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Progressive supranuclear palsy (PSP): Management and prognosis

Progressive supranuclear palsy (PSP): Management and prognosis
Authors:
Stewart A Factor, DO
Christine Doss Esper, MD
Section Editor:
Howard I Hurtig, MD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Feb 2022. | This topic last updated: Jun 07, 2021.

INTRODUCTION — Progressive supranuclear palsy (PSP) is an uncommon but not rare parkinsonian syndrome. Characteristic features of PSP include vertical supranuclear gaze palsy and postural instability with unexplained falls. This topic will review the management and prognosis of PSP. Other aspects of PSP are reviewed elsewhere. (See "Multiple system atrophy: Clinical features and diagnosis".)

Other neurodegenerative parkinsonian syndromes are discussed separately. (See "Clinical manifestations of Parkinson disease" and "Corticobasal degeneration" and "Multiple system atrophy: Clinical features and diagnosis" and "Diagnosis and differential diagnosis of Parkinson disease", section on 'Differential diagnosis'.)

MANAGEMENT — There are no treatments that alter the natural history of disease in PSP and no drugs that provide significant symptomatic benefits as seen with levodopa in idiopathic Parkinson disease. However, several nonpharmacologic and pharmacologic supportive measures are available for the treatment of PSP.

Multidisciplinary interventions — A multidisciplinary approach is essential, involving health care professionals from neurology, physical therapy, occupational therapy, speech pathology, nutrition, neuropsychology, psychiatry, social work, and palliative care [1].

Dietitians as well as speech and language therapists can help to manage dysphagia and dysarthria. Specific modalities for dysarthria include facial exercises, Lee Silverman Voice Treatment [2], written communication, and a talking keyboard. Some experts advise routine swallowing evaluations (eg, every six months) to assess the risk for dysphagia and aspiration, which are major causes of mortality in patients with PSP [1]. Treatments for dysphagia include head posturing, dietary changes, and percutaneous gastrostomy tube placement in more advanced cases. However, a gastrostomy tube does not diminish the risk of aspiration.

Early occupational therapy is essential in promoting longer independence in performing activities of daily living. Mirror-prism lenses can allow patients with severe limitation of extraocular movements to read and feed themselves [3]. Eyelid crutches, alone or in combination with botulinum toxin therapy, may be useful for eyelid opening apraxia and blepharospasm, which can be severe enough to render a patient with PSP functionally blind [4]. Decreased blink rate can be effectively treated with artificial tears, in addition to dark glasses to reduce photophobia.

Physical therapy and aerobic exercise may provide symptomatic treatment for postural instability and falls, such as gait and balance training. However, a systematic review that included three randomized, controlled trials demonstrated at best modest benefit [5]. This differs from Parkinson disease.

Walking aides, such as weighted walkers and low-heel nonstick shoes, are recommended [6,7]. The combination of frontal-lobe disturbance and postural instability results in significant difficulty in the management of patients with PSP, exposing them to even higher risks of falling. Freezing of gait can be improved by the use of walkers with lasers, visual cues, rhythmic cues, and arc turns.

Palliative care needs may be present from the time of diagnosis. Advance care planning should be addressed as soon as possible [8], ideally while the patients retain decision-making capacity, to express their wishes on the goals of care, future treatments such as artificial feeding, intensive care unit interventions, resuscitation status, the place of care, the place of death (eg, home, hospice, or hospital), making a will, and funeral plans. (See "Palliative approach to Parkinson disease and parkinsonian disorders" and "Physician-assisted dying".)

Support groups — Expert nursing support and lay associations are invaluable for providing helpful information to families and caregivers. Local, regional, and national associations can play an integral role to benefit the lives of patients, families, and caregivers. These groups include the following:

CurePSP – North America

The PSP Association – United Kingdom

Pharmacologic treatments — Neurotransmitter replacement strategies have not had a major therapeutic impact in PSP.

The main role of levodopa in patients with suspected PSP is diagnostic; a poor or unsustained response to levodopa therapy is generally observed in patients with PSP and can help to distinguish PSP from idiopathic Parkinson disease. (See "Progressive supranuclear palsy (PSP): Clinical features and diagnosis", section on 'Supportive features'.)

However, levodopa therapy may provide some degree of transient benefit, as suggested by several small retrospective reports. One study found that 4 of 12 patients with postmortem-confirmed PSP showed a "modest improvement" while receiving levodopa with a peripheral decarboxylase inhibitor [9]. The improvement was not sustained and resulted in adverse effects in more than half of the patients. In a later report of 15 cases of autopsy-confirmed PSP, 9 showed some benefit to levodopa used in combination with other drugs, and 5 had some improvement on levodopa alone [10]. However, the benefit was generally minimal and was observed only in the early stages of the disease.

Therefore, a trial of levodopa is suggested for symptomatic treatment of patients with PSP who have disabling or troublesome parkinsonism to determine responsiveness. Although regimens vary, many experts suggest treating with levodopa 1000 to 1200 mg per day (up to 300 mg per dose) if tolerated for at least one month [1]. The variant PSP with predominant parkinsonism (PSP-P) is often initially responsive, whereas the classic PSP with Richardson syndrome (PSP-RS) is generally not responsive to levodopa.

A common side effect of levodopa in patients with PSP is visual hallucinations, although there have also been reports of dyskinesia [9,11], oromandibular dystonia [12], and apraxia of eyelid opening [13]. Speech dysfunction potentially related to dystonia in a patient taking levodopa should be considered a possible side effect of the drug; a cautious trial of lowering the dose or discontinuing the drug may improve the speech difficulties.

There are only limited data for a variety of other drugs that have been used for symptomatic treatment of PSP [1,8,14].

Botulinum toxin injections can effectively treat various forms of focal dystonia and drooling.

Amantadine can provide a transient therapeutic benefit for gait, including freezing, and dysphagia in a minority of cases and can also help drooling and dyskinesia [1,15-17].

Zolpidem administration was associated with improved motor function in 2 of 10 patients compared with placebo or levodopa [18].

Amitriptyline has been assessed in a few patients with variable results for improvement of motor function [17,19,20].

Cholinesterase inhibitors have been used to treat rare types of dementia but there are inadequate data to determine if they have any benefit in PSP [21]. The results of one small trial suggested that donepezil may worsen motor function [22].

Other interventions — Electroconvulsive therapy, while helpful in some patients with idiopathic Parkinson disease, has been used in a small number of patients with PSP with mixed results [23,24]. Early anecdotal reports suggested negative results in patients with PSP who had neurosurgical treatments including pallidotomy and subthalamic or pallidal deep brain stimulation (DBS) [25,26]. In a case report, DBS of the pedunculopontine nucleus was associated with modest benefit in a patient with PSP-P [27]. However, there was no benefit of DBS in a subsequent trial of eight patients with PSP-RS who received unilateral pedunculopontine nucleus DBS and were randomly assigned to blinded evaluation in both the off-stimulation and on-stimulation states at 6 and 12 months [28].

There has been interest in spinal cord stimulation (SCS) for gait disorders in Parkinson disease and related disorders. One small study examined this treatment modality in three patients with PSP-RS [29]. Improvements in freezing-of-gait frequency, turning duration, step length, and stride velocity were observed, and ambulatory gait parameters improved by approximately 30 percent. Further studies are needed to confirm these findings.

Investigational therapies — Research into potential disease-modifying therapies for PSP has focused on agents with tau-active properties [30]. One approach involves agents such as tideglusib, which inhibits a key enzyme (glycogen synthase kinase 3 beta) that plays a role in the hyperphosphorylation of tau [31]. Another approach involves the neuroprotective agent davunetide, which is thought to maintain microtubule function, reduce tau phosphorylation, and inhibit apoptosis [32]. Unfortunately, randomized placebo-controlled trials of tideglusib [33] or davunetide [34] for patients with PSP found no benefit.

Treatments targeting tau aggregation, tau phosphorylation, and microtubule stabilization are also under investigation in PSP [35]. The anti-tau monoclonal antibody tilavonemab (ABBV-8E12), which targets extracellular tau fragments, was safe and well tolerated in a multicenter trial of 378 patients but did not alter disease course compared with placebo and was terminated when prespecified futility criteria were met [36]. A similar fate was found with BIIB092, which did not show efficacy on the primary endpoint (change in PSP-RS at one year) or secondary endpoints in a phase II randomized controlled trial [37]. Other trials are ongoing [37,38].

There is some evidence that mitochondrial dysfunction may play a role in the pathophysiology of PSP [39]. In a preliminary six-week placebo-controlled trial of 21 patients with PSP, coenzyme Q10 improved brain energy metabolism via magnetic resonance spectroscopy and improved the PSP rating scale and the Frontal Assessment Battery [40]. However, a subsequent one-year placebo-controlled trial of 61 subjects with PSP failed to demonstrate any disease-modifying effect of high-dose coenzyme Q10 [41].

PROGNOSIS — Disease progression in PSP usually occurs fairly rapidly and relentlessly [42]. Most patients become dependent for care within three or four years from presentation. The disorder culminates in death at a median of six to nine years after the diagnosis [43-48]. In addition, quality of life is significantly reduced [49].

In a 2017 systematic review and meta-analysis, predictors of shorter survival included the PSP with Richardson syndrome (PSP-RS) phenotype compared with the PSP with parkinsonism (PSP-P) phenotype, early falls, and early cognitive symptoms (both more common in the PSP-RS phenotype) [50]. Early onset of dysphagia, which is seen in both the PSP-RS and PSP-P phenotypes, was also predictive of shorter survival. The prognostic effect of the presence of a supranuclear gaze palsy was inconsistent across studies. Levodopa response, as often seen in the early stages of the PSP-P phenotype, did not predict longer survival. (See "Progressive supranuclear palsy (PSP): Clinical features and diagnosis", section on 'Variant phenotypes'.)

SUMMARY AND RECOMMENDATIONS

There are no treatments that alter the natural history of disease in progressive supranuclear palsy (PSP) and no drugs that provide significant symptomatic benefits as seen with levodopa in idiopathic Parkinson disease. However, several nonpharmacologic and pharmacologic supportive measures are available for the treatment of PSP. A multidisciplinary approach is essential. (See 'Management' above.)

Multidisciplinary interventions for PSP included speech and language therapy for managing dysphagia and dysarthria, and occupational and physical therapy for managing activities of daily living, postural instability, and falls. Advance care planning should be addressed as soon as possible. (See 'Multidisciplinary interventions' above.)

Disease progression in PSP usually occurs fairly rapidly and relentlessly compared with Parkinson disease. Most patients become dependent for care within three or four years from presentation. The disorder culminates in death at a median of six to nine years after the diagnosis. (See 'Prognosis' above.)

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Topic 113998 Version 5.0

References

1 : Diagnostic Approach to Atypical Parkinsonian Syndromes.

2 : Effects of Lee Silverman Voice Treatment (LSVT LOUD) on Swallowing in Patients with Progressive Supranuclear Palsy: A Pilot Study.

3 : Toward future therapies in progressive supranuclear palsy.

4 : "Apraxia of lid opening," a focal eyelid dystonia: clinical study of 32 patients.

5 : Exercise and physical activity for people with Progressive Supranuclear Palsy: a systematic review.

6 : Progressive supranuclear palsy: clinical presentation and rehabilitation of two patients.

7 : Rehabilitation in progressive supranuclear palsy: Effectiveness of two multidisciplinary treatments.

8 : Progressive Supranuclear Palsy and Corticobasal Degeneration: Pathophysiology and Treatment Options.

9 : Pharmacological therapy in progressive supranuclear palsy.

10 : Progressive supranuclear palsy diagnosis and confounding features: report on 16 autopsied cases.

11 : Progressive supranuclear palsy: clinical features, pathophysiology and management.

12 : Levodopa-induced oromandibular dystonia in progressive supranuclear palsy.

13 : "Apraxia of eyelid opening" induced by levodopa therapy and apomorphine in atypical parkinsonism (possible progressive supranuclear palsy): a case report.

14 : Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches.

15 : Amantadine effectiveness in multiple system atrophy and progressive supranuclear palsy.

16 : Progressive supranuclear palsy: clinical features and response to treatment in 16 patients.

17 : Retrospective study of drug response in 87 patients with progressive supranuclear palsy.

18 : Zolpidem in progressive supranuclear palsy.

19 : Treatment of progressive supranuclear palsy with amitriptyline: therapeutic and toxic effects.

20 : Treatment of progressive supranuclear palsy with tricyclic antidepressants.

21 : Cholinesterase inhibitors for rarer dementias associated with neurological conditions.

22 : Randomized placebo-controlled trial of donepezil in patients with progressive supranuclear palsy.

23 : Limited usefulness of electroconvulsive therapy in progressive supranuclear palsy.

24 : Initial experience with electroconvulsive therapy for progressive supranuclear palsy.

25 : Management of referred deep brain stimulation failures: a retrospective analysis from 2 movement disorders centers.

26 : Treatment of progressive supranuclear palsy and corticobasal degeneration.

27 : Implantation of the nucleus tegmenti pedunculopontini in a PSP-P patient: safe procedure, modest benefits.

28 : Peduncolopontine nucleus stimulation in progressive supranuclear palsy: a randomised trial.

29 : Spinal cord stimulation therapy for gait dysfunction in progressive supranuclear palsy patients.

30 : Progressive supranuclear palsy.

31 : Evidence for irreversible inhibition of glycogen synthase kinase-3βby tideglusib.

32 : Critical appraisal of the role of davunetide in the treatment of progressive supranuclear palsy.

33 : A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy.

34 : Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial.

35 : Therapeutic advances in multiple system atrophy and progressive supranuclear palsy.

36 : Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled trial.

37 : Immunotherapy in progressive supranuclear palsy.

38 : Progressive Supranuclear Palsy: an Update.

39 : Mitochondrial dysfunction as a therapeutic target in progressive supranuclear palsy.

40 : Short-term effects of coenzyme Q10 in progressive supranuclear palsy: a randomized, placebo-controlled trial.

41 : CoQ10 in progressive supranuclear palsy: A randomized, placebo-controlled, double-blind trial.

42 : Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges.

43 : Comparison of natural histories of progressive supranuclear palsy and multiple system atrophy.

44 : A clinical rating scale for progressive supranuclear palsy.

45 : Clinical outcomes of progressive supranuclear palsy and multiple system atrophy.

46 : Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes.

47 : The phenotypic spectrum of progressive supranuclear palsy: a retrospective multicenter study of 100 definite cases.

48 : Predictors of survival in a series of clinically diagnosed progressive supranuclear palsy patients.

49 : Health-related quality of life in multiple system atrophy and progressive supranuclear palsy.

50 : Predictors of survival in progressive supranuclear palsy and multiple system atrophy: a systematic review and meta-analysis.