US Pharm. 2009;34(11):20-22. 

Progressive supranuclear palsy (PSP) is an uncommon neurodegenerative disorder often misdiagnosed, most frequently as Parkinson's disease (PD).1,2 Although PSP is less common than PD, both are characterized by progressive loss of selected neurons in certain areas of the brain, which causes disease.3,4 Approximately 4% of patients experiencing parkinsonian symptoms have PSP.2 Few clinicians are proficient at recognizing the nonclassic presentations of PSP and also at treating it.5 Pharmacists should be aware of this distinct condition with an unknown cause, also known as Steele-Richardson-Olszewski syndrome. Although PSP usually strikes individuals after age 50 years, some patients can develop signs in their fourth decade.1,2 

Disability develops in PSP patients within 3 to 5 years of diagnosis; death usually occurs within 10 years of symptom onset, often secondary to infection (e.g., pneumonia) or other complications of immobility.2,6,7 Advance directives, such as a living will or durable power of attorney (see Reference 8), should be prepared by patients diagnosed with PSP so that they have the opportunity to indicate the type of medical treatment they wish to receive as part of their end-of-life care plan.6,8   

Pathophysiology and Diagnosis

While PD is slowly progressive and primarily involves the substantia nigra, patients with PSP show a degeneration of neurons that occurs in the basal ganglia--the part of the brain that helps coordinate and ensure smooth body movements--and in the brain stem, the part of the brain that controls vital body functions (e.g., breathing, heart rate, swallowing) and eye movements.1,6 In addition, neurofibrillary tangles are detected (containing abnormal tau protein), and strokes (lacunar) may occur in the basal ganglia and deep white matter.1

According to Schneider and Mandelkow, neurofibrillary tangles are a hallmark of Alzheimer's and other neurodegenerative diseases (e.g., PSP, Pick's disease, frontotemporal dementia, and parkinsonism linked to chromosome 17) referred to as tauopathies, since neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau.9 While the mechanisms underlying tau-mediated neurotoxicity are not well understood, neurodegeneration and neuronal dysfunction are associated with pathologic hyperphosphorylation and aggregation of tau.9 A shared characteristic of PD and PSP is the presence of Lewy bodies (abnormal intracytoplasmic inclusion deposits), although Lewy bodies are found in a minority of PSP cases.3

Diagnosis of PSP is clinical, by history and physical examination.2 Neuroimaging is not required for diagnosis since findings are not specific.2 

Signs and Symptoms

A core feature of PSP is known as vertical supranuclear gaze palsy, where the voluntary vertical gaze is impaired; this causes difficulty looking up or down without extending or flexing the neck, or difficulty climbing up and down stairs, and may be the first noticeable symptom of the disease.1,2 Shortly after onset of the disorder, patients present with postural instability, causing gait unsteadiness and falls (typically backward).2,3 A staring, astonished appearance may be caused by retraction of the upper eyelids.2 Other findings (TABLE 1) may include dysphagia and dysarthria with emotional lability (pseudobulbar palsy). Emotional lability (with a propensity to laugh or cry easily) is referred to as pseudobulbar affect.2 Rigidity, bradykinesia, and dystonic neck extension may be present, and language functions resemble those evident in PD (i.e., speech may become incomprehensible, repetitive/babbling, or mute).1-3,7 While only occasional, a subtle resting tremor may be present.2


Deficits, similar to those secondary to multiple strokes, occur in a progressive and usually rapid fashion.2 In terms of the patient's cognition, mental slowing, executive dysfunction (i.e., impairment of volitional activities such as planning, organizing, self-awareness, self-regulation, and initiation of action), and memory impairment (less severe than in Alzheimer's disease) occur.1,3,6 Later in the disease, depression and dementia are common, causing some individuals to experience sleep disturbances, agitation, and irritability.2,3 Eventually, most PSP patients require a wheelchair and a feeding tube.7

Upon initially seeing a patient with symptoms of PSP, pharmacists may recognize symptoms that resemble drug-induced pseudoparkinsonism, most commonly seen with the use of first-generation antipsychotic agents of the phenothiazine (e.g., chlorpromazine), thioxanthene (e.g., thiothixene), or butyrophenone (e.g., haloperidol) classes. Based on the parkinsonian signs and symptoms and considering that the core symptom of vertical supranuclear gaze palsy is not always present in the early stage of PSP, it is not difficult to understand how this disease may be misdiagnosed as PD, especially since diagnosis is determined clinically and not by any substantiating diagnostic test. 

Schmidt et al note the most important features that characterize and differentiate PSP from other parkinsonian syndromes as the following: 1) supranuclear gaze palsy; 2) postural instability; 3) pseudobulbar palsy; and 4) cognitive disturbances.10 Litvan et al indicate that which specifically differentiates PSP from other diseases: 1) PSP from PD is unstable gait, absence of tremor-dominant disease, and absence of a response to levodopa; 2) PSP from diffuse Lewy body disease is supranuclear vertical gaze palsy, gait instability, and the absence of delusions; 3) PSP from Pick's disease is postural instability; 4) PSP from multiple system atrophy is supranuclear vertical gaze palsy and increased age at symptom onset; and 5) PSP from corticobasal degeneration is gait abnormality, severe upward gaze palsy, bilateral bradykinesia, and absence of alien limb syndrome.11

Significant autonomic dysfunction may be seen in patients with PSP as well as in patients with PD.10 According to Schmidt et al, the parasympathetic cardiovascular system appears to be involved to a similar extent in patients with PD and patients with PSP, as compared to sympathetic cardiovascular dysfunction, which is more frequent and severe in patients with PD but can also be seen in patients with PSP.10 

Treatment

PSP is an incurable condition. Treatment is supportive and far less effective than that for Parkinson's disease.2 The treatment of PSP remains unsatisfactory, since only occasionally do levodopa, dopamine agonists (TABLE 2), amantadine, or amitriptyline partially relieve rigidity.1,2 It is presumed that the reason PSP is not responsive to dopamine replacement or dopamine agonist therapies is that dopamine receptors are decreased as a result of postsynaptic damage beyond pathological changes seen in PD.12 Symptomatic treatment with drugs and other therapies should be targeted at reducing morbidity and improving quality of life (e.g., depression can be treated with selective serotonin reuptake inhibitors).5,7  Pharmacists should note that prior to initiating any treatment, the overall benefit-to-risk ratio to the individual patient must be considered.

Due to adverse effects associated with dopamine agonists--including nausea, hypotension, confusion, and hallucinations--their utility is severely limited.4 A recently published reassessment of risks and benefits of dopamine agonists in PD has revealed the occurrence of increasingly recognized adverse effects such as lower extremity edema, daytime somnolence, impulse control disorders, and fibrosis.13

The antiviral agent amantadine was accidentally discovered to have an antiparkinsonism action (e.g., increasing release of dopamine among other effects).4 Adverse effects associated with amantadine therapy include restlessness, agitation, confusion, and hallucinations; high doses may result in an acute toxic psychosis.4 Peripheral edema, orthostatic hypotension, urinary retention, dry mouth, and livedo reticularis (i.e., red to blue skin discoloration on the limbs and trunk that intensifies upon exposure to cold) may also occur.1,4

The geriatric patient population may be more susceptible to the central nervous system effects of amantadine; the use of two divided daily doses may minimize this effect.14 In patients with renal impairment, amantadine requires renal dosing based on estimated creatinine clearance. Monitoring parameters for amantadine therapy include renal function, Parkinson's symptoms, mental status, and blood pressure.14

Nonpharmacologic measures introduced early in the course of disease may include weighted walking aids or wheelchairs to prevent falls, and adaptive eyeglasses (e.g., bifocals, prisms) to improve vision.2 Also important in the early stage of the illness is the introduction of physical therapy, occupational therapy, and speech therapy as supportive measures.2 Thus far, surgical approaches to PSP have proven ineffective.5

A randomized, placebo-controlled trial in Germany looked at the short-term effects of coenzyme Q10 in PSP.15 Results indicated significant changes in the occipital lobe and a consistent trend in the basal ganglia.15 Coenzyme Q 10 treatment compared to placebo showed clinical improvement according to the PSP rating scale and the Frontal Assessment Battery; although the improvement was slight, it was noted as significant.15 The researchers concluded that since coenzyme Q 10 appears to improve cerebral energy metabolism in PSP, long-term treatment might have a disease-modifying, neuroprotective effect.15 

Conclusion

In PSP, neurodegenerative changes take place in the brain stem, basal ganglia, and elsewhere; neurofibrillary tangles are present. While PSP continues to be an underrecognized disorder and is often misdiagnosed, it can be differentiated from other akinetic rigid syndromes such as PD.5 Diagnosis of this debilitating disorder is clinical and treatment is supportive. Risks associated with potential adverse effects of treatment should be considered in the formulation of an individualized pharmaceutical care plan. Early discussion about end-of-life issues is advised. 

REFERENCES

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3. Craft S, Cholerton B, Reger M. Aging and cognition: what is normal? In: Hazzard WR, Blass JP, Halter JB, et al, eds. Principles of Geriatric Medicine and Gerontology. 5th ed. New York, NY: McGraw-Hill, Inc; 2003:1355-1372.
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6. Beers MH, Jones TV, Berkwits M, et al, eds. The Merck Manual of Health & Aging. Whitehouse Station, NJ: Merck Research Laboratories; 2004:367-369.
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9. Schneider A, Mandelkow E. Tau-based treatment strategies in neurodegenerative diseases. Neurotherapeutics. 2008;5(3):443-457.
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12. Nelson MV, Berchou RC, LeWitt PA. Parkinson's disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York, NY: McGraw-Hill, Inc; 2005:1075-1088.
13. Antonini A, Tolosa E, Mizuno Y, et al. A reassment of risks and benefits of dopamine agonists in Parkinson's disease. Lancet Neurol. 2009;8:929-937.
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