Clinical Vignette

A 71-year-old woman presented with poor balance starting 2 years ago. She would describe multiple episodes where she would suddenly fall backwards. She also recently noted visual blurring especially when she would be reading or going down the stairs. Frequently, she noted her eyes would be closed and she had difficulties opening them. Occasionally while drinking, she would spontaneously cough or choke; her speech became softer and slurred.

Neurologic examination demonstrated her to have a blank staring appearance, and dysarthric speech. She also demonstrated a vertical more than horizontal supranuclear gaze palsy; however, her vertical eye movements were preserved with oculocephalic reflex maneuvers. Blepharospasm, prominent axial rigidity, and mild bradykinesia in all four extremities with minimal cogwheel rigidity and brisk muscle stretch reflexes were also identified. She was able to stand up slowly and walked with erect posture, stiff gait, and bilateral decreased arm swing. She had no postural reflexes and during pull test, she fell backwards easily.

PSP is a sporadic tauopathy that has a progressive clinical course characterized by parkinsonism with supranuclear gaze palsy (Fig. 34-1), early postural instability, falls, bradykinesia, and dysarthria as well illustrated in this vignette. PSP typically does not respond to dopaminergic therapy. Its prognosis is poor, with a median survival of 5–7 years. PSP’s etiology, like that of CBD, is unknown. A genetic susceptibility may be invoked; however, to date, only the H1 MAPT haplotype has been consistently associated with a risk of developing progressive supranuclear palsy

Figure 34-1 Progressive Supranuclear Palsy.

Pathophysiology

PSP is primarily a subcortical neurodegenerative tauopathy in contrast to both CBD and FTPD-17 having involvement of the cerebral cortex. Macroscopically, depigmentation is observable within the substantia nigra (SN) and locus coeruleus (LC), as well as atrophy of the pons, midbrain, and globus pallidum (Fig. 34-2). Microscopically, the most affected regions are brainstem nuclei III, IV, IX, and X, the red nucleus, LC, SN, globus pallidus, and cerebellar dentate nucleus. Tau protein accumulates within neurons as neurofibrillary tangle (NFT) and in glia as spherical neuropil threads.

Figure 34-2 Pathology of Progressive Supranuclear Palsy.

Clinical Presentation

PSP typically occurs between the sixth and seventh decades. Onset before age 40 years is rare. Prevalence varies between 1 and 6.4/100,000. PSP is sporadic in most individuals, but rarely an autosomal dominant inheritance is suggested.

Patients usually present with gait instability and tendency to unexpectedly fall backwards; in contrast, neither of these symptoms occurs early on in Parkinson disease. The parkinsonism of PSP is typically axial and symmetric, unlike the asymmetric often single limb presentation of PD. Most patients with PSP carry an erect posture in contrast to the flexed PD stance (see Fig. 34-1). Often they lack the typical PD tremor. Dystonia is a common finding particularly early on affecting limbs, neck dystonia, or even as blepharospasm.

The hallmark of PSP is the classic and characteristic finding of limited vertical eye movements; eventually a horizontal supranuclear gaze palsy may also become evident. In this clinical setting, the patient usually does not recognize the loss of eye movement per se but rather perceives these limitations as blurry vision particularly manifested by difficulties with routine activities such as reading or walking down the stairs. Dysarthria and dysphagia are also commonly experienced early in the disease course. Cognitive dysfunction is a later development for most PSP patients.

Diagnosis

PSP and other atypical parkinsonian syndromes including CBD, MSA, and dementia with Lewy bodies are often misdiagnosed as PD or as cerebrovascular disease (atherosclerotic parkinsonism). The most important diagnostic clues are (1) the results of a careful clinical evaluation and (2) a poor response to dopaminergic therapy.

Computed tomography (CT) and magnetic resonance imaging (MRI) (Fig. 34-3) often demonstrate generalized or brainstem (dorsal midbrain) atrophy. The combination of atrophy of the midbrain tegmentum with relative sparing of the basis pontis resembles “a lateral view of a standing penguin (especially, the king penguin), with a small head and big body” on a midsagittal MRI scan. Previously, appearance of the midbrain tegmentum was stated to resemble the head of a hummingbird. Whether the penguin or hummingbird sign will take flight remains to be seen, but the implication of both studies is the same: the midbrain in PSP is atrophic and MRI can be helpful to verify the clinical diagnosis.

Figure 34-3 Magnetic Resonance Imaging in Progressive Supranuclear Palsy.

There are no more specific diagnostic studies available. Metabolic positron emission tomographic (PET) studies have demonstrated global reduction in cerebral metabolism; ¹⁸F-fluorodopa PET uptake studies revealed reduced caudate and putamen uptake. Single photon emission computed tomography (SPECT) revealed bifrontal hypometabolism.

Treatment

There are no effective specific therapies available for the PSP patient. Although some of these individuals with slowness, stiffness, and balance problems initially may respond to antiparkinsonian therapies such as levodopa, or levodopa combined with anticholinergic agents, this effect is usually limited and at best a temporary one. Visual limitations, dysarthria, and dysphagia are usually unresponsive to any pharmacologic intervention.

Antidepressant drugs have had modest success in PSP; fluoxetine, amitriptyline, and imipramine are the most commonly used, although their benefit seems to be unrelated to their ability to relieve depression. Botulinum toxin injections are used when blepharospasm is an issue. Physical and occupational therapy are the most important patient management aspects.