Historical note and nomenclature
In 1877, Dr. Charcot described a 40-year-old woman who had rigid-akinetic parkinsonism, neck dystonia, dysarthria, and ophthalmoparesis. His term for her condition was “paralysis agitans sine agitione” (Charcot 1877). Chavany and others reported the clinical and pathologic features of a 50-year-old man with rigid-akinetic parkinsonism, postural instability, neck dystonia, dysarthria, and a staring gaze (Chavany et al 1951). Their diagnosis was “postencephalitis without encephalitis.” Richardson and Steele recognized the same clinical syndrome in 8 patients and described the autopsy findings in 6 of them with Dr. Olszewski (Richardson et al 1963). Progressive supranuclear palsy is not a “new” disease, since 22 well documented case reports were identified in the neurologic literature between 1877 and 1963 (Brusa et al 2004). The disorder is now commonly recognized, comprising 4% to 5% of cases of parkinsonism evaluated at movement disorder centers (Golbe et al 1988). The unique frontal lobe cognitive changes of progressive supranuclear palsy (slowing of thought processes and loss of executive function) were first described by Albert and colleagues (Albert et al 1974). Several PET studies have since shown decreased metabolic activity in the frontal lobes, giving support to the frontal lobe hypothesis for cognitive change in this disease (Foster et al 1988; Blin et al 1990).
Clinical manifestations
The principle clinical manifestations of progressive supranuclear palsy are unsteady gait, postural instability with falls, vertical gaze palsy, parkinsonism (bradykinesia and rigidity), dysarthria, cognitive slowing, and executive dysfunction (Litvan et al 1996a; Cordato et al 2006). Onset of symptoms is insidious, and progression is usually gradual. Recent reports have shown that age of onset is now in the late 60s (Baba et al 2006; Josephs et al 2006), whereas most patients reported before 1963 experienced onset in the 40s or 50s (Brusa et al 2004). Research criteria for probable progressive supranuclear palsy require that onset is at least 40 years of age, that progression is gradual, and that vertical gaze palsy is present, along with postural instability and falls (Litvan et al 1996a).
Cognitive changes. About 52% of progressive supranuclear palsy patients experience cognitive symptoms characteristic of frontal lobe disease within the first year (Brusa et al 1980). By 3 years, about 60% meet research criteria for dementia (Pillon et al 1991). Symptoms of dysfunction of the dorsolateral prefrontal circuits appear early, including lack of initiative, decreased verbal fluency, increased central processing time, and loss of mental flexibility (Pillon et al 1991; Donnelly et al 1997). Both short- and long-term memory are affected to a lesser degree (Aarsland et al 2003). The dissociation between normal memory storage and impaired memory retrieval in progressive supranuclear palsy suggests that memory problems are due to dysfunction in the frontostriatal system, rather than the hippocampal system (Pillon et al 1994). As the disease progresses, cognitive changes progressively worsen (Soliveri et al 2000), but the psychobehavioral profile remains unique to this disease. Generally speaking, the executive dysfunction of supranuclear palsy patients is much more severe than that observed in other subcortical movement disorders, such as Parkinson disease, dementia with Lewy bodies, or multiple system atrophy.
Cognitive slowing. Cognitive slowing appears early in patients with progressive supranuclear palsy; patients answer questions and solve the simplest problems only after long delays. Central processing is slower in supranuclear palsy than in Parkinson disease patients or age-matched controls (Cordato et al 2006). Besides using simple and choice reaction times, cognitive slowing has been demonstrated in supranuclear palsy patients by using event-related potentials (Johnson 1992).
Memory storage. Impairment of short-term memory in supranuclear palsy can be measured with the Brown-Peterson paradigm, a working memory task in which patients are more sensitive than controls to interference (Litvan et al 1989). Long-term memory is also disturbed, as demonstrated by the delayed recall subtests of the Wechsler Memory Scale, the Rey Auditory Verbal Learning Test, the Selective Reminding Test, and the California Verbal Learning Test (Litvan et al 1989; Pillon et al 1994; Van der Hurk and Hodges 1995; Donnelly et al 1997; Sommer et al 2001). Using the Mattis dementia rating scale, Aarslund and colleagues showed in 2003 that supranuclear palsy patients had better memory function than those with Parkinson disease or dementia with Lewy bodies (the severity of dementia was matched in these three groups). Donnelly and colleagues (Donnelly et al 1997) compared early supranuclear palsy patients with those who had early Parkinson disease using the logical memory test of the Weschler scale, as well as the New Dot test. They found similar memory functions in these 2 groups of patients. These findings were consistent with those of Pillon and colleagues (Pillon et al 1994).
Memory retrieval. Several groups have identified a memory retrieval problem in patients with progressive supranuclear palsy. Donnelly's group was able to document this retrieval problem by using the Selective Reminding Test (Donnelly et al 1997). Pillon and others demonstrated that when memory encoding is controlled by using semantic category cues, memory retrieval is improved (Pillon et al 1994). By using this cuing procedure, recall performance of patients with supranuclear palsy dramatically improves and total recall scores become similar to those of age-matched controls (Pillon et al 1994). In testing Alzheimer patients with this cuing procedure, memory performance is still severely impaired. Their sensitivity to semantic cues (45%) is significantly less than that of supranuclear palsy patients (94%). Thus, there is no genuine amnesia in progressive supranuclear palsy, but rather a difficulty in accessing stored information. The dissociation between normal storage and impaired retrieval has also been reported in Parkinson and Huntington disease (Pillon et al 1994), confirming the contrast between hippocampal storage processes (disrupted in Alzheimer disease) and frontostriatal storage systems (disrupted in supranuclear palsy, Huntington, and Parkinson disease).
Procedural learning. Procedural learning, which is measured with eye blink classical conditioning, is impaired in progressive supranuclear palsy (Sommer et al 2001). In the Serial Reaction Time Task, no significant learning was observed in response to a repeated sequence, in contrast to patients with Alzheimer disease (Grafman et al 1995). It should be noted, however, that patients with progressive supranuclear palsy were able to press the correct key in only 50% of the trials; their impaired performance in the Serial Reaction Time Task might, therefore, result from too great a complexity of this motor task, as well as from impaired procedural learning ability. Skill-learning deficits were found in other tasks, such as the mirror reading procedure, where poor performance cannot be explained by sensorimotor factors alone.
Behavioral changes. Cordato and colleagues documented that frontal lobe behavioral symptoms are more prevalent among supranuclear palsy patients than among age-matched Parkinson patients: verbal apraxia, apathy, loss of spontaneous speech, lack of spontaneity, disorganization, personal neglect, and inflexibility (Cordato et al 2006). Verbal apraxia, the loss of ability to perform normal tongue, lip and palate movements in the absence of weakness, was found in 86% of supranuclear palsy patients. Apathy, which was identified in 92%, is thought to be related to pathologic changes in the cingulate cortex (Hauw et al 1990). In contrast to Parkinson disease, depression occurs infrequently in supranuclear palsy (18%). Nevertheless, pseudobulbar affect, with inappropriate laughing and crying, is not uncommon. Disinhibition, with inappropriate sexual behavior, aggression, or rage, may occur in 33% of those with progressive supranuclear palsy (Litvan et al 1998). Agitation and irritability occur at the same rate as in Parkinson disease (Cordato et al 2006), but they are seen less frequently than in Huntington or Alzheimer disease (Litvan et al 1996b; Lichter 2001).
Instrumental disorders. Word-finding difficulty may be a problem in progressive supranuclear palsy, but it is less severe than that seen in Alzheimer disease (Pillon et al 1991). Syntactic comprehension disorders are mild in supranuclear palsy (Albert et al 1974). These are attributed to problems of visual attention, rather than to a genuine syntactic impairment (Bak and Hodges 1998). Surprisingly, the semantic memory impairment of supranuclear palsy is as severe as that of mild Alzheimer disease, but this probably reflects difficulty with word retrieval, rather than with word storage (Van der Hurk and Hodges 1995). Therefore, instrumental disorders that develop in patients with supranuclear palsy are assumed to be a consequence of impaired attention, executive dysfunction, and memory retrieval, rather than of specific language dysfunction.
Etiology
The etiology of progressive supranuclear palsy is probably at least partially genetically determined, since recent studies have shown a link to the tau gene, microtubule-associated protein tau (MAPT). Tau is a protein involved in axonal transport, and the aggregation of abnormal tau protein in supranuclear palsy results in the development of neurofibrillary tangles (Galpern and Lang 2006). In normal brains, there are equal numbers of the 3- and 4-repeat isoforms of the tau protein. In brains of patients with supranuclear palsy and corticobasal degeneration, there is preferential accumulation of the 4-repeat isoform of tau (Houlden et al 2001). In both of these diseases, there is also overrepresentation of the H1 haplotype of MAPT (Bennett et al 1998; Pittman et al 2005; Caffrey and Wade-Martins 2007).
Pathogenesis and pathophysiology
The most prominent pathologic changes in progressive supranuclear palsy consist of neuronal loss and neurofibrillary tangle formation in the brainstem and basal ganglia (Hauw et al 1990; 1994). These tangles consist of clusters of straight filaments of tau, different from the paired helical filaments of tau seen in the brains of Alzheimer patients.
Before it was learned that tangles accumulated in the frontal cortex of supranuclear palsy patients, Albert and colleagues postulated that frontal lobe cognitive changes might be the result of deafferentation of the cortex due to subcortical cell loss (Albert et al 1974). Indeed, pathologic changes are observed in several subcortical structures in supranuclear palsy: basal forebrain (nucleus basalis of Meynert), basal ganglia (substantia nigra pars compacta, internal pallidum, subthalamic nucleus), brainstem (locus ceruleus, pontomedullary reticular formation, periaqueductal gray, and superior colliculus) and cerebellum (cerebellar dentate nucleus). Neurofibrillary tangles have been observed in the prefrontal cortex (Brodmann area 4) and to a lesser extent in the cingulate cortex (area 23) in patients with progressive supranuclear palsy (Hauw et al 1990; 1994). This frontal distribution of tangles differs from that seen in Alzheimer brains, where parietal association neurons are most prominently involved in tangle formation. These new neuropathological observations are consistent with the "frontal-subcortical dementia” hypothesis, postulating that changes in cognitive and behavioral function are based on both subcortical and cortical pathology.
The pathophysiology of progressive supranuclear palsy involves all 5 of the recognized basal ganglia-thalamocortical circuits (Lichter 2001). A number of neurotransmitters and neuromodulators are involved in the organization and modulation of these circuits (Rampello 2005), including dopamine, norepinephrine, and GABA. Cholinergic dysfunction in supranuclear palsy brains is related to loss of cholinergic interneurons in the striatum, as well as loss of neurons in the nucleus basalis of Meynert (Warren et al 2005).
Epidemiology
The estimated prevalence for progressive supranuclear palsy in the United States and the United Kingdom ranges from 5 to 7 per 100,000 inhabitants, similar to the 10 per 100,000 prevalence for myasthenia gravis (Schrag et al 1999; Nath et al 2001). The annual incidence rate is about 3 to 4 new cases per million per year (Golbe 1994). Mean survival after symptom onset is now 6 to 7 years (Livan et al 1996;(Josephs et al 2006), longer than the 4-year mean survival recorded in earlier studies (Brusa et al 2004). The male:female ratio in 1 series was 1.7:1 (Litvan et al 1996a) and 1.6:1 in another (Josephs et al 2006).
Differential diagnosis
Parkinson disease, dementia with Lewy bodies, corticobasal degeneration, fronto-temporal dementia, and multiple system atrophy are the conditions most commonly confused with progressive supranuclear palsy (Boeve 2007). Several clinical features are helpful in distinguishing these conditions. For example, patients with supranuclear palsy are more likely to fall within the first year of diagnosis, compared to those with Parkinson disease, dementia with Lewy bodies, or multiple system atrophy (Litvan et al 1996a; Cordato at al 2006; Suchowersky et al 2006). In 1 recent study, rest tremor was seen in only 19% of patients with supranuclear palsy, whereas it was present in 82% of an age-matched group of Parkinson patients (Cordato et al 2006). Gaze palsy was seen in 100% of those with supranuclear palsy and in none of those with Parkinson disease. Hershey and others (unpublished) found that many more supranuclear palsy patients had instability of visual fixation (83%), compared to only 18% of Parkinson patients. Rascol and colleagues had earlier shown similar disease differences in this neuro-ophthalmologic finding (Rascol et al 1991). Other eye movement changes that Hershey's group found in supranuclear palsy patients included jerky pursuit movements (67%) and loss of the Bell phenomenon (67%). By comparison, these eye findings were much less common in patients with Parkinson disease (18% had jerky pursuit, and none showed loss of the Bell phenomenon). Response to a single oral dose of levodopa may also help to distinguish Parkinson disease from supranuclear palsy. According to Suchawersky and colleagues, this test has 77% sensitivity and 71% specificity for Parkinson disease (Suchowersky et al 2006). Patients who have dementia with Lewy bodies are more likely than supranuclear palsy patients to respond to levodopa. They also experience visual hallucinations and cognitive fluctuations. Multiple systems atrophy patients have symptomatic postural hypotension and early urinary urge incontinence (Litvan et al 1996b; Suchowersky et al 2006). None of these symptoms are common in supranuclear palsy.
Diagnostic workup
The following neuropsychological tests may be helpful to define cognitive slowing and executive dysfunction in patients with suspected progressive supranuclear palsy: (1) the Mattis Dementia Rating Scale to evaluate global cognitive abilities; (2) the Wisconsin Card Sorting Test and Trail-making Tests to assess mental flexibility; (3) the Stroop Interference Test for selective attention; (4) Go/no-go and conflicting instructions to assess motor control and inhibition; (5) category and phonemic fluency tests for semantic memory; (6) the Grober and Buschke procedure, to compare free and cued recall; and (7) the Comprehension subtests of the Boston Diagnostic Aphasia Examination and Limb Apraxia Examination, to exclude cortical signs that may be encountered in other neurodegenerative diseases with extrapyramidal features, such as cortical-basal degeneration or diffuse Lewy body disease. Two short bedside batteries of frontal lobe dysfunction have been described: the Frontal Behavioral Inventory (Kertesz et al 1997) and the Frontal Assessment Battery (Dubois et al 2000). Finally, whenever supranuclear palsy is suspected, the “applause sign” should be elicited (Dubois et al 2005).
When asked to imitate the examiner clapping three times in succession, the patient with supranuclear palsy perseverates, clapping more than 3 times. This perseveration of clapping does not occur in patients with Parkinson disease or fronto-temporal dementia.
PET studies have demonstrated that there is lower than normal metabolic activity in the frontal lobes of patients with progressive supranuclear palsy (Foster et al 1988; Blin et al 1990). SPECT studies with HMPAO are less expensive ways to assess regional changes in brain perfusion. Hershey and colleagues examined SPECT in patients who were in the early stages of progressive supranuclear palsy and Parkinson disease (Hershey et al 1994). They used a “double-blind” method (neurologists making the clinical diagnoses were blinded to SPECT results; nuclear medicine specialists were blinded to the clinical data when they interpreted the SPECT studies). Bilateral hypoperfusion was present on SPECT in 50% of patients with early progressive supranuclear palsy. The sensitivity rose to 67% (specificity = 83%) if only demented patients were analyzed. Although SPECT is insensitive as a diagnostic tool, its specificity is sufficiently high to justify its use in cases where the clinical diagnosis is unclear.
Management
Even though central cholinergic neurons are known to die in patients with progressive supranuclear palsy, placebo-controlled trials with cholinesterase inhibitors have shown disappointing results. One small study of physostigmine demonstrated some improvement in long-term memory and visuospatial attention, but no benefit for gaze palsy, parkinsonism, or pseudobulbar symptoms (Litvan et al 1998). Spinal fluid levels of the neuronal enzyme, acetyl-cholinesterase, are reduced by 31% in progressive supranuclear palsy patients (Blin et al 1995), consistent with known losses of cholinergic neurons in the striatum, brainstem, and basal forebrain (Warren et al 2005). Blin's group found that physostigmine produced increased glucose entry into the brain; nevertheless, there was little associated change in cognitive or motor function. In a double-blind, crossover trial of donepezil in 21 patients with progressive supranuclear palsy, modest improvements in memory function were observed, but these came at the expense of worsening motor and functional abilities (Litvan et al 2001).
Nonpharmacologic interventions should be considered for managing the behavioral complications of progressive supranuclear palsy (verbal aggressiveness, restlessness, repetitive behaviors, and negativism). In one approach, the A-B-C method, asks the caregiver to keep a diary that identifies the antecedent event for the change in behavior, along with the behavior itself and its consequences (Slattery et al 1999). Strategies can then be developed to change the patient's schedule or to modify his environment. Changes in behavior typically have an underlying cause that can be remedied without the need for pharmacologic intervention. Caregiver burden in progressive supranuclear palsy is related to disease severity, disease duration, and caregiver gender, since women are more likely than men to report burden (Uttl et al 1998). Caregivers should be advised to join either national or local support groups (see The Society for Progressive Supranuclear Palsy Inc.
Since pathologic changes extend far beyond the substantia nigra in progressive supranuclear palsy, it is not surprising that dopaminergic therapies are limited in their ability to improve motor function (Lang 2005). Levodopa is only effective in 26% of patients, comparable to previous trials of bromocriptine (22%) and pergolide (29%). These benefits rarely last more than a few years. Nevertheless, some caregivers want to continue levodopa for a longer period of time, simply because its beneficial effect on rigidity facilitates their ability to help the patient with self-care. In some advanced cases of supranuclear palsy, targeted injections of botulinum toxin have been shown to relieve rigidity and spasticity (Baba et al 2004).
Several nonpharmacologic interventions can assist in preventing falls in progressive supranuclear palsy (Lang 2005). These include physical therapy, weighted walkers, wheel-
chairs, bathroom safety equipment, and occupational therapy. A wheelchair is the safest option when falling becomes a regular occurrence. Another important intervention to prevent falls in these elderly patients is to stop benzodiazepines, tricyclics, antipsychotic agents and other psychotropic drugs, if possible (Fink et al 2003;(Tinetti 2003).
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