Version May 2024
INTRODUCTION — Progressive supranuclear palsy (PSP) is an atypical parkinsonian disorder characterized by 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 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 [2,3], 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 [4]. 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 [5]. 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. Although supporting evidence for physical therapy and exercise is robust in patients with Parkinson disease, direct evidence in patients with PSP is more limited [6-8]. An uncontrolled pilot study in 20 patients with PSP showed promising results from a customized exercise program including resistance training, balance training, and walking exercises, with measurable improvement in both the pull test and the Berg Balance Scale [7]. (See "Nonpharmacologic management of Parkinson disease", section on 'Exercise and physical therapy'.)
Walking aides, such as weighted walkers and low-heel nonstick shoes, are recommended [9,10]. The combination of frontal lobe disturbance and postural instability poses significant challenges in patients with PSP and contributes to even higher risks of falling. Fear of falls also correlates with increased anxiety and depression [11]. 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 [12], 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. Palliative care in patients with parkinsonian disorders is reviewed in detail separately. (See "Palliative approach to Parkinson disease and parkinsonian disorders".)
Support groups — Caregivers experience significant burdens over the course of the disease [13]. 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 [14]. 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 [15]. 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. Rare patients who respond to levodopa but do not tolerate higher oral doses may derive benefit from continuous intestinal gel delivery [16]. (See "Device-assisted and lesioning procedures for Parkinson disease", section on 'Continuous levodopa-carbidopa intestinal gel infusion'.)
A common side effect of levodopa in patients with PSP is visual hallucinations, although there have also been reports of dyskinesia [14,17], oromandibular dystonia [18], and apraxia of eyelid opening [19]. 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 [1,12,20].
●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 [1,21-23].
●Zolpidem administration was associated with improved motor function in 2 of 10 patients compared with placebo or levodopa [24].
●Amitriptyline has been assessed in a few patients with variable results for improvement of motor function [23,25,26].
●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 [27]. The results of one small trial suggested that donepezil may worsen motor function [28].
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 [29,30]. Early anecdotal reports suggested negative results in patients with PSP who had neurosurgical treatments including pallidotomy and subthalamic or pallidal deep brain stimulation (DBS) [31,32]. In a case report, DBS of the pedunculopontine nucleus was associated with modest benefit in a patient with PSP-P [33]. 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 [34].
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 [35]. 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 [36].
Investigational therapies — Research into potential disease-modifying therapies for PSP has focused on agents with tau-active properties [37,38]. 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 [39]. Another approach involves the neuroprotective agent davunetide, which is thought to maintain microtubule function, reduce tau phosphorylation, and inhibit apoptosis [40]. Unfortunately, randomized placebo-controlled trials of tideglusib [41] or davunetide [42] for patients with PSP found no benefit.
Treatments targeting tau aggregation, tau phosphorylation, and microtubule stabilization are also under investigation in PSP [43]. 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 [44]. 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 [45]. Other trials are ongoing [45,46].
There is some evidence that mitochondrial dysfunction may play a role in the pathophysiology of PSP [47]. 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 [48]. 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 [49].
PROGNOSIS — Disease progression in PSP usually occurs fairly rapidly and relentlessly [50]. 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 [51-56]. In addition, quality of life is significantly reduced [57].
In a 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) [58-60]. 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. Emerging technology, including wearable sensors to provide objective, sensitive quantitative evaluation of gait changes in PSP, may be a complementary tool to predict disease severity and progression [61]. (See "Progressive supranuclear palsy (PSP): Clinical features and diagnosis", section on 'Variant phenotypes'.)
SUMMARY AND RECOMMENDATIONS
●Disease-modifying therapy – No disease-modifying therapies have yet been identified for progressive supranuclear palsy (PSP). A variety of therapies are under investigation, but results thus far have been disappointing. (See 'Investigational therapies' above.)
●Symptomatic pharmacotherapy – Unlike in idiopathic Parkinson disease, levodopa and other dopaminergic therapies are not usually effective for motor parkinsonism in patients with PSP. Nonetheless, a trial of levodopa is reasonable in patients with predominant parkinsonism, as some patients can derive benefit, particularly at first. Ineffective therapies should not be continued long-term. (See 'Pharmacologic treatments' above.)
●Nonpharmacologic interventions – Multidisciplinary interventions for PSP include 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 early in the disease course. (See 'Multidisciplinary interventions' above.)
●Caregiver support – Expert nursing support and patient advocacy groups are invaluable for providing helpful information to families and caregivers. (See 'Support groups' above.)
●Prognosis – 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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