therapist, an occupational therapist, a speech-swallow therapist, and, if available, a neuropsychologist and a nurse.[10]

  • The goal is to address the whole spectrum of symptoms including parkinsonism, gait and balance problems, swallowing and speech impairments, behavioral changes, and cognitive impairment.

  • Ensure the initial treatment plan for any patient with a diagnosis of PSP includes referral to a movement disorder specialist.

  • Full neuropsychological evaluation is usually necessary to determine the degree and pattern of cognitive impairment, evaluate decision-making capacity, and inform the treatment plan.[10]

  • Early initiation of daily physical therapy/occupational therapy exercises and speech therapy is important to optimize management of gait, language difficulties, and swallowing impairment.

  • Occupational therapy (OT) is recommended to include an evaluation for devices such as splints and braces to support the affected body part, and exercises to optimize upper limb function. It can also include advice to manage executive dysfunction (e.g., structured daily routine, daily planners).[10]

  • Caregiver education is recommended. Advise the caregiver/family that a false or exaggerated impression of dementia can be created by the patient’s apathy, depression, dysarthria, fixed expression, and poor eye contact.[10]

  • Advice on lifestyle modifications is also important. This might include aerobic exercise where feasible and safe, healthy diet advice, ensuring adequate sleep, and encouraging social and cognitive engagement.[10]

  • Palliative care can improve the patient’s quality of life and is important to consider from the point of diagnosis, with discussions around advance care planning started within the first year and regularly reviewed thereafter.[10]

​As a general rule, avoid polypharmacy and discontinue any medications that are found to be ineffective or are causing significant adverse effects.[98]

  • Anecdotal evidence suggests that medications for dementia, motor parkinsonism, and bladder dysfunction are especially likely to be continued past their limit of utility.[10]

Parkinsonism

Parkinsonism (bradykinesia, rigidity, and tremor) affects all patients with PSP with the Richardson syndrome (PSP-RS) or parkinsonism (PSP-P) phenotype and eventually, as the condition progresses, with all other phenotypes.

In contrast with Parkinson disease (PD), parkinsonism in patients with PSP does not show a sustained benefit from levodopa therapy.[3][30][31][32]

  • Any benefit tends to be minimal or transient, although, by definition, patients with the parkinsonian subtype of PSP (PSP-P) are initially better levodopa responders than those with other PSP phenotypes.[10][44]​​​​

A therapeutic trial of levodopa for at least 1 month is recommended in any patient with PSP with bradykinesia, rigidity, or tremor affecting daily activities.[10]

  • Because in retrospective studies up to 40% of patients with PSP showed some response to levodopa and also because of the difficulty in distinguishing the early stages of PSP-P and PSP-RS from PD, it is worthwhile initiating a levodopa trial for any patient diagnosed with PSP who has parkinsonism.[98] In PSP, a response tends to occur only early in the disease course and persist for only a few months.[10]

  • The dose of levodopa is up-titrated over a 4-week period from a low starting dose to the therapeutic dose (or maximum tolerated dose, if lower).[10] Based on findings from PD studies, a noticeable effect might take weeks to become evident so treatment should be continued for at least 1-3 months before any judgment on effectiveness is made.[99] If no effect is observed, levodopa can be tapered off over at least 2 weeks and discontinued.[10] If the patient does show benefit and adverse effects are minimal, in practice it is worth continuing the levodopa but with frequent re-evaluation so that tapering and discontinuation can be undertaken as soon as the benefit disappears.

​Avoid other dopaminergic treatments such as dopamine receptor agonists, monoamine oxidase type B inhibitors, and catecholamine-O-methyltransferase inhibitors. Also avoid anticholinergics.[10]

  • These medications have no clinical utility in PSP and should be avoided.[10][100]​​

Gait and balance

Gait and balance impairments in PSP are not responsive to dopaminergic treatments.[10]

A daily physical therapy home exercise program, started early in the disease course, is recommended for all patients with PSP who have gait and balance problems.[10]

  • Physical therapy can improve gait and balance, thereby reducing the risk of falls. Falls are a major cause of morbidity and a predictor of mortality among all parkinsonian patients but are especially more frequent and occur earlier in the course of PSP.[101][102] Patient and caregiver education on falls prevention is essential.[10][33]

  • Interventions that address visual impairment (including gaze shifting and eye movement training) may provide additional benefit when coupled with gait and balance therapy.[10]

  • Use of a weighted, wide-based walking stabilizer that has a reverse braking mechanism (e.g., a U-Step® walker) is very helpful.[10]​ A wheelchair may be needed as the condition progresses and mobility declines but this requires shared decision-making with the patient and caregiver.[10]

  • One systematic review of 11 small studies evaluating physical therapy and exercise in PSP showed a small to moderate effect on gait and walking but this did not reach statistical significance.[103] A subsequent uncontrolled but larger study of 117 patients with PSP found that a multiple therapeutic exercise program that included a customized mix of resistance training, balance training, and walking exercises was effective in improving gait and balance scores.[104] The program was administered for 60-80 minutes daily, 5 days per week for 4 weeks. 

Nonpharmacologic measures can be helpful for patients with freezing of gait.

  • Freezing of gait is a significant symptom in some patients with PSP and is difficult to treat because it does not respond to levodopa and other medications have a minimal or modest effect.

  • The use of an auditory or visual cue to show the patient the next step can help decrease the frequency and duration of freezing episodes (e.g., a device to make a click sound before every step or a line projected on the floor where the next step should be, using a laser device on the shoe or the walker). The evidence to support this comes mainly from patients with Parkinson disease, because studies involving patients with PSP are scarce.[105][106]

​Evidence about amantadine, an NMDA-receptor antagonist, is very scarce and that which is available is contradictory. An expert consensus group has suggested that a 1-month trial may be worthwhile in patients with PSP who have significant gait impairment.[10]​ However, the evidence to support this is extremely weak and opinions differ on this point.

  • One crossover study that tested amantadine on 7 patients with PSP reported a decrease in the freezing of gait score. However, a retrospective study of 310 patients with PSP showed no effect on gait.[107][108]​​​ Another study reported a general subjective improvement in a subset of patients with PSP.[109]

  • An expert consensus group recommends a 1-month trial of amantadine in patients with PSP with significant gait impairment, with the dose titrated upward at intervals of at least 2 weeks and careful monitoring for psychosis, confusion, and constipation.[10] In practice, patients aged <60 years are more likely to report benefits from amantadine whereas those >75 years are more likely to experience serious adverse effects.[42]

  • Based on expert opinion, rasagiline (a monoamine oxidase type B inhibitor) may also improve freezing of gait but is less effective than amantadine.[10]

​Coenzyme Q10 may improve gait (based on expert opinion). Although only a few patients will respond, the adverse effects are minimal; therefore, a 2-month trial is recommended.[10]

  • Discontinue if no benefit is seen after 2 months.[10]

Dysphagia and drooling

Oropharyngeal dysphagia occurs earlier and is more severe in PSP compared with other parkinsonian disorders. Evaluation and treatment of dysphagia is an important part of management.

  • An early presentation of dysphagia in PSP is associated with poor prognosis.[10][110]

  • Complications include sialorrhea (excessive drooling), malnutrition, and aspiration pneumonia. Pneumonia is the leading cause of death in PSP.[111]

Dysphagia must be evaluated at every visit of a patient with PSP.

  • This can be done through history, oral motor exam, a water swallow test, and/or a swallowing questionnaire.[112]​ If any sign of dysphagia is noted, including coughing on liquids or sialorrhea, a full evaluation by a speech-language pathologist (SLP) is essential.[10]

  • The SLP will perform a clinical swallow evaluation. If silent aspiration, which is common in PSP, cannot be excluded then a modified barium swallow test is indicated.[10]

Interventions that can improve swallowing include:[10]

  • Postural maneuvers such as chin-tuck and head turns

  • Alternating bite and sip or taking multiple swallows

  • Thickening liquid consistency and optimizing soft/pureed food consistency

  • Early speech and language therapy. Evidence is scarce for PSP but a benefit for dysphagia was demonstrated for patients with PD who had a speech and language therapy program specifically designed for patients with PD (Lee Silverman Voice Treatment® or LSVT).[10]​ A small uncontrolled pilot study of LVST in patients with PSP suggested improvements in swallowing function.[113][114][115]​​​​

​Percutaneous endoscopic gastrostomy (PEG) for tube feeding can be considered in severe cases of swallowing impairment.[10]

  • It may be appropriate when a modified barium swallow has shown aspiration or laryngeal penetration of all textures that cannot be improved by feeding modification or therapy and there is one or more of: a significant (>10%) weight loss; increased work of eating (>1 hour); a first episode of aspiration pneumonia; or fever of unknown origin.[10]

  • However, there are no studies that evaluate whether PEG increases survival.

Management of excessive drooling in PSP is similar to in other neurologic disorders except that in patients with PSP it is important to avoid anticholinergics with blood-brain barrier penetrance because of their detrimental effect on cognition.

  • Glycopyrrolate is an anticholinergic agent with no significant blood-brain barrier penetration. It has been shown to be effective in decreasing sialorrhea in patients with PD in a double-blind clinical trial.[10][116]

  • Botulinum toxin injection is also effective in decreasing sialorrhea in parkinsonian patients, including those with PSP, with botulinum toxin type A and type B both being good options.[10][117][118]​ It is important to note that dysphagia is a potential side effect of botulinum toxin injection.[10][119]

  • There is less experience with parotid or submandibular gland irradiation in patients with PSP but, based on a small controlled trial, it may be considered as a last resort.[120]

Speech impairment

Evidence is scarce regarding therapeutic options to improve speech impairment in PSP.

  • Referral for speech therapy is recommended for any patient with decreased speech intelligibility.[10]​ A small uncontrolled study suggested that LSVT improves voice quality and articulation in patients with PSP.[121]

  • As the disease progresses, use of augmentative and alternative communication strategies (e.g., alphabet board, text-to-speech system, eye-gaze speech-generating device) might be necessary for most patients with PSP.[10]​ Early referral to a speech-language pathologist can ensure advance planning and preparation for this stage.[122]

  • If palilalia (involuntary repetition of words and phrases) is a significant problem, pacing techniques may be helpful.[10]

Behavioral symptoms

It is important to differentiate apathy from depression in patients with PSP.[10]

  • Apathy is not usually amenable to treatment.[10]

  • Treat depression using a standard dose of an antidepressant such as a selective serotonin-reuptake inhibitor (SSRI). Avoid tricyclic antidepressants due to possible detrimental effects on cognition.[10]

  • Nonpharmacologic measures such as cognitive behavioral therapy can also be offered.

Aggression and irritability, if present, are usually mild and do not require specific treatment or can be managed by explaining or distraction.

  • If aggression is bothersome, use caution when considering benzodiazepines for patients who are mobile, due to an increased risk of falls.[10] Avoid antipsychotics due to exacerbation of parkinsonism.

Impulsivity is a very difficult symptom to treat effectively.[10]

  • If significant impulsivity is present, it may be necessary to discontinue levodopa and other drugs with a dopaminergic effect.[10] Nondopaminergic SSRIs (e.g., escitalopram, sertraline) can be tried, although they are often ineffective.[10][123]

​Pseudobulbar affect (PBA) with labile emotions might be encountered in some patients.[10]

  • Dextromethorphan/quinidine is the most effective treatment for PBA with emotional lability in PSP although its use may be limited by cost.[10] Multiple clinical trials in different neurologic disorders have confirmed its effectiveness and safety in the treatment of PBA.[124][125][126]​​​​​

  • SSRIs can be considered as an alternative treatment option for emotional lability based on anecdotal evidence and expert opinion.[10]

Caregiver education is an important component of management for cognitive and behavioral aspects of PSP.[10]

Cognitive impairment

Executive dysfunction and verbal fluency deficits are the predominant symptoms of cognitive impairment in PSP. No symptomatic therapy is available for these.[37][58]

In a sizable proportion of patients, episodic Alzheimer-type memory loss is a significant part of the deficit.[127]

  • One small controlled trial suggested that donepezil, a cholinesterase inhibitor, can modestly improve memory in these patients, but this benefit was considered to be outweighed by worsening of motor function and a negative impact on activities of daily living scores.[128]

  • Consensus guidelines recommend cautious consideration of a trial of a cholinesterase inhibitor only if Alzheimer-type impaired memory encoding (i.e., difficulty with learning new information) predominates and the patient does not have severe postural instability.[10]​ However, these authors advise against this on the basis that the harms in terms of worse mobility outweigh any potential benefits in cognitive function.

  • Avoid memantine as it may worsen cognition in PSP.[10] Memantine has not been specifically studied in PSP but did not improve cognition in frontotemporal dementias.[129][130]

Dystonia

Limb dystonia can severely impair patients’ daily functioning. Facial/neck dystonias are sometimes painful and can prevent eating/feeding.

  • Botulinum toxin injection is probably the best treatment option for localized dystonias.[131][132] Treatment can be repeated every 3 months to maintain effect.[10] For use in cervical dystonia, the American Academy of Neurology assigns level A efficacy rating to abobotulinumtoxinA and rimabotulinumtoxinB, and level B efficacy rating to onabotulinumtoxinA and incobotulinumtoxinA.[131]

  • Anticholinergics and muscle relaxants are usually effective in the treatment of primary dystonia but their use is limited in PSP due to the adverse effects of worsening cognitive function and gait. Muscle relaxants such as baclofen or clonazepam can be tried at low doses as a last resort.[10]

​Botulinum toxin injection is recommended for blepharospasm.[10]

  • Eyelid-opening apraxia, which can coexist with blepharospasm in the same patient, is more difficult to treat and requires the input of a neuro-ophthalmologist.

  • If decreased blink rate leads to dry eye, blepharitis, and exposure keratitis, conservative treatment with humidifiers, warm wet compresses, and protective eyewear is recommended. Tear volume can be improved by using artificial tear drops and preservative-free lubricants.[10]

Refer to an ophthalmologist if eye movement problems cause diplopia or significant visual impairment.

Other symptoms

Sleep issues are common. Pharmacologic and nonpharmacologic management options exist but evidence for efficacy specific to PSP is scarce. Standard sleep hygiene advice is recommended.[10]

  • Insomnia can be treated with melatonin. This is also an effective and well-tolerated option if REM sleep behavior disorder is present.[10]

  • Modafinil, armodafinil, or methylphenidate can be considered at low doses if excessive daytime sleepiness is a problem.[10]

  • Great caution is required regarding benzodiazepines in patients with PSP because of the risk of falls.[10] In addition, retrospective analysis of 305 patients with PSP-RS suggested that those who were prescribed benzodiazepines (lorazepam, clonazepam, alprazolam, diazepam) experienced an increased worsening of their PSP compared with those not prescribed benzodiazepines, as measured by the PSP Rating Scale (PSPRS) during the 1-year follow-up period.[133]​ The effect persisted after adjusting for indications for benzodiazepine administration (including insomnia, anxiety, and sleep disturbance). Benzodiazepines were the only drug class being taken by ≥10% of the participants that was found to be associated with this more rapid worsening of PSP.

  • Obstructive sleep apnea is managed with advice on lateral decubitus positioning, weight loss if obesity is present, and elevation of the head of the bed, together with standard approaches such as continuous positive airway pressure (CPAP), surgical removal of obstructive tissue, or implantation of a hypoglossal nerve stimulator.[10]

  • Similar treatment approaches can be used for periodic limb movement disorder and restless legs syndrome. The medications indicated for these problems in the setting of other conditions (e.g., gabapentin, pregabalin, cabergoline) require great caution in PSP because of the adverse effects of sedation and psychosis. If iron deficiency or low ferritin levels are present, a trial of oral iron replacement is recommended.[10] See Iron-deficiency anemia.

Constipation occurs frequently and is managed using standard approaches. Initial treatment centers on nonpharmacologic measures including increased hydration, physical activity (where feasible), and fiber supplementation.[10]

  • First-line pharmacologic treatment is a stool softener such as docusate. Osmotic laxatives (e.g., polyethylene glycol, magnesium citrate, lactulose) can then be used if needed. Stimulant laxatives (e.g., bisacodyl, sennosides) should only ever be used short-term and sparingly. Bowel stimulants such as linaclotide or prucalopride were found to be effective in a small cohort of patients with parkinsonism but should be reserved for those with refractory constipation as their long-term safety requires further evaluation.[10]

Urinary symptoms affect more than half of people with PSP and generally require input from a urologist.[10]

  • Behavioral advice on avoiding caffeine and alcohol is the first-line treatment for overactive bladder. If nocturia is a problem, daytime use of compression stockings and elevation of the lower limbs in the late afternoon can be advised. Bladder training and pelvic floor exercises with biofeedback may improve symptoms but are often difficult for patients with PSP to perform.[10]

  • An alpha-blocker (e.g., terazosin, doxazosin, tamsulosin) is the first-line pharmacologic option for bladder outlet obstruction.[10]

  • A 5-alpha reductase inhibitor (e.g., finasteride, dutasteride) may improve urinary dysfunction in men with PSP.[10]

  • A beta-3 adrenergic agonist (e.g., mirabegron) can be helpful for overactive bladder.[10]

  • Avoid the use of nonselective antimuscarinic agents (e.g., oxybutynin, tolterodine, fesoterodine) due to their central anticholinergic adverse effects.[10]

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