Clinical Aspects of Progressive Supranuclear Palsy

Handbook of Clinical Neurology, Vol. 89 (3rd series) Dementias C. Duyckaerts, I. Litvan, Editors # 2008 Elsevier B.V. All rights reserved

Progressive supranuclear palsy Chapter 43

Clinical aspects of progressive supranuclear palsy SHAHEDA N. AZHER 1, 2 AND JOSEPH JANKOVIC 1 * 1

Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, TX, USA 2

Hudson Valley Neurology, PC, Poughkeepsie, NY, USA

43.1. Introduction Progressive supranuclear palsy (PSP), also known as Steele-Richardson-Olszewski syndrome, is a progressive neurodegenerative disorder first described as a separate clinicopathological entity by Steele, Richardson and Olszewski in 1964 (Steele et al., 1964; Steele, 1972). The first volume solely devoted to PSP was published in 1993 (Litvan and Agid, 1992) and a summary of the 1999 “First Brainstorming conference on PSP” was published in 2000 (Litvan et al., 2000). It is the second most common form of parkinsonism after Parkinson’s disease (PD) with a mean age at onset between 60 and 65 years and an estimated prevalence of 6.4 per 100, 000 (Schrag, 1999) (see Ch. 42 for further details). Supranuclear ophthalmoplegia (SNO) initially affecting saccadic eye movements in a downward direction is the hallmark of the disease. The diagnosis of PSP should be considered in any patient with progressive parkinsonism and disturbance of ocular motility (Maher and Lees, 1986; Jankovic et al., 1990; Friedman et al., 1992; Cardoso and Jankovic, 1994). With a median survival of about 6 years, PSP is characterized by progressive postural instability leading to early falls, vertical ophthalmoparesis, akinetic-rigid features, pseudobulbar palsy, levodopa-unresponsive parkinsonism and frontal cognitive disturbances. In general, symptoms and signs in PSP progress rapidly and steadily. In advanced stages, patients require a wheelchair and may even become bedridden, their swallowing becomes severely impaired, requiring a feeding

tube in some cases, and their speech becomes unintelligible (Goetz et al., 2003). The pathogenesis of PSP is still poorly understood: the disorder is categorized as a four-repeat tauopathy, characterized pathologically by neuronal loss, gliosis and intracellular accumulation of tau in neurons (neurofibrillary tangles) and in glia (astrocytic tufts) in many brain areas, including the cerebral cortex, basal ganglia and the brainstem (Hauw et al., 1994; Daniel et al., 1995; Litvan et al., 1996c). Although typical cases are characterized by akinesia, supranuclear gaze palsy, rigidity, axial dystonia, gait disturbance and dementia, there are patients with atypical symptoms and typical pathology (Daniel et al., 1995). Furthermore, patients without the clinical hallmarks of PSP, including ophthalmoparesis, have been found to have typical pathological features of PSP at autopsy (Daniel et al., 1995; Wakabayashi et al., 2004).

43.2. Clinical features 43.2.1. Gait, postural instability and falls One of the earliest and, certainly, most disabling symptoms of PSP relates to gait and balance impairment. Development of postural instability and recurrent falls early in the course of the disease are important features that distinguish PSP from PD (Birdi et al., 2002; Nath et al., 2003). While supranuclear vertical gaze palsy may occur in other parkinsonian disorders such as corticobasal degeneration (CBD), dementia with Lewy bodies (DLB) or, less commonly,

*Correspondence to: Joseph Jankovic M.D., Professor of Neurology, Director of Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030, USA. E-mail: [email protected], Tel: þ1-713-798-5998, Fax: þ1-713-798-6808.

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multiple system atrophy (MSA), when associated with early balance disturbances and falls, it differentiates PSP from other disorders. In the National Institutes of Neurological Disorders and Stroke (NINDS) study (Litvan et al., 1996a), 96% of 24 PSP patients had gait disorder and postural instability (83% history of falls) at the first visit to a specialized neurological center. In contrast to the classic short and shuffling steps, stooped posture, narrow base and flexed knees typically seen in PD, patients with PSP have a stiff and broad-based gait with a tendency to have their knees extended (Jankovic et al., 2001; Bloem and Bhatia, 2004). Furthermore, instead of turning en bloc, they tend to pivot, which further compromises their balance. When turning, their head often lags behind the body rotation as their eyes remain fixated in the primary position. Based on a series of pathologically proven PSP cases two distinct clinical phenotypes have been proposed: (1) Richardson’s syndrome, characterized by early falls, early cognitive dysfunction, abnormalities of gaze and postural instability, and (2) PSP-parkinsonism, characterized by asymmetric onset, tremor, early bradykinesia, non-axial dystonia and a response to levodopa medications (Williams et al., 2005). Mobility difficulties and falls probably result from a combination of bradykinesia, axial rigidity, retrocollis (neck held in extension), postural instability and ophthalmoparesis, coupled with poor insight, possibly related to frontal lobe dysfunction (Jankovic et al., 1990; Birdi et al., 2002; Nath et al., 2003). Injuries occur much more frequently in PSP than in other parkinsonian disorders, partly due to motor recklessness and lack of appropriate preventive measures. There is increasing evidence that abnormal sensory (e.g., visual, proprioceptive, and vestibular) processing also contributes to balance and gait problems (Nieuwboer et al., 2004). Patients may fall while climbing or descending stairs because of the vertical gaze palsy and retrocollis impairing proper judgment. Eventually the falling frequency tapers off because severely affected patients move only with much assistance or become completely immobilized and wheelchair-bound. Because of widespread pathology in PSP, it is impossible to pinpoint a particular lesion as being responsible for the postural deficits and falls. The most distinctive pathological features are neurofibrillary tangles, neuropil threads and tufted astrocytes, which are found predominantly within the substantia nigra, globus pallidus, subthalamic nucleus, midbrain, pontine reticular formations and, to a lesser extent, the thalamus (Albers and Augood, 2001; Hauw and Agid, 2006). The pedunculopontine nucleus (PPN) is also severely affected, with approximately 60% neuronal loss, with neurofibrillary tangles in the remaining neurons suggesting cholinergic dysfunction in PSP (Zweig et al., 1987 and Warren et al., 2005). Central dopami-

nergic deficits only partly explain the observed balance and gait problems. Non-dopaminergic systems, including the adrenergic locus coeruleus and the cholinergic/glutaminergic PPN, have been increasingly implicated in the pathophysiology of various disorders of gait and balance in patients with PSP and other parkinsonian disorders. Freezing of gait (FOG) is also common in PSP (Giladi, 1992). In advanced disease, approximately 50% of DLB, MSA and PSP patients and 25% of those with CBD developed FOG. In a series of pathologically proven PSP reported by Daniel and associates (1995) two patients presented with pure akinesia resulting in freezing. Of special interest is the clinical presentation of PSP as an isolated gait ignition failure, which can be the only symptom of the disease throughout life. The observed association between urinary incontinence and FOG in these disorders suggests a similar neuropathological substrate for the two symptoms. 43.2.2. Ocular manifestations of PSP 43.2.2.1. Supranuclear ophthalmoparesis Supranuclear ophthalmoparesis is typically manifested by paralysis of down gaze. It is the most characteristic sign of PSP (Litvan et al., 1997). However, vertical supranuclear gaze palsy is rarely (8%) present as the initial symptom or sign; it usually takes 3–4 years for it to develop (Litvan, 1996c). In PSP the vertical supranuclear gaze palsy usually precedes the development of the horizontal gaze palsy, whereas in CBD the supranuclear palsy, when present, often affects both horizontal and vertical gaze and is usually preceded by limitation of convergence. Both downward and upward gaze palsy may be present in PSP, but the upward gaze palsy needs to be differentiated from the limitation of upward gaze observed in elderly patients and as a nonspecific sign of a variety of parkinsonian and other neurodegenerative disorders. In one pathological study, brains of patients with PSP with gaze palsy had 2-fold greater loss of neurons in the substantia nigra reticulata (SNr) (Halliday et al., 2000). Since SNr projects to the superior colliculi, degeneration of SNr may contribute to the limitation of eye movements. The ophthalmoparesis can be overcome by the oculocephalic (doll’s eye) maneuver, but with disease progression, and brainstem involvement, vestibular-ocular reflexes may be lost, suggesting additional nuclear involvement (Ishino et al., 1974). 43.2.2.2. Saccades Slowing of vertical saccades (rapid eye movement between two stimuli) usually precedes the development of supranuclear vertical gaze palsy. In fact, marked

CLINICAL ASPECTS OF PROGRESSIVE SUPRANUCLEAR PALSY slowing of vertical in addition to suppression of saccades, particularly downward saccades, best demonstrated by observing optokinetic nystagmus when moving an optokinetic tape in an upward direction, should point toward the diagnosis of PSP. In early stages of PSP, patients may have only mild limitation of voluntary down gaze, inability to converge, but slowing of vertical saccades appears to be the earliest oculomotor sign of PSP. Deficient generation of the motor command by midbrain burst neurons has been suggested as the primary mechanism for the slow vertical saccades (Bhidayasiri et al., 2001). Bilateral impairment of the antisaccade task (looking in the direction opposite to a visual stimulus) correlates well with frontal lobe dysfunction in PSP (Vidailhet et al., 1994). This sign is also present in patients with other frontal lobe and basal ganglia disorders (Condy et al., 2004; Munoz and Everling, 2004). In addition to impairment of saccades, square-wave jerks are frequently present in PSP (Rascol et al., 1991; Garbutt et al., 2004). Subjective eye complaints in PSP patients include blurred vision, diplopia, eye irritation or discomfort, and photophobia (Friedman et al., 1992). Dry eyes and blepharitis usually result from inadequate tear film produced by the decreased blink rate. Involuntary persistence of ocular fixation is a typical, although rarely mentioned, feature of PSP. It is most frequently observed when the patient turns and the head lags behind the body rotation as the eyes remain fixated in the backward direction. The head and neck eventually align with the body after some delay. Blink rate is usually profoundly slowed in PSP, although decreased blink rate is also seen in other parkinsonian disorders. The combination of rare blinking, facial dystonia and rigidity, and gaze abnormalities leads to the development of a particular “staring” facial expression. Exaggerated elevation of eyebrows often gives PSP patients an “astonished” facial expression. Some patients also have a “frowning” and “worried” expression, known as the “procerus sign” (Romano and Colosimo, 2001) (Fig. 43.1), named after the muscle that is responsible for the “frown”. Spontaneous or stimulus-induced blepharospasm (a forceful contraction of orbicularis oculi squeezing the eyes shut and making the eyebrows descend) may be also present in PSP (Lepore and Duvoisin, 1985; Collins, 1995; Nath, 2003). “Apraxia of eyelid opening” (difficulty, slowness, or delay in eye opening, often accompanied by compensatory elevation of the eyebrows and frontalis overactivity) or “apraxia of eyelid closure” (difficulty, slowness, or delay in eye closure), analogous to sudden transient freezing, is thus sometimes termed “eyelid freezing” (Krack and Marion, 1994; Jankovic, 1995).

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Fig. 43.1. Typical worried expression and procerus sign in a patient with PSP.

43.2.3. Cognitive and behavioral changes Cognitive and behavioral changes are part of the clinical picture of PSP, but despite emphasis on dementia in the original descriptions, these features do not usually significantly contribute to the overall deterioration in the quality of life until more advanced stages of the disease. In their landmark description of PSP as a clinicopathological entity, Steele et al. (1964) reported that cognitive disturbances were present in seven out of their nine patients. Despite a relative preservation of short-term memory, cognitive slowing and impairment of executive (goal-directed) functions, characteristic of sub-cortical dementia are typically present in patients with advanced PSP (Johnson et al., 1991; Pillon et al., 1994, 1996; Litvan et al., 1996d, 1998). Patients with PSP are particularly impaired when a task requires sequential movements, reasoning, conceptual shifting, monitoring the frequency with which stimuli are presented, and rapid retrieval of verbal knowledge. These deficits indicate that above and beyond a general slowing of cognitive processes, the patient with PSP finds it difficult to perform on some tasks traditionally associated with prefrontal lobe functioning (Grafman, et al., 1990). The cognitive processes impaired in patients with PSP have their effect across a wide range of reasoning, memory, attentional, and linguistic tasks, and this

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involvement of a large number of processes leads to the concept of “subcortical dementia” according to which subcortical lesions may induce cortical dysfunctions (Albert et al., 1974). Evidence of frontal dysfunction includes apathy, disinhibition, dysphoria, and perseveration. This deficit is best illustrated by the “applause sign” (“signe de l’applaudissment”) (Dubois et al., 2005). This automatic behavior, characteristically present in patients with PSP, but also seen in some patients with CBD and frontotemporal dementia with parkinsonism associated with mutations in the tau gene on chromosome 17 (FTDP-17), is manifested by persistence of clapping after the patient is instructed to clap consecutively three times, but only three times, as quickly as possible. Limb apraxia, although found more frequently and more severely in other tauopathies, has been recognized in PSP (Pharr et al., 2001; Zadikoff and Lang, 2005). Arm levitation, although typically seen in CBD, can be also seen in some patients with PSP (Barclay et al., 1999). 43.2.4. Pseudobulbar features Pseudobulbar symptoms in PSP patients are responsible for dysarthria, dysphagia and “emotional incontinence” or pseudobulbar affect. Speech in PSP is characterized by a spastic, hypernasal, hypokinetic, ataxic, monotonous, low-pitched dysarthria (Kluin et al., 1993). The speech rate may be slow or fast and some patients have severe palilalia and stuttering. “Apraxia of phonation” was reported in one patient who was aphonic except during periods of excitement or during sleep (Jankovic, 1984). In contrast some patients have almost continuous, involuntary vocalizations, including loud, groaning, moaning, humming and grunting sounds (Jankovic et al., 1990). Progressive dysphagia causes most patients to modify their diet, and some eventually need a feeding gastrostomy to maintain adequate nutrition. As a result of chewing difficulties, inability to look down, and poor hand coordination, PSP patients are often described as “sloppy eaters”. In a review of 177 cases, the KaplanMeier analysis indicates that those with early bulbar features had around 5 years less life expectancy than those who had late or absent bulbar features (Nath et al., 2003). Drooling of saliva and the voluntary down-gaze palsy, causing food to fall from the fork, may lead to the reported “sloppy tie or shirt sign”. 43.2.5. Dystonia Prominent retrocollis, while typically associated with PSP (Fig. 43.2), is actually quite rare although in some cases it may be quite severe and may even be

Fig. 43.2. Typical retrocollis in a patient with PSP.

associated with opistotonic posture of the trunk. Although PSP is usually a symmetrical disorder, dystonia represents an occasional exception in that unilateral dystonia may be present, particularly in the more advanced stages of the disease (Oide et al., 2002). One of the most common forms of dystonia in PSP is blepharospasm. In one study of 83 patients, 20 (24%) had blepharospasm, 22 (27%) had limb dystonia, and 14 (17%) had axial dystonia (Barclay and Lang, 1997).

43.3. Familial progressive supranuclear palsy Progressive supranuclear palsy is generally considered a sporadic disease, but rare familial cases have been reported in the literature (Brown et al., 1993; de Yebenes et al., 1995; Teturd et al., 1996; Rojo et al., 1999). Ohara et al. (1992) described two siblings of a consanguineous marriage who exhibited parkinsonism, supranuclear ophthalmoplegia, and dementia, but no tremor and no cerebellar or corticospinal tract findings. The presence of atypical features such as early dementia in the family (Brown et al., 1993) and relatively early age at onset (53 years) as reported by de Yebenes et al. (1995) suggest that these families had a neurodegenerative disorder distinct from idiopathic PSP. Supranuclear ophthalmoparesis, the clinical hallmark of sporadic PSP, is not well defined in these cases. In a reported series of 133 family members including first- and second-degree relatives in 12 pedigrees, 22 were found to have some features of PSP (Rojo et al., 1999). Among them 12 had supranuclear gaze palsy and/or frequent falls or gait disturbance early in the course of the disease. Others presented with other neurological disorders, including isolated tremor (3), parkinsonism (1), gait disturbance (1), and tremor, dystonia,

CLINICAL ASPECTS OF PROGRESSIVE SUPRANUCLEAR PALSY gaze palsy and tics (2). Another atypical feature of the reported PSP cases is improvement with L-dopa, noted in 7 of 16 (44%) patients; in three of them the response was sustained for more than 3 years. Improvement with L-dopa is considered typical of PD and rare in PSP to the point that lack of response is considered a support criterion for the diagnosis of PSP. The pattern of inheritance in the reported cases seemed to be mostly autosomal dominant. A recent study showed association of G303V mutation of tau in a family with early-onset autosomal dominant PSP (Ros et al., 2005). The pathogenesis of this disease seems to be related to overexpression of the 4R tau isoforms.

43.4. Clinical variants and unusual presentations As noted before, pathologically proven PSP may present without an ophthalmoparesis or it may be delayed for years or be absent throughout the clinical course (Jellinger et al., 1980). Some PSP patients may present with the syndrome of “pure akinesia”, also referred to by some as motor blocks (Matsuo et al., 1991; Giladi et al., 1992; Riley et al., 1994) and gait ignition failure (Atchison et al., 1993; Nutt et al., 1993), manifested chiefly by akinesia of gait, start hesitation, freezing, motor blocks, festination, disequilibrium with frequent falling, marked impairment of speech (stuttering, stammering, hypophonia), handwriting difficulty (micrographia), eyelid motor disturbances (blepharospasm, eyelid freezing), without rigidity, tremor, or dementia, and without response to levodopa. Although the PSP gait appears ataxic, the patients usually do not exhibit prominent cerebellar findings. Absence of tremor or dementia persists despite obvious progression of the disease. In some pathologically proven PSP cases, dementia was the dominant clinical manifestation throughout life, often misdiagnosed as Alzheimer’s disease (Gearing et al., 1994). Cases have been reported in the literature with prominent neuropsychiatric disorder with disinhibition, violent behavior, aggressiveness and restlessness and subsequent admission to psychiatric hospitals, suggesting an overlap with the syndrome of frontotemporal dementia (Jellinger et al., 1980; Goedert, 2005). PSP may present as one of the other tauopathies. Pathologically proven PSP has been described in patients presenting as CBD, primary progressive aphasia, FTDP-17, and Pick’s disease (Gearing et al., 1994; Daniel et al., 1995; Mochizuki et al., 2003). There are many causes of PSP-like disorders termed secondary PSP (Table 43.1), including vascular PSP (Winikates and Jankovic, 1994).

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Table 43.1 Secondary PSP 1. Primary phospholipids antibody syndrome (Reitblat et al., 2003). 2. CADASIL, and cerebral amyloid angiopathy (Van Gerpen et al., 2003). 3. Whipple’s disease (Averbuch-Heller et al., 1999). 4. Diffuse Lewy body disease (Nakashima et al. 2003). 5. Striato-dentato-pallidal calcification (Watanabe et al., 2003). 6. Creutzfeldt-Jakob disease (Shimamura et al., 2003). 7. Brain tumor (Siderowf et al., 1998). 8. Gaucher’s disease (Patterson et al., 1993). 9. Neuroleptic-induced PSP (Campdelacreu et al., 2004). 10. Obstructive hydrocephalus (Curran and Lang, 1994). 11. Exposure to organic solvents (McCrank et al., 1989). 12. Paraneoplastic syndrome (Jankovic, 1985). 13. After aortic surgery (Mokri et al., 2004).

43.5. Diagnostic tests 43.5.1. Neuroimaging CT/MRI studies CT and magnetic resonance (MR) studies of patients with PSP typically show generalized and midbrain atrophy (Schrag et al., 2000; Savoiardo, 2002), the cardinal neuroradiologic feature of PSP, present in at least 75–89% of clinically diagnosed patients. In addition to midbrain atrophy, there is thinning of the quadrigeminal plate, enlargement of the third ventricle, pontine tegmental atrophy and increased periaqueductal signal intensity. Warmuth-Metz et al. (2001) found that PSP patients had significant lower anterior posterior diameter (13.4 mm) of the suprapontine midbrain on axial T2 weighted MRI images compared with that of PD patients (mean 18.5 mm). The “humming bird sign” is due to atrophy of rostral midbrain tegmentum, the pontine base, and the cerebellum on mid-sagittal view of the MRI, corresponding to the bill, head, body, and wing respectively of a humming bird (Fig. 43.3). It was demonstrated in all eight MRI scans of PSP patients, but not in any of the 12 of PD or 10 normal controls (Kato et al., 2003). This MRI finding has been also called the “penguin sign” (Oba et al., 2005) (Fig. 43.4). The “morning glory sign”, a peculiar MRI finding of midbrain atrophy with concavity of the lateral margin of the midbrain tegmentum, resembling the lateral margin of the morning glory flower, is observed in PSP patients with supranuclear gaze-palsy (Fig. 43.5). (Adachi et al., 2004). The corpus callosum, putamen, caudate nucleus and superior cerebellar peduncle may also be atrophic. One of the features that

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B A

a

B

Fig. 43.3. Humming bird sign. In PSP patients this represents the atrophy of the midbrain tegmentum (rostral and caudal) and a relative increase in the length of the anteroposterior diameter of the midbrain tegmentum. It strongly suggests the involvement of interstitial nucleus of the medial longitudinal fasciculus and can be used for diagnosis of PSP.

Fig. 43.4. Penguin sign. Midsagittal MR images in patients with PSP show small midbrain to pons ratio. The shapes of midbrain tegmentum (bird’s head) and pons (bird’s body) on midsagittal MR images look like a lateral view of a standing penguin with a small head and a big body. (MRI reprinted from Oba et al., 2005, with permission.)

A b

Fig. 43.5. Morning glory sign. An axial section of the normal midbrain at the mammillary body level. Point A is the point at which the transverse line running through the edge of the aquaduct crosses the lateral margin of the midbrain. Point B is the pit between the tegmentum and the cerebral peduncle. The lateral margin of the normal tegmentum runs on or outside the straight line between points A and B. The morning glory sign (the concave appearance of the lateral margin of the tegmentum of the midbrain). The lateral margin of the tegmentum runs inside the straight line between points A and B. This morphological change in the midbrain resembles a lateral view of the morning glory flower. (Reprinted from Adachi et al., 2004, with permission.)

PSP. In a study using diffusion-weighted MRI, PSP was differentiated from PD with 90% sensitivity and 100% specificity, but this technique could not differentiate between PSP and MSA (Seppi et al., 2003). In a volumetric quantitative MRI study PSP patients were identified based on superior cerebellar peduncle atrophy with a sensitivity of 74% and a specificity of 94% (Paviour et al., 2005). 43.5.2. Magnetic resonance spectroscopy

could also be observed on sagittal MR images is hyperextension of the head. This feature may be a clue and one should look closely at the midbrain to confirm the suspicion of PSP (Savoiardo et al., 1994, 2002). Signal changes usually consist of mild hyperintensity in proton density and T2 weighted images in the tegmentum and periaqueductal region where gliosis and tau-positive lesions are found in pathological sections (Aiba et al., 1997). Diffusion studies were not helpful in diagnosing

Magnetic resonance spectroscopy (MRS) allows the safe and noninvasive in vivo study of the concentrations of specific molecules and of energy metabolism. N-Acetylaspartate (NAA) is a marker of neuronal integrity. Its concentration is reduced in conditions with neuronal loss. Choline (Ch) and other lipids are markers of altered neuronal membrane synthesis, whereas creatine (Cr) is a marker for defective energy metabolism

CLINICAL ASPECTS OF PROGRESSIVE SUPRANUCLEAR PALSY and is usually resistant to change, and is thus used as an internal standard to which the concentrations of other metabolites are normalized. Relatively few MRS studies have examined PSP and other atypical parkinsonian disorders. Tedeschi et al. (1997) found a reduced NAA/Cr ratio in the brainstem, centrum semiovale, and frontal and precentral cortex, and a reduced NAA/Ch ratio in the lentiform nucleus in 12 patients with PSP compared with healthy controls. New methods of spectral analysis, such as the use of neural networks, high-field-strength machines and water referencing, may improve our ability to differentiate these different atypical parkinsonian disorders.

43.5.3. PET and SPECT studies 18F-dopa PET is a marker of dopamine storage capacity. Tropane-based tracer imaging, such as 123I-bCIT and 123I-FP-CIT SPECT, determines dopamine transporter availability. All these modalities reveal a uniform loss of caudate and putamen dopamine terminal function in PSP, discriminating 90% of cases from idiopathic PD, where caudate function is relatively preserved (Brooks, et al., 1990; Messa et al., 1998). Basal ganglia, cerebellar, and thalamic glucose metabolism is also decreased in PSP, thus distinguishing it from PD. Marked involvement of caudate in addition to putamen is considered an indicator of the presence of atypical parkinsonism rather than a specific marker of PSP, as widespread reduction in the striatal metabolism is also seen in Parkin and PARK6 forms of PD and in MSA. In PSP the 18FDG-PET shows decreased resting basal ganglia, thalamic, and frontal glucose metabolism (rCMRGIc) (Foster et al., 1988; Goffinet et al., 1989). This finding contrasts with what is found in idiopathic PD, where the rCMRGIc in the lentiform nucleus is increased, and, therefore, this difference in distribution of the metabolic abnormality enables one to distinguish over 80% of patients with PSP from those with PD. Decreased frontal glucose metabolism in PSP is evident particularly in the frontal eye field region (area 8) and has been shown to correlate with performance on tests of executive function such as working memory, verbal fluency, and sorting (Blin et al., 1990; Piccini et al., 2001). Striatal opioid receptor binding, measured with 11C-diprenorphine PET, and striatal and thalamic acetylcholinesterase activity, measured with 11C-NMP4A PET, are also reduced in PSP but preserved in PD. In a series of 32 patients with probable PSP, reduction of basal ganglia/frontal cortex [123 I]IBZM signal ratios was found in 20 patients, indicating a reduction of D2 receptors. The PET and SPECT findings of moderate reductions of

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striatal D2 receptor binding in PSP are in agreement with neuropathological findings reporting 30% reductions in D2 density in the caudate and putamen of these patients (Pierot et al., 1988). 43.5.4. Neurophysiological tests in PSP Neurophysiological tests including brainstem reflexes may be helpful in PSP, but they are rarely diagnostic (Valls-Sole´, 2005). Clinical evidence of eye movement abnormalities is not always present in the initial phases of the disease. When the diagnosis of PSP is suspected, recording of eye movements by electrooculography might be of some help (Heide et al., 1999; Rivaud-Pechoux et al., 2000). Electro-oculogram recordings may show characteristic abnormalities in patients with PSP, including slowness of vertical eye movements, absent Bell’s phenomenon, and square-wave jerks (Chu et al., 1979; Vidailhet et al., 1994). 43.5.5. Behavioral and neuropsychological evaluations Various neuropsychological tests, including the Wisconsin Card Sorting Test, Trail Making test, Wechsler Adult Intelligence Scale and the motor series of Luria, demonstrated an early and prominent difficulty in executive function (Pillon et al., 1991, 1994; Robbins, 1994; Litvan et al., 1996d). Lack of benefit from L-dopa therapy and the presence of severe frontal cognitive and/or behavioral deficits help support the diagnosis of PSP and differentiate this disorder from other related disorders. Treatment is discussed in Chapter 46.

43.6. Differential diagnosis The term “vascular PSP” has been used when clinical features similar to those observed in Steele-Richardson-Olszewski syndrome are present in patients with clear evidence of a multi-infarct state, particularly involving the midbrain and the striatum (Josephs et al., 2002). Vascular PSP may be clinically identical to the degenerative form of PSP (Dubinsky and Jankovic, 1987; Stern et al., 1989; Winikates and Jankovic, 1994). Patients with vascular PSP can be differentiated from the more typical form of PSP by increased frequency of stroke risk factors and abnormal imaging studies. Clinically, they have asymmetric and predominantly lower-body involvement, cortical and pseudobulbar signs, dementia and bowel and bladder incontinence (Winkates and Jankovic, 1994). Ghika and Bogousslavsky (1997) found that 81.0% of patients with clinically diagnosed PSP had hypertension, providing

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support for the notion of vascular PSP in some predisposed individuals and, indeed, some of the patients included in this clinical cohort may have had vascular PSP. This high prevalence of hypertension, however, was not confirmed in a series of cases with post mortem diagnosis of PSP (Colosimo et al., 2003). A pathological study of four cases clinically diagnosed with PSP but found to have vascular PSP at autopsy showed that vascular PSP is characterized by asymmetric signs, frequent falls beginning 1 year after symptomatic onset, and vascular lesions on MRI (Josephs et al., 2002). Three of the four (75%) patients carried the H2 tau haplotype, whereas 93.7% of idiopathic PSP have the H1 tau haplotype. The substantia nigra, subthalamic nuclei, and periaqueductal gray matter, which are prominently affected in PSP, are not usually directly involved in vascular PSP; the vascular lesions mainly involved the thalamus or the basal ganglia, often unilaterally or asymmetrically. The differential diagnosis of PSP involves disorders characterized by supranuclear ophthalmoplegia or dementia, such as dementia with Lewy bodies, Pick’s disease, and progressive subcortical gliosis. A pseudobulbar syndrome at onset can resemble bulbar amyotrophic lateral sclerosis and prominent isolated ophthalmoplegia can resemble ocular myasthenia or ocular myopathy. Even though it is rare, the presence of occasional incontinence may have to be differentiated from multiple system atrophy. In a review of 17 cases with pathologically diagnosed PSP, Daniel and coworkers (1995) found that six of 17 patients indeed had been diagnosed as PSP during life but of the remaining 11 patients, six had a clinical diagnosis of PD, three cerebrovascular disease, one of Alzheimer’s disease and one was diagnosed with a nonspecific parkinsonian syndrome. Birdi and associates (2002) evaluated the clinical diagnosis and course of the illness in 16 autopsy-confirmed PSP patients. Eight patients had been diagnosed correctly as PSP during life. Diagnosis of PSP was not made in the other eight cases (50%), who never manifested ophthalmoplegia. The diagnostic difficulties seemed to arise from the lack of vertical gaze palsy as well as the presence of associated symptoms such as hemidystonia, early dementia, and benefit from treatment with levodopa. There are a number of conditions that manifest with a clinical picture similar to “pure akinesia” such as PD (Barbeau, 1972). Finally, Whipple’s disease should be considered in patients with supranuclear ophthalmoparesis, but these patients often have facial myorhythmia and gastrointestinal symptoms that provide clues to the correct diagnosis (Jankovic, 1986; Averbuch-Heller et al., 1999). Features distinguishing PSP from related disorders are

Table 43.2 Features distinguishing PSP-related disorders from PSP Corticobasal ganglionic degeneration Alien limb syndrome Severe limb apraxia Cortical sensory deficits Markedly asymmetric onset of bradykinesia Focal frontal or temporoparietal atrophy Parkinson’s diesease Asymmetric onset of bradykinesia symptoms Tremor-dominant disease Marked and maintained levodopa benefit Dementia with Lewy bodies Hallucinations or delusions unrelated to depaminergic therapy Cortical dementia, especially aphasia Alzheimer’s disease Cortical dementia (severe amnesia and aphasia, or agnosia, NINCDS-ADRDA criteria) Multiple system atrophy Prominent cerebellar symptomatology or unexplained early and prominent incontinence, importance, or marked postural hypotension Multiinfarct parkinsonism (vascular parkinsonism) Multiple strokes, one of which involves the brainstem and basal ganglia Whipple’s disease Ocular-masticatory myorhythmia, laboratory confirmation (e.g., polymerase vhain reaction), if indicated Postencephalitic parkinsonism History of encephalitis, oculogyric crisis Creutzfeldt-Jakob disease Disease course of <1 year, myoiclonus, EEG abnormalities. Mild, or late onset urinary disturbances occur in some PSP patients.

summarized in Table 43.2 (Litvan et al., 1996a) and mimickers of PSP due to some other causes (secondary PSP) are listed in Table 43.1.

43.7. Clinical diagnostic criteria Early and accurate diagnosis allows for better prognostication of the neurological disorder and would increase participation in research studies, leading ultimately to better disease management. There is, however, no biological marker available for the diagnosis of PSP and therefore clinicians must become skilled in recognizing the early symptoms and signs. Neuropathological examination remains the “gold standard” for definitive diagnosis (see Ch. 45). Clinical criteria (Table 43.3) for the diagnosis of PSP have been standardized and validated and are widely accepted

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Table 43.3 NINDS-SPSP clinical criteria for the diagnosis of PSP PSP Possible

Mandatory inclusion criteria

Mandatory exclusion criteria

Supportive criteria

Gradually progressive disorder Onset at age 40 or later

Recent history of encephalitis Alien limb syndrome, cortical sensory deficits, cortical sensory deficits, focal frontal or temporoparietal atrophy Hallucinations or delusions unrelated to dopaminergic therapy Cortical dementia of Alzheimer’s type (severe amnesia and aphasia or angnosia, according to NINCDS-ADRA criteria) Prominent, early cerebellar symptoms or prominent, early unexplained dysautonomia (marked hypotension and urinary disturbances) Severe, asymmetric parkinsoian Sings (i.e., bradykinesia) Neuroradiologic evidence of relevant structural abnormality (i.e., basal ganglia or brainstem infarcts, lobar atrophy)

Symmetric akinesia or rigidity proximal more than distal Abnormal neck posture, especially retrocollis Poor or absent response of parkinsonism to levodopoa therapy Early dysphagia and dysarthria Early onset of cognitive impairment including at least two of the following: Apathy, impairment in abstract thought, decreased verbal fluency, utilization or imitation behavioir, or frontal release signs

Either vertical (upward or downward gaze) supranuclear palsy or both slowing of vertical saccades and prominent postural instability with falls in the first year of disease onset

Probable

Definite*

No evidence of other disease that could explain the foregoing features, as indicated by mandatory exclusion criteria Gradually progressive disorder Onset at age 40 or later Vertical (upward or downward gaze) supranuclear palsy and prominent postural instability with falls in the first year of disease onset No evidence of other diseases that could explain the foregoing features, as indicated by mandatory exclusion criteria Clinically probable or possible PSP and histropathologic evidence of typical PSP

Whipple’s disease, confirmed by polymerase chain reaction, if indicated

*Definite PSP is a clinicopathologic diagnosis. Modified from Litvan (2005).

(Litvan et al., 1996b, 2005; Lopez et al., 1999). Because of their high sensitivity and specificity, the NINDSSPSP criteria have been adopted as the standard criteria for probable and definite PSP (Table 43.4) (Litvan, 2005). Criteria for clinically possible PSP are being developed and will require validation. There are atypical cases with unusual features reported in the literature, confirmed to have PSP based on neuropathological studies. The diagnosis of PSP is unlikely when symptoms develop before age 40 or last longer than 20 years, because none of these characteristics has been reported in neuropathologically confirmed cases of PSP.

43.8. Future directions No suitable biomarkers for PSP in cerebrospinal fluid or in serum have yet been identified that are specific and sensitive enough to be used in the diagnosis of PSP. The neuroimaging findings are very characteristic when present but are not diagnostic. Imaging techniques that would identify areas of oxidative stress, excitotoxicity, mitochondrial deficiency, microglial activation, accumulation of abnormal tau, and other processes that are thought to play a role in the pathogenesis of PSP would be helpful not only in the diagnosis of PSP but also in

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Table 43.4 Revised NINDS-SPSP consensus criteria for clinical diagnosis Definite PSP: Clinically probable or possible PSP and histologically typical PSP Clinically definite PSP Step 1: Mandatory inclusion criteria: 1. Graduallly progressive disorder with onset at age 40 or later and 2. Vertical supranuclear ophthamoparesis (either moderate to severe upward or any downward gaze abnormalities) and 3. Prominent postural instability with falls (or tendency to falls) in the first year of symtptom onset Clinically probable PSP Step 1: Mandatory inslusion criteria: 1. Gradually progressive disorder with onset at age 40 or later and either: 2a. Vertical supranuclear ophthalmoparesis (either moderate to severe upward- or any downward gaze abnormalities) or 2b. Slowing of vertical saccades and prominent postural instability with falls (or tendency to falls) in the first year of symptom onset For both clinically definite and clinically probably PSP Step 2: Mandatory exclusion criteria: 1. History compatible with encephalities lethargica 2. Alien hand syndrome, cortical sensory deficits, focal frontal or temporoparieta; atrophy 3. Hallucinations or delusions unrelated to dopaminergic therapy 4. Cortical dementia of Alzheimer’s type (severe amnesia and aphasia or agnosia, NINCDS-ADRDA criteria) 5. Prominent cerebellar symptomatology or unexplained dysautonomia (early, prominent incontinence, impotence, or symptomatic postural hypotension) 6. Severe asymmetry of parkinsonian sings (bradykinesia) 7. Neuroradiologic evidence of relevant structural abnormality (basal ganglia or brainstem infarcts, lobar atrophy) 8. Whipple’s disease, confirmed by polymerase chain reaction, if indicated Clinically possible PSP To be defined

gaining insight into the mechanism of cell death and treatment of this neurodegenerative disorder (Encarnacion and Chase, 2005).

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